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01

Antibiotic resistance

For a long time, humans have been fighting diseases caused by various microorganisms. In the 1930s and 1940s, sulfa drugs and penicillin appeared successively and mass production was achieved. Humans have the weapon to resist microbes and are no longer so fearful of infection. When people used these antibacterial drugs unscrupulously, Sir Alexander Fleming, one of the inventors of penicillin, warned the public not to abuse penicillin in an interview with The New York Times in 1945, otherwise it would produce resistant bacteria. And it will spread, and the effect of penicillin will be greatly reduced.

Why is there resistance? When the bacteria are exposed to the antibacterial agent, they will spontaneously change their metabolic pathways or produce corresponding inactivated substances to resist the antibacterial drugs. As a result, drug-resistant bacteria are gradually screened out as pathogenic bacteria that are dominant growth, or cause resistance to the original sensitive bacteria. The bacteria rapidly multiply new resistant bacteria by mutation and inheritance. Drug resistance and antibacterial drugs follow the pattern, as long as the use of antibacterial drugs will produce drug resistance, the more used, the faster the formation of drug resistance, and gradually from single resistance to multi-drug resistant (MDR), Extensively drug resistant (XDR), and even pandrug-resistant (PDR).

However, people did not cause enough vigilance. In the decades that followed, the issue of resistance was not prominent, as people have been vigorously developing new antibacterials. After the previous emergence of drug resistance, the new drug soon came out, followed by drug resistance, but it does not matter, and new drugs have come out. Repeatedly, humans have invented hundreds of antibacterial drugs, but the problem of drug resistance has appeared faster and faster. Moreover, if the infection is not effectively treated because of drug resistance problems, the bacteria will continue to grow and spread to other pathogens, further exacerbating the problem of drug resistance.

Finally, with the emergence of some pan-resistant bacteria that humans can’t beat, commonly known as “superbugs”, the existing treatments can’t do anything. They can only take adjuvant therapy, just like before the invention of penicillin, but only for patients. Miracle or death. Today, the number of deaths due to drug resistance problems in the world is estimated to be about 700,000 people. According to the current situation, it is expected to reach 10 million by 2050, with a cumulative economic loss of 100 trillion US dollars. People gradually realized the seriousness of the drug resistance problem and began to publicize and limit the abuse of antibacterial drugs.

Antibacterial drugs used to be the core business of the pharmaceutical industry. In the past 100 years, hundreds of antibacterial drugs have been discovered and concentrated in the decades after the Second World War. These antibacterial drugs have different mechanisms of action, helping humans to effectively control most infections. Nowadays, antibacterial drugs have also passed the patent protection period, and a large number of generic drugs are on the market, so it is very cheap. As the problem of drug resistance becomes more and more serious, the use of antibacterial drugs has been strictly restricted around the world, and the market scale and profit return are no longer growing as crazy as ever. In addition, antibacterial agents that invent new mechanisms of action are becoming more and more difficult. In fact, in the late 1980s, scientists no longer found new antibacterial agents.

Technical difficulty and market size determine the return on investment, while capital is always profit-seeking, and it is a field that flows to higher returns. Between 2003 and 2013, a total of $38 billion of venture funds were invested in new drug research and development, of which only $1.8 billion was spent on antibacterial drug development, less than 5%. Antibacterial drugs began to fall out of favor, and gradually became a cold palace, rarely interested. However, the problem of controlling the abuse of antibacterial drugs is not solved overnight. The problem of drug resistance is still expanding. What is more terrible is that the superbugs are more powerful, and the weapons used for confrontation are not as fast as the previous ones, so humans are about to face The unhelpful dilemma is not alarmist.

