How did the drug go from research and development to market

Reading patiently will definitely give you a lot of gains, give you a clear understanding of the pharmaceutical industry, and help understand the process of pharmaceutical giants fighting each other.

We all know that chemical drug research and development is a big investment, long cycle, high risk, and high return.
Once the drug is successfully marketed, the rewards are also amazing.
There is a term in the industry called "blockbuster", which refers to drugs with annual sales of more than $1 billion.
An extreme example is Pfizer's patent-protected lipid-lowering drug Lipitor (Lipitor), which had global sales of US$10.
133 billion in 2010.

It takes an average of 12 years for the drug to go from the initial laboratory research to the final placement in the medicine cabinet.
It takes 6.
614 billion yuan, 7000874 hours, 6587 experiments, 423 researchers, and finally 1 drug.
What process does it need?

1.
Pre-clinical research

1.
Look for compound molecules that can develop drugs

In the world, the number of possible molecular structures is huge, more than the number of seconds that have elapsed since the Big Bang.
It is estimated that their number is around 10 to the 60th power.

Countless molecular structures, but only a few can become medicines.

Researchers use their expertise and advanced scientific tools to combine known elements in the laboratory to create thousands of new synthetic compounds.

Then, they screened these compounds to find out which compounds can develop drugs, that is, the confirmation of drug targets.

2.
Find the best compound

New insights into the etiology of diseases at the molecular level are the starting point for innovative strategic research, which has led to the emergence of new drugs with selective effects.

Once the target is confirmed, the researchers design a development plan that shows how the candidate drug affects specific physiological structures or physiological properties.
The researchers then evaluate these candidate drugs through further tests or computer programs.

In this process, drug candidates are often revised.
(The work at this stage is mainly responsible for the structural transformation and optimization of the new compounds previously selected for the development of new drugs)

3.
Screening of active compounds

Not all synthetic compounds can have the desired activity.
At this stage, it is necessary to screen out the preliminary active compounds as candidates through biological experiments.
These compounds are called lead compounds.
The obtained activity data can be combined with the structure of the compound to obtain a preliminary structure-activity relationship analysis.
The structure-activity relationship can effectively guide the subsequent optimization of the compound structure.
This step is mainly carried out at the level of cell experiments.

Cell culture

At the same time, there are cases where a compound has no effect on target A, but it may have very good activity on other B targets and C targets.

4.
Return to (2) to modify the structure of the compound to obtain a compound with better activity

(2) to (4) This is a cycle until we get a compound with sufficient activity.

The above content is the general scope of work in the field of medicinal chemistry.

5.
Develop new therapies: determine the effectiveness and safety of drugs

We need to develop new therapies and test the efficacy of new compounds.
We want to cure serious diseases—at least to relieve symptoms.
We want to save lives.

To achieve these goals, animal experiments are essential, even in the 21st century.
After all, many investigations can only be conducted on animals.

Animal test

For example, generally speaking, only animal experiments can reveal dangerous side effects that are difficult to distinguish between experimental drugs.
In other words, animal experiments provide a guarantee for the safety of patients.

To evaluate the pharmacological effects, safety and toxicity of the drug, the absorption, distribution, metabolism and excretion of the drug (ADME).

This part of the experiment needs to be carried out at the animal level.
The results of cell experiments and live animal experiments sometimes differ greatly.
The purpose of this step is to determine the effectiveness and safety of the drug.

6.
Development of preparations

You can't just pour some compound directly into your mouth.
Preparation development is an important part of drug application.
For example, some medicines have poor gastrointestinal absorption and need to be developed as injections.
Some medicines lose their activity in gastric acid and need to be developed as enteric-coated preparations.
Some compounds have poor solubility, which can also be partially solved by formulations.

The development of pharmaceutical dosage forms has gone through five stages:  

The first generation (traditional dosage form): pills, pills, powders, ointments, etc.
;

The second generation (conventional dosage form): conventional preparations produced by mechanization;

The third generation (sustained and controlled release formulations): sustained release formulations, controlled release formulations;

The fourth generation (targeted formulation): targeted drug delivery system;

The fifth generation (time-released dosage form): pulsed drug delivery system.

The latter three generations are new drug formulations that have only been developed in the past 30 years.
They can also be collectively referred to as a controlled release drug delivery system.
The fundamental purpose is to improve the clinical efficacy of drugs and reduce adverse reactions.

2.
New drug clinical research application

After a compound has passed the pre-clinical test, it needs to submit a new drug clinical research application to the FDA so that the compound can be used in human trials.
If the FDA does not reject the application within 30 days after submitting the application, the new drug clinical research application is deemed valid and can be tested in humans.

3.
Clinical research

Once the drug candidates pass the preliminary tests, their real challenge begins.
They must be shown in clinical trials that they are effective and well tolerated.

1.
Clinical Phase I: Tolerability and Safety

Clinical trials at this stage generally need to recruit 20 to 100 normal and healthy volunteers for experimental research.
The main purpose of the trial is to provide safety information of the drug, including the safe dose range of the drug.
At the same time, it is necessary to obtain data and information on its absorption, distribution, metabolism and excretion, as well as the duration of drug effect through this phase of clinical trials.

