Thread by @IsoMedSTU, Alright, as requested by @sbh_kc, here is a thread on Drug Development [...]

Alright, as requested by @sbh_kc, here is a thread on Drug Development and Clinical Trials that are undertaken in order to test how effective the drug is for usage and whether it's side effects equal or outweigh it's beneficial effects (1/n)

Disclaimer : The process of development of a drug and the clinical trials involved is lengthy and exhausting and in this thread, I've omitted all the non essential details and kept it as simple as I can for the lay person to have a better understanding of this process (2/n)

...without being caught up in the excessive jargon associated with Pharmacology as a whole.

Alright then, let's begin :
Okay, Step 1 - The Development of a New Drug.

Now, how exactly is a new drug developed? Well, the answer lies in the following points : (3/n)

(a) The first thing that is done is the identification of a the target for the drug that is the entity or the compound with which the drug will react with at a "molecular level".

(b) Now, once this target molecule has been identified, a new molecule (4/n)

a new molecule which is our "new drug" here is created or identified that acts accordingly with the target molecule.

(c) Once it's been created or identified, our new drug now will now be put through a screening process (will get into that shortly) (5/n).

(d) Post screening, the new drug discovered is then modified to make it a better fit for the target molecule that it has to act upon.

Okay, moving on to Screening :
Now, drug screening is essentially the testing of this new compound that has been created or (6/n)

created or been discovered at various levels such as
1. Molecular level
2. Cellular level
3. Organ system
4. Animals as a whole (plz don't tag PETA here, thankyou)

The aim of this process of screening is to define the activity of the drug, (7/n)

The Activity as in its "Pharmacologic Profile." This includes the "Mechanism of Action" that is the way with which a drug reacts with the target for eg. Does it inhibit the target or does it activate it to do it's function.

Also important to determine ..(8/n)

..determine is how selective the drug is when it comes to acting on its target meaning that does the drug act on its target only or does it also end up acting on adjacent molecular compounds that are not the targets here.

This inadvertently can lead to the (9/n)

can lead to the discovery of any possible toxic effects the drug may have although that's not usually the aim here.

Anyways, that was for screening..
Now, once you've put the durg through the process of screening, you get what is called a "Lead Compound" (10/n)

This "Lead Compound" is nothing but your new drug that has now been screened and has passed the screening process satisfactorily.

This Lead Compound is now subjected to Step 2 :

Step 2 : Pre Clinical Safety and Toxicity Testing. (11/n)

Let me begin with the following quote :
"All drugs are toxic in some individuals at some dose."

With that being said, as the name suggests, this Step 2 is done to determine the risk that may come along with the exposure to the new drug (Lead Compound) (12/n)

Once identified, these risks or these "toxic effects" or side effects of the new drug/ Lead Compound can help the researchers estimate how well the drig will work when it is introduced to human beings as a whole.

This Step of Pre Clinical Toxicity Testing ... (13/n)

...Is done on animals once again (I didn't design this, don't blame me, plz don't tag PETA, thankyou).

The following three notable parameters can be determined in this Step
(a) No Effect Dose - The maximum dose at which a specified toxic effect is not seen ... (14/n)

..meaning that if you go above The No Effect Dose, you'll start to observe the toxic effect of the drug/ Lead Compound in the subject.

(b) Minimum Lethal Dose : This is the smallest possible dose that is needed to "kill" the animal under study (Sorry PETA) (15/n)

(c) Median Lethal Dose : determined only if needed, this is the dose of the new drug/ Lead Compound that kills approximately 50% of the animas involved in the study

A very big limitation of this Pre Clinical Trials is the time needed..(16/n)

Now, on an average, toxicity testing is time consuming and expensive and may need anywhere from 2 to 6 years to collect and analyse all possible data required before the drug can be considered ready for testing in humans.

Attached below is a photo of the tests done in this step.

Alright, now that we are done with the pre clinical trials, let's move on to the Clinical Trials that is, the testing of drugs on human subjects.

Before we begin, let me tell you that there is a bunch of information and jargon on the types of trials and .. (18/n)

...and the various biases that hinder human beings and the methods adapted to minimise them. I will NOT be getting into that because to do so would require I add atleast 50 to 70 more tweets to an already voluminous thread and besides, you won't find it all that ineresting.(19/n)

Step 3 : The Clinical Trials (done on humans).