02

Antibacterials in China

Like the people of the world, Chinese people also have a natural good feeling for antibacterial drugs. After the founding of New China, in order to break the foreign drug blockade and resolve the dependence on imported drugs, one of the tasks of the first five-year plan formulated by the state was to establish a pharmaceutical factory to produce antibacterial drugs. This is North China Pharmaceutical. The origin of the later, known as the “eldest son of the Republic”, became the pride of countless Chinese medicine people. Since then, antibacterial research institutes and factories have been established throughout the country, which are basically self-sufficient, and the disability and death caused by bacterial and fungal infections have fallen sharply, thus deepening the Chinese people’s good feelings for antibacterials. In the field of medicine, many new pharmaceutical companies have sprung up, and some of them have been fermented or distributed from antibacterial drugs.

Time came to 2001, when China joined the World Trade Organization and the Chinese market fully integrated into global competition. Soon after, the import and export management rights were fully liberalized and no longer the exclusive authority of a few state-owned enterprises. In the field of pharmaceutical industrial products, antibacterial intermediates and APIs are undoubtedly the products with the highest export volume, with annual output exceeding hundreds of thousands of tons or even hundreds of tons. There are many large-scale factories built in many parts of the country. In some places, even the air is filled with the unique taste of antibacterial drugs.

The scale of clinical application of Chinese antibacterial drugs is also huge. One data sums up to say that China consumes 50% of the world’s antibacterial drugs by 20% of the world’s population, nearly half of which is for human use, and the rest is mainly used for agriculture and animal husbandry. If no effective measures are taken, by 2050, the problem of drug resistance will cause 1 million Chinese deaths each year, resulting in a total loss of 20 trillion US dollars to China.

Chinese drug research and development institutions and pharmaceutical companies have always been fond of antibacterial drug development and production, especially the pursuit of antibiotics is unique in the world. But when it comes to antibiotics listed in any corner of the world, Chinese people can always find ways to find strains, fermentation and synthesis processes, and finally produce them, and then spread them widely in the industry. The most typical one is cephalosporin antibiotics, which can be found in China. At one time, people were particularly keen on setting up a formula, making a compound, adding a product, and a small cephalosporin. It is really a “new cephalosporin” flowering everywhere, a scene of prosperity.

However, the so-called extremely necessary, in the face of more and more serious abuse of antibacterial drugs, and the resulting resistance problems, a series of limited resistance policies, the use of antibacterial drugs continue to tighten, resist the abuse of antibacterial drugs, delay The spread of resistant bacteria.

After several years of rectification, from 2010 to 2017, the average antibacterial use rate of inpatients in China dropped from 67.3% to 36.8%; the use rate of antibiotics in outpatients dropped from 19.4% to 7.7%. The trend of bacterial and fungal resistance in China is generally stable, and the level of clinical rational drug use continues to increase.

However, for many companies that use antibacterial drugs as their main business, they face enormous challenges and their performance is affected. While struggling to hold this position, we are also looking for new business and avoiding excessive dependence on antibacterial drugs.

In recent years, the heat of research and development of antibacterial drugs has been ruined like a splash of cold water. Once upon a time, there were no antibacterial drug market strategy research and development projects on the hot topics in major medical forums. Over the years, I have occasionally heard that the development of antibacterial drugs is mostly due to consistency evaluation, and companies have to face difficulties and complete the mission of fate. There are few manufacturers to declare new antibacterial drugs, whether it is 3 categories of imitation of foreign products already listed, or 4 types of generic drugs.

03

Antibacterials in the United States

New drug research and development in the United States has long been a leader, and many antibacterial drugs are also the first to be promoted in the United States. The problem of drug resistance has naturally emerged very early in the United States. Therefore, the United States has also begun to take measures to limit the abuse of antibacterial drugs very early, but the problem of resistant bacteria is still not optimistic. Like other parts of the world, public health in the United States is also threatened by antimicrobial-resistant infections. According to a report released by the Centers for Disease Control and Prevention (CDC) in 2013, there are more than 2 million cases of infectious diseases caused by new drug-resistant bacteria in the United States each year, of which more than 23,000 people die. Significant advances in many areas of modern medicine, including cancer, organ transplants and other receipt infections, rely on the ability to effectively treat infections. Antibiotic resistance threatens the advancement of modern medicine. In some patients, once the infection occurs, the treatment is very limited, and even no medicine is available. The pathogens have evolved various resistance mechanisms, and even with the careful use of antibacterial drugs, drug resistance will continue to exist.

