Do you know how a small tablet is produced from scratch? From cells to mice, rats to primates to humans, how many twists and turns did an original innovative drug go through when it became a commodity and put it on the market?

According to authoritative statistics, the cost of marketing a single drug is more than one billion US dollars, which takes about a decade, and the failure rate of drug screening is as high as 97%. In addition to small molecule compounds in the traditional sense, such as aspirin and paracetamol, the concept of modern drugs also includes peptides, proteins and antibodies, nucleotides, and vaccines. This article briefly talks about the basic process of a new drug from scratch to the final market.

1.Determination of target molecules and screening models

Identifying target molecules implicated in targeting specific diseases is the basis for modern new drug development. A target is a biomolecule closely related to a disease, such as protein and nucleic acid, and intervention of this biomolecule can cure or alleviate the disease associated with it. For selected targets, a bioactivity assay is designed to evaluate and screen compounds, which we call a screening model. The screening model should be able to reflect the corresponding disease status of the human body and can be quantitatively repeated. Commonly used screening models are at the molecular and cellular levels, observing the interaction between drugs and molecular targets, which can directly understand the basic mechanism of action of drugs.

2.Search for seedling compounds

After selecting the target and screening model of drug action, medicinal chemists have to find a compound that has an effect on this target, and we call the initially found compound with preliminary activity a Hit.

Pathways to discover Hit include random screening and rational design. Although random screening has certain blindness, it is currently the way to screen drugs with the highest success rate. High-throughput screening techniques can complete the screening of a large number of candidate compounds in a short period of time and become the main way of drug development today. The effectiveness of lead compound discovery through high-throughput drug screening depends on the number of compounds in the compound sample library and their quality. Screening compound libraries with diversity, drug-like properties, and stable repeated large supply can greatly improve the success rate of drug screening discovery, shorten the time of R & D, and reduce R & D costs.

3.Optimize lead compounds and identify drug candidates

The initial discovery of the Hit is only a potentially active compound, but it is not sufficiently active, disorganized and may be toxic. Medicinal chemists want to expand the structure of hit, and if a series of structurally similar compounds show activity on selected targets, we call the initially selected compounds Lead. Lead compounds are compounds with certain biological activity and chemical structure, and are the starting point for modern new drug research and development.

Medicinal chemists should continue to modify the structure of lead compounds based on the principles of structure-activity relationship, bioelectrons and other arrangements, prodrugs, soft drugs and twins. At the same time, biochemists should study the kinetics and toxicology of modified compounds. This process is called Lead Optimization, in which ideal drug candidates are obtained. The identification of drug candidates is a key link in the research and development of new drugs, and the structure of drug candidates determines the fate of clinical studies.

4.Preclinical toxicological studies of new drugs

Next, the research and development of new drugs enters the development stage. The primary goal is to complete the preclinical toxicological study and submit the application for investigational new drugs to the regulatory authority. At this stage, various disciplines such as synthetic process, toxicology, pharmacology, kinetics and preparation need to cooperate with each other, and each discipline needs the support of analytical chemistry.

To carry out these studies requires a large number of APIs, so the first step is the development of the API synthesis process, which needs to be continuously improved. The first batch of raw materials obtained are mainly used for toxicological research, and the preparation department will administer it in the simplest form in order to speed up the process. Immediately thereafter, pharmacokinetic studies and safety pharmacological evaluations should be carried out to guide the clinical administration form, dosage and evaluation of side effects. With the advancement of the project, the mode of administration and preparation prescription should be continuously improved. If some drugs have poor gastrointestinal absorption, they should be developed into injections, and some drugs will inactivate in the stomach, they should be developed into intestinal solvents.

5.Clinical study of new drugs

The above process is collectively referred to as preclinical research, which is only the first stage of drug development. Each test link is not carried out in strict accordance with the above sequence, but a mutually coordinated process. If the result of any step is not good, the candidate drug should be determined again. When the drug candidate passes the preclinical test, it is necessary to submit the application for new drug clinical study to the regulatory authority.

For the first time, a trial in which a new drug is used in humans to study the nature of the new drug is called a phase I clinical trial. In phase I clinical trials, 20 to 100 normal and healthy volunteers are generally recruited. It is a preliminary clinical pharmacology and human safety evaluation trial. The purpose is to observe the tolerance of the human body to new drugs and provide the basis for formulating the dosing regimen and safe dose. Phase II clinical trials usually require the collection of 100 to 500 relevant patients for trials in order to obtain data on the effectiveness of drug treatment. Phase II clinical trials will preliminarily evaluate the efficacy and safety of new drugs and provide the basis for designing phase III clinical trials and determining the dosing regimen. Phase III clinical trials usually require 300 to 5,000 clinical and inpatients, which is the confirmatory stage of therapeutic effect and provides the basis for the registration application of drugs. This phase is the most important step in clinical trials and generally takes several years. Poor feedback at any step in clinical trials may allow a drug candidate to die.

6.New drug application for marketing

After successfully completing all three stages of clinical trials, the new drug holder can submit a new drug application to the regulatory authority, and the new drug can be officially marketed and sold after obtaining approval. Approval for marketing does not mean that the drug is safe, and its efficacy and adverse reactions need to be continuously monitored after the drug is used in a wide range of populations. Some drug regulatory authorities require phase IV clinical trials to observe their long-term side effects.