Patience to read will make you a great gain, so you clearly understand the pharmaceutical industry, conducive to understanding the process of fighting each other pharmaceutical giants.
We all know that chemical research and development is a big investment, long cycle, high risk, high return on life. Once the drug is successfully listed, then the return is amazing. The industry has a word called “blockbuster”, referring to the annual sales of more than 1 billion US dollars of drugs. An extreme example is Pfizer’s patented lipid-lowering drug, Lipitor, with global sales of $ 10.133 billion in 2010.
Drugs from the initial laboratory study to the final placement to the drug store sales to spend an average of 12 years, need to invest 6.6194 billion yuan, 7000874 hours, 6587 experiments, 423 researchers, and finally get a drug. What process do it require?
First, clinical research
(1) to find compounds that can develop drugs
In the world, there may be a huge number of molecular structures, more than the time since the Great Battle of the passage of time even more. It is estimated that the number of their 60 in the 60 or so.
Countless molecular structures, but only a few can become drugs
Researchers use their expertise and advanced scientific tools to combine known elements together in the lab to create thousands of new synthetic compounds.
Then they screened these compounds to identify compounds that could develop a drug, that is, a drug target.
(2) Find the best compound
At the molecular level, the new insights into the cause of the disease are the starting point for starting the innovation strategy, which leads to the emergence of new drugs with selective effects.
Once the target has been identified, the researcher designed the development plan and showed how the candidate drug affected the specific physiological structure or physiological characteristics. The investigators then evaluated these candidate drugs for further testing or computer procedures. In this process, the candidate drug will often be modified. (This stage of the work is mainly responsible for the previously selected new compounds can be developed new drug structure transformation and optimization)
(3) Screening of active compounds
Not all synthetic compounds have the desired activity, at this stage the need for bio-experimental means to screen out the initial active compounds used as an alternative. 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. Structure – activity relationship can be used to guide the subsequent optimization of compound structures. This step is mainly in the cell experimental level.
There is also a case where a compound has no effect on the target A target and is likely to have a very good activity against other target B targets.
(4) return to 2 to carry out the next step in the modification of the compound structure to obtain a more active compound.
2 to 4 This is a cycle until we get a compound that is ideal for activity.
The above is the general scope of work in the field of medicinal chemistry.
(5) the development of new therapies: to determine the effectiveness of drugs and safety
We need to develop new therapies to test the efficacy of new compounds. We want to cure serious illnesses – 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 surveys can only be done on animals.
For example, in general, only animal experiments can reveal the dangerous side effects that are difficult to distinguish from experimental drugs. In other words, animal experiments provide a guarantee for the safety of the patient.
Assess the pharmacological effects of drugs, safety and toxicity, drug absorption, distribution, metabolism and excretion (ADME).
This part of the experiment needs to start at the animal level. The results of cell experiments and the results of live animal experiments sometimes vary widely. The purpose of this step is to determine the effectiveness and safety of the drug.
(6) formulation development.
Can not get the compound directly to the mouth down it. Formulation development is an important part of drug application. For example, some medicine gastrointestinal absorption is poor, you need to develop as an injection. Some drugs in the stomach acid will lose their activity, you need to develop as enteric preparations. Some compounds have poor solubility, which can also be partially resolved by the preparation of this problem.
Second, the clinical application of new drugs
When a compound has passed a preclinical trial, a new drug clinical application is required to be submitted to the FDA so that the compound can be applied to human trials. If the FDA does not reject the application within 30 days of filing the application, the clinical application for the new drug is considered valid and can be tested in the human body. New drug clinical research applications need to provide the material of the previous trial; and where the plan will be, by whom and how to conduct a clinical trial; the structure of the new compound; the mode of administration; all the toxicities found in the animal test; Happening. All clinical programs must be reviewed and approved by the Institutional Review Board (IRB). Reports and results of a clinical trial must be reported annually to the FDA and IRB.
Third, clinical research
Once the candidate drugs pass the initial test, their real challenge begins. They must show in clinical trials that they are effective and well tolerated.
Clinical Phase 1: Tolerance and Safety
This phase of clinical trials generally requires 20-100 normal and healthy volunteers to conduct a pilot study. The main purpose of the trial is to provide information on the safety of the drug, including the safe dose range of the drug. But also through this stage of clinical trials to obtain its absorption, distribution, metabolism and excretion and duration of efficacy data and information.
In the development of new drugs, the new drug for the first time for the human body to study the nature of the new drug test, called the first phase of clinical trials, that is, under strict control conditions, to a small number of test drugs in a few carefully selected and selected Of healthy volunteers (usually cancer patients for cancer drugs), and then carefully monitor the blood concentration of the drug \ excretory properties and any beneficial reactions or adverse effects to assess the nature of the drug in the human body. Phase I clinical trials usually require health Volunteers are hospitalized for 24 hours of intensive care. With the increase in the safety of new drugs to understand the increase in the dose can be gradually increased, and can be multi-dose administration.Through the first phase of clinical trials, you can get some drugs the highest and At the lowest dose of information in order to determine the appropriate dose to be used in the patient in the future.It can be seen that the phase I clinical trial is the preliminary clinical pharmacology and human safety assessment test, the purpose is to observe the body’s tolerance to new drugs and pharmacokinetics , To provide a basis for the development of dosing regimen.