In addition to the rational use of antibacterial drugs and the delay in the emergence of drug-resistant bacteria, the development of new antibacterial drugs is still an important means to deal with the public health threats of drug resistance. It is essential to establish a strong antibacterial drug research and development product line. However, this matter is faced with scientific and economic challenges:

1) There have been 30 years of vacuum in discovering new targets or new mechanisms of action;
2) Recruit patients with severe acute infections to participate in clinical trials. These people are desperate to take immediate antibacterial treatments, have no time to complete the procedures before using the test drugs, and are more hopeful of the existing treatments;
3) Uncertainty in diagnosis, the disease may be caused by infection, or it may be caused by non-infection, even if the diagnosis is a pathogen infection, then what is the pathogen?
4) Patients have different sensitivities to antibacterial drugs, and the efficacy of antibacterial drugs is also affected by other conditions or physical conditions of patients;
5) The return on investment is low. Nowadays, common common infections are already filled with a large number of generic drugs. The newly developed antibacterial drugs are basically used for drug-resistant infections. The market capacity is small, and capital is more willing to flow to major diseases such as cancer, or Chronic diseases such as diabetes.

It is precisely because of the above scientific and economic reasons that the pharmaceutical companies that originally engaged in the research and development of antibacterial drugs have reduced or even abandoned the antibacterial drug product line, which is directly reflected in the FDA approved antibacterial drugs for systemic infections since the 1980s. The year has plummeted, and it was not until 2013 that it began to pick up significantly.

Obviously, 2012 is an important turning point. On July 9 of this year, when the US President Barack Obama signed the FDA Security and Innovation Act, the eighth chapter is the GAIN (Generating Antibiotic Incentives Now). In addition, the United States has introduced other legislation to improve FDA approval of antibiotics, allowing patients to be reduced in clinical trials for patients with severe or life-threatening infections with limited treatment options. In 2016, the Obama administration also approved a $1.2 billion budget to address drug resistance issues, more than half of which are used for diagnostics and drug discovery. Therefore, relying on policy guidance, the development of antibacterial drugs in the United States began to recover.

According to the GAIN Act, anti-bacterial or anti-fungal drugs for the treatment of serious or life-threatening infections, including diseases caused by antibacterial and antifungal drug-resistant pathogens (including new pathogens), or by A drug that certifies a disease caused by a qualifying pathogens can apply to the US FDA for a qualified infectious disease product (QIDP). This qualification will not be revoked under any circumstances unless it is found to provide false information.

According to the requirements of the Act, the US Department of Health and Human Services (HHS) commissioned the US FDA to develop and maintain a list of qualified pathogens based on four factors and to make a public basis. These four factors include

1) The impact of resistant bacteria on human public health;
2) the growth rate of resistant bacteria in humans;
3) The increase in resistance rates in humans and
4) Human morbidity and mortality. The list lists pathogens that pose a serious threat to public health, such as (A) resistant Gram-positive bacteria; (B) multi-drug resistant Gram-negative bacteria; (C) multi-drug resistant tuberculosis And (D) C. difficile.

The FDA held a multi-party hearing in December 2012 and published a proposal in June 2013. In this proposal, 18 species (1-18) were listed as certified pathogens, but three more (19-21) were added in the version that came into effect in July 2014, so a total of 21 species. However, it does not mean that QIDP can be granted as long as it is a disease caused by the treatment of these bacteria, and it must satisfy the treatment of serious infections or life-threatening infections. Similarly, as long as it is a drug for treating serious infections or life-threatening infections, even if it is not for these 21 pathogens, you can apply for QIDP.

However, priority review grants first-time application and efficacy supplementation application, while other applications have no priority review; in addition, follow-up on new indications, routes of administration, dosing cycle, dosage form, drug delivery system, drug delivery device or specification Apply, do not enjoy a 5-year exclusive period.

The same active ingredient, depending on the dosage form or indication, the applicant can obtain multiple QIDP qualifications. However, since this Act only accepts applications filed in Section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), biologics and medical devices are not eligible for QIDP.