In the process of new drug development, the trial of applying a new drug to the human body to study the properties of the new drug for the first time is called a phase I clinical trial.
That is, under strict control conditions, a small number of experimental drugs are carefully selected and screened out.
Healthy volunteers (usually cancer patients for cancer drugs), and then carefully monitor the blood concentration of the drug, its excretion properties and any beneficial or adverse effects to evaluate the properties of the drug in the human body.

Phase I clinical trials usually require healthy volunteers to be hospitalized for 24 hours of close monitoring.
As the understanding of the safety of new drugs increases, the dose of administration can be gradually increased, and multiple doses can be administered.
Through the phase I clinical trial, Information on the highest and lowest doses of some drugs can also be obtained in order to determine the appropriate dose for future use on the patient.

It can be seen that the phase I clinical trial is a preliminary clinical pharmacology and human safety evaluation test.
The purpose is to observe the human body's tolerance and pharmacokinetics of new drugs, and to provide a basis for formulating dosing regimens.

The candidate drugs were first tested for safety and tolerability on healthy volunteers.
These studies are equipped with specialized medical facilities to ensure that participants receive the best care.

Researchers can see the activity of the new drug in the human body and obtain preliminary information about the drug's impact and the most appropriate dosage.

2.
Clinical Phase II: Observation of Clinical Efficacy

This phase of clinical trials usually requires 100 to 500 relevant patients to be recruited for the trial.
Its main purpose is to obtain information on the effectiveness of drug treatment.

Through the Phase I clinical study, the information on the pharmacokinetics of the drugs required to achieve a reasonable blood drug concentration was obtained in healthy people, that is, pharmacokinetic data.
However, it is usually impossible to verify the drugs in healthy people.
Therapeutic.

In the second phase of the clinical study, the Phase II clinical trial, the drug will be administered to a small number of patient volunteers, and then the pharmacokinetics and excretion of the drug will be re-evaluated.
This is because the mode of action of the drug in the body of the diseased state is often It is different, especially for drugs that affect the intestines, stomach, liver, and kidneys.

Take the development of a new anti-arthritis medicine as an example.

Phase II clinical studies will determine how effective the drug is to relieve pain in patients with arthritis, and determine the incidence of adverse reactions at different doses to determine the dose that achieves sufficient pain relief but minimal adverse reactions.
It can be said that the Phase II clinical trial is the preliminary evaluation stage of the therapeutic effect.

The next step is to determine the mechanism of action of the drug, which is to prove that it is effective.

Researchers work with carefully grouped patients to receive a range of medications.
This is used to determine the ideal dose.

Patients participating in the second phase of the study are taken care of by physician investigators and they are closely monitored to identify potential risks as early as possible.

3.
Clinical Phase III

This phase of clinical trials usually requires 1,000 to 5,000 clinical and hospitalized patients, mostly in multiple medical centers.
Under the strict supervision of doctors, further information on the effectiveness of the drug and identification of side effects, as well as interactions with other drugs, are obtained.
Role relationship.
This phase of the trial generally adopts a multi-center, placebo (or/and effective control agent) controlled and double-blind trial.
The third phase clinical trial is the most important step in the entire clinical trial.

On the basis of Phase I and Phase II clinical studies, the trial drug will be applied to a wider range of patient volunteers, and an expanded multi-center clinical trial will be conducted to further evaluate the effectiveness and tolerability (or safety) of the drug.
This is a phase III clinical trial.
Phase III clinical trials can be said to be the stage of confirmation of the therapeutic effect, and it is also a key stage for providing the basis for the approval of the drug registration application.

Only now, developers have carried out large-scale trials involving 5,000 people in a situation similar to clinical drug delivery.

This provides a realistic picture of how the drug is used in clinical trials.
The information obtained at this stage is also very important for drug marketing when the time is ripe.

If the results of any of the above feedback steps are not good, it may cause a drug candidate to die.
The most tragic result may be that this project was simply cancelled.

There are fewer and fewer new drugs that can be marketed through all phase 3 clinical evaluations, partly because it is becoming more and more difficult to develop new drugs that have a better comprehensive evaluation than the existing drugs on the market.
However, it is a costly process to develop a drug from the source to phase 3 clinical trials.

4.
The fourth stage: continuous monitoring

Even after being approved, the drug is still under the supervision of experts.
All side effects observed in patients taking the medication must be recorded and listed on the label.

4.
New drug application

After completing all three phases of clinical trials and analyzing all the information and data, if the safety and effectiveness of the drug are proved, a new drug application can be submitted to the FDA.
New drug applications need to provide all collected scientific data.
Usually a new drug application material can be as many as 100,000 pages or more! According to regulations, the FDA should review the new drug application within 6 months.
However, because most of the application materials are too many and there are many irregularities, they often cannot be completed in such a short time.

Once the FDA approves the new drug application, the drug can be officially marketed for doctors and patients to choose from.

Some of the content that will be involved at this stage are the research of drug compatibility and drug use contraindications (for example, some drugs have been found on the market that taking grapefruit during the medication period will affect the metabolism of the drug).

If a drug approved for marketing is discovered at this stage, serious adverse reactions not found in the previous studies, such as a significant increase in the incidence of cardiovascular disease in the population taking the drug, will be forced to remove the drug by the regulatory authorities.