Okay, so now there are 4 Phases in which the Clinical Trials are carried out. I will break each one down for you and explain it in as simple a manner as I can to you.

Let's begin then... (20/n)

Phase 1 : Okay so in Phase 1, the underlying aim or the issue addressed is "the effect of a drug as a function of its dosage" meaning how the drug will react with changing its dosages in the body.

For eg, let's say that 50 mg of a drug X is considered safe... (21/n)

So now in this trial, we can determine how the drug will react of it is given above 50 mg..
Will it be toxic?? If yes, then that will be the upper limit of the "Safe Dosage Range" which is determined in this study.

So this Phase 1, it's normally done ... (22/n)

...normally done on healthy volunteers.
However, in cases where the drug developed and being used is "expected" to be toxic in its action, instead of healthy volunteers, you can have the diseased volunteers take their place instead. A good example here would be .. (23/n)

... here would be for the drugs being developed for AIDS or Cancerous diseases. They usually turn out to have toxic side effects and as a result, healthy volunteers are not risked exposure to them.

This phase is carried out in research centres by pharmacologists (24/n)

The number of volunteers that take part is usually small ranging between 20 to 100.

Moving on to Phase 2 :
The basic aim here in Phase 2 is to determine the "proof of concept" of the drug meaning that does the drug even function in humans as it is supposed to?? (25/n)

For that, you take about 100 to 200 diseased volunteers or patients suffering from the disease. They're the ones the drug is tested on in this phase.

Important points about Phase 2 are that :
(a) It is done in special clinical centres such as university hospitals (26/n)..

(b) Phase 2 trials can also identify any broader range of toxic effects that may be present with the drug.

Keep in mind that Phase 2 Trials have the highest rate of drug failures and that only about 25% of the drugs being tested barely make it to Phase 3.. Yes, only 25% (27/n)

Phase 3 : Pretty simple, the drug is now evaluated in a much larger sample size that is usually within thousands (may allow patients from different geographical regions) to further test for drug safety and it's effectiveness in achieving it's targets. (28/n)

Now once the drug has satisfactorily passed Phase 3, an application for its marketing is filed with the body responsible for approval of its usage in the general population...
In India, it is the ICMR. In the US, it is the FDA.

Please keep in mind that given the enormous (29/n)

volume of research done to reach this phase, the FDA or the ICMR may take a long long time to go through it all and allow the drug to be used sometimes even years.

Now... Once the drug has been approved for general use, it's prescribed by licenced (30/n)

... prescribed by the licenced physician for the general population. These physicians now monitor if there is any toxicity related to the drug that may develop with immediate or long term usage.
If so, it is reported or a "feedback" is done to the FDA/ICMR ... (31/n)

...To the FDA/ICMR by these licenced physicians..
This is what is known as Phase 4 or the "feedback" phase and it may last for as little as 6 months or may last for years, at times even a decade or so.

Now while some people consider this phase unnecessary, here is (32/n)

... consider this unnecessary, the following example will prove other wise.

In 1961, there were reports published in the USA that suggested that a particular drug going by the name "Thalidomide" was responsible for causing an increase in the incidence of a (33/n)

... incidence of a rare birth defect known as "Phocomelia" when taken by pregnant women in 1st trimester. This defect is characterised by the presence of shortened or complete absence of arms or legs in the fetus ("baby" for the lay person).

As a result.. (34/n).

..As a result, there were studies carried out by epidemiologists which proved the co relation between the drug and the birth defect in this case and as a result of that, the drug was withdrawn.

This was made possible due to the feedback effect of Phase 4. (35/n)

So you see... Every Phase is important, even Phase 4 and it's best if taken seriously.

And that brings us to the end of this thread.
I hope you've learnt something new today and I thank you for reading up to this point. (36/n).

This thread is long no doubt but that's what it is.. it's Medical Science .. it will be long.
And with that being said, DO NOT FALL FOR ANY SUCH PROPAGANDAS about miracle drugs being developed in days or weeks..
You can't do that... Can't be done.

End of thread (37/n).

Source : Basic and Clinical Pharmacology by Bertram G Katzung, 13th Edition.

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