Once the FDA grants QIDP status, the preferential measures can be described as a large basket:

• Give a five-year market exclusivity without affecting the exclusive period enjoyed by other qualifications, which can be accumulated;

• Priority review (Norient Review), NDA review time reduced to 6 months;

• Fast Track, where applicants receive more efficient communication with the FDA, as well as rolling applications and reviews.

In addition, HHS and its affiliates FDA need to revise and improve the guidelines for antibacterial drug development; participate in the research and development of antibacterial drugs in academia and industry; develop and implement antibacterial drug use supervision plans; regularly maintain a list of qualified pathogens Submit a summary report on the implementation of the GAIN Act every five years.

According to incomplete statistics, from July 9, 2012 to July 2018, the FDA granted a total of 197 QIDP qualifications, and only rejected 14 applications, including non-conforming to serious or life-threatening infections, and including vaccines. Products and medical devices are not included. These QIDP qualifications focus on the following five categories for indications:

1. Acute bacterial skin and skin structure infection (ABSSSI)

2. Complex urinary tract infection (cUTI)

3. Community acquired bacterial pneumonia (CABP)

4. Hospital and / or ventilator-associated bacterial pneumonia (HABP / VABP)

5. Complex abdominal infection (cIAI)

As of July 2018, the GAIN Act has been in force for less than six years, and the FDA has approved 13 new antibacterial drugs for the treatment of systemic infections. The incentive measures have been effective.

04

China’s antibacterial drug research and development, where is the road?

As mentioned above, the heat of research and development of antibacterial drugs in China has plummeted, and it can be said that it has fallen to freezing point. This is not surprising, and it will not even be a pity, because China already has a large number of antibacterial generic drugs. The existing varieties can basically meet the domestic clinical needs through the consistency evaluation work to achieve the same quality and efficacy as the original research drugs. However, in the face of pan-drug-resistant infections, the last line of defense in China still remains in vancomycin, carbapenemase and tigecycline. Where are the new antibacterial drugs that enhance the hardness of the line?

The United States has the GAIN Act to encourage the development of antibacterial drugs. So what incentives does China have?

First of all, China needs a new antibacterial drug. The first work goal proposed by the National Health and Family Planning Commission and other 14 departments in the “National Action Plan for Combating Bacterial Resistance (2016-2020)” jointly formulated in August 2016 is to strive for R&D and listing of new antibacterial drugs by 2020. -2″. This goal seems to be very modest compared to the listing of more than 10 new antibacterial drugs in the same cycle in the United States.

Second, China is very supportive of the development of anti-drug resistant drugs. The Ministry of Science and Technology issued the “Major New Drug Creation” Science and Technology Major Project 2018 Annual Public Choice Project, which clearly proposes to support the development of major new drugs for “drug-resistant pathogen infection” and “drug-resistant tuberculosis and other major infectious diseases prevention and treatment drugs and drug-resistant bacteria” The prevention and treatment of drugs is urgently needed for drug development.

Thirdly, the National Drug Administration can also give priority treatment for antibiotics that meet the requirements, such as innovative drugs, obvious therapeutic advantages, major national science and technology projects, tuberculosis and clinical emergency needs.

05

Summary and outlook

The implementation of the limit-resistance policy for many years, the rational use of drugs has been widely publicized, the abuse of antibacterial drugs has been clearly controlled, more and more people are beginning to realize the problem of drug resistance, and accept the new concept of drug use. In fact, the majority of practitioners in the pharmaceutical industry understand the seriousness of the drug resistance problem and know the dangers of superbugs.

Capital is profit-seeking and ruthless. Current new drug research and development projects focus on cancer, immunity and various chronic diseases because of high return on investment. However, when these areas become a hot spot for investment, it seems to be a red sea. At this time, we look back and see, the field of research and development of antibacterial drugs, which has been forgotten, can be called a blue ocean. Here, the rewards that can be obtained may not only be economic, but perhaps a feeling of doing medicine.

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