Candidate drugs are first tested for safety and tolerance in healthy volunteers. These studies are equipped with specialized medical facilities to ensure that the participants receive the best care.
Researchers can see the activity of the new drug in the human body and obtain preliminary information about the effects of the drug and the most appropriate dose.
Clinical Phase 2: Clinical Efficacy Observation
This phase of clinical trials usually require 100-500 patients to collect the trial. Its main purpose is to obtain information on the effectiveness of drug treatment.
Through the first phase of clinical studies, information on the pharmacological requirements of the drug required to achieve a reasonable plasma concentration is obtained in healthy people, ie, pharmacokinetic data, but it is usually not possible to confirm the drug in healthy humans In the second phase of the clinical study, Phase II clinical trials, will be administered to a small number of volunteers, and then re-evaluate the pharmacokinetics and excretion of the drug, which is because the drug in the sick state of the human body The mode of action is often different, especially for those drugs that affect the intestine, stomach, liver, and kidney. Take a new example of the development of arthritis for the treatment of arthritis. Phase II clinical studies will determine how the drug relieves arthritis patients, but also determine the incidence of adverse reactions at different doses to determine the pain is fully relieved but the minimum dose of adverse reactions. It can be said that Phase II clinical trials are the initial evaluation stage of the therapeutic effect.
The next step is to determine the mechanism of action of the drug, that is, to prove that it is effective.
Researchers work with carefully grouped patients to receive a range of doses. This is used to determine the ideal dose.
Participants in the second phase of the study were looked after by physician investigators who were closely monitored to identify potential risks as early as possible.
Clinical Phase 3
This period of clinical trials usually require 1000-5000 clinical and inpatient patients, more than in a number of medical centers, under the strict supervision of the doctor, to further obtain the effectiveness of the drug information and identification of side effects, and other drugs with each other Action relationship. The trials were generally conducted in a multicenter, placebo (or / and effective control) control and double-blind trial. Phase III clinical trials are the most important step in the overall clinical trial.
On the basis of clinical studies in phases I and II, the trial drug was used in a wider range of patient volunteers, with expanded multicenter clinical trials to further evaluate the efficacy and tolerability (or safety) of the drug. For the phase Ⅲ clinical trial. Phase III clinical trial can be said to be a confirmation stage of treatment, but also for the drug registration application to obtain the basis for approval to provide a critical stage,
Only now, the developer carried out a large-scale trial involving 5,000 people in a similar manner to clinical administration.
This provides a realistic picture of how a drug is used in clinical trials. The information obtained at this stage is also important for drug marketing at the time of maturity.
Any of the above feedback results are not good, are likely to make a candidate drug aborted. The most tragic result may be that the project was canceled directly.
More and more new drugs that can be marketed through all three clinical evaluations are partly due to the development of new drugs that are better than the existing comprehensive evaluation of drugs on the market. And a drug from the source of R & D to Phase 3 clinical is a costly process.
The fourth stage: continuous monitoring
Even after being approved, the drug is still under the supervision of the expert. All the side effects observed in the patient’s medication must be recorded and listed on the instructions.
Fourth, the new drug application
To complete all three phases of clinical trials and to analyze all data and data, if the drug is certified for safety and efficacy, you may submit a new drug application to the FDA. New drug applications need to provide all the scientific information collected. Usually a new drug application material can be up to 100,000 pages, or even more! In accordance with the regulations, the FDA should review the application for new drugs within six months. But because most of the application materials too much, and there are many non-standard, so often can not be completed in such a short period of time. The average time for reviewing individual chemical molecular drugs in 1999 was 12.6 months.
5, drug approval listed
Once the FDA approves a new drug application, the drug can be officially listed for sale by doctors and patients. But the FDA must also be regularly submitted to the FDA, including the side effects of the drug and quality management records. For some drugs the FDA will also require a fourth clinical trial to observe its long-term side effects.
Drug post-marketing monitoring. Mainly concerned about the efficacy of drugs in a wide range of people after the application of adverse effects and monitoring. The use of drugs (in fact, the addition of the instructions) need to be revised according to the results of this phase.
This stage will also involve some of the content, the use of drug compatibility research, drug use taboos (such as some drugs listed on the medication during the treatment of grapefruit will affect the metabolism of drugs).
If the approved drug is found at this stage before the study did not find serious adverse reactions, such as significantly increased the incidence of cardiovascular disease and other drugs, the drug will be forced by the regulatory authorities shelves. Some drugs even listed only one year, due to poor clinical evaluation of 4 and was forced to shelves.