America's first generic drug system

The concept of the first generic drug originated from the United States and originated from the Drug Price Competition and Patent Term Restoration Act (also known as the Hatch-Waxman Act) promulgated on September 24, 1984. The bill stipulates that the first applicant to submit a simplified new drug application (Abbreviated New DrugApplication, referred to as ANDA) to the US Food and Drug Administration (FDA) will have a 180-day market exclusivity period if "the patent is invalid or the approval of the drug being applied for will not infringe the patent. Within those 180 days, generic companies can quickly recoup their investment and establish themselves before the market is flooded with other generics. Therefore, since the promulgation of the Hatch-Waxman Act, more and more domestic and foreign pharmaceutical companies have joined the battle for the first generic drug. As a big country of generic drugs, China has also begun to pay attention to the first generic drugs in the United States in recent years. Many famous pharmaceutical enterprises, such as Fosun Pharmaceutical, Huahai Pharmaceutical, Haizheng Pharmaceutical and Dongyangguang Pharmaceutical, have begun to develop and declare the first generic drugs in the United States in the process of promoting the internationalization of medicine. On the one hand, with the improvement of the technological innovation level of Chinese pharmaceutical companies and the introduction of high-end talents, generic drugs produced in China can already meet European and American pharmaceutical standards. Many domestic pharmaceutical companies such as Renfu Pharmaceuticals and Dongyangguang Pharmaceuticals have obtained the United States. FDA certification, this undoubtedly provides a good foundation for the development of the first generic drug in the United States. In addition, domestic pharmaceutical companies have many years of experience in the production and export of APIs. Therefore, from a technical perspective, China already has the foundation and ability to declare the first generic drug in the United States. In addition to the technology platform, well-known domestic pharmaceutical companies are also equipped with a relatively complete legal and regulatory platform, drug international registration platform, patent platform and clinical trial platform. With the cooperation of these platforms, several first imitation varieties have been declared by Chinese enterprises, such as Fosun Pharmaceutical's sustained-release quetiapine tablets, East Sunshine Pharmaceutical's fingolimod capsules, Huahai Pharmaceutical's linagliptin tablets, etc.

U.S. drug patent linkage refers to the "link" between generic drug marketing approval and new drug patent expiration, that is, generic drug registration applications should consider the patent status of previously listed drugs, so as to avoid possible patent infringement. The U.S. drug patent link system has two meanings: one is the procedural link between the approval of the listing application for generic drugs and the corresponding drug patent validity review; the other is the functional link between the U.S. FDA and the U.S. Patent and Trademark Office (USPTO). Specifically, the system contains the following five aspects:

(1) Drug Patent Term Extension Extension (PTE) System

The patent extension system is a system that supplements the patent period lost by drugs and medical devices due to clinical trials and administrative approval. As we all know, the development of new drugs has the characteristics of large investment, high risk, difficulty and long cycle. From the discovery of new lead compounds that may become drugs and the application of patents, it takes a long time to carry out research work in order to finally bring a new drug to the market. In the field of biomedicine, the launch of every blockbuster new drug represents a strict drug patent protection network silently guarding the wisdom crystallization of the creator. The original drug research enterprises can firmly grasp the market initiative through continuous innovation, continuous technological innovation and intellectual property layout. However, often quite a number of drugs on the market, the core patent can protect the validity period has been very short. In order to mobilize the enthusiasm of the original drug research companies and enable them to obtain sufficient drug research and development returns, the Hatch-Waxman Act stipulates that new drug applicants can obtain patent extension periods to compensate for the time spent in clinical trials and drug review, but not more than 5 years, and the extension period plus the remaining patent period when the drug is on the market cannot exceed 14 years. However, if the duration of the patent is delayed due to the applicant's failure to do so, the period shall not be included in the extension period. The patent period can only be extended once for the same drug, even if the drug has multiple patents, and only the core patent of the drug can be extended, and subsequent patents cannot be extended.

Original pharmaceutical companies usually choose to add PTE to one of the compound patents to ensure that their core patents can effectively prevent the listing of generic drugs, but the determination of PTE is sometimes a long process. Therefore, when developing products, generic drug companies should pay special attention, especially the first generic drug applicants, PTE extension directly determines the formulation of their patent strategy.

(2) Market exclusive period (Market Exclusivity) provisions.

In addition to the patent period extension system, FDA also gives approved drugs a certain market exclusive period, including: New Chemical Entity (NCE) exclusive period of 5 years, Orphan Drug Exclusivity (ODE) exclusive period of 7 years, pediatric drug Pediatric (PED) Medication 6 months, new dosage forms, new uses and other 3 years, etc. During the market exclusivity period, the FDA will not approve generic drug companies to market the corresponding generic products, so even if the patent expires within that period, the original drug company can still occupy the market alone.

The market monopoly period is the research and development incentive for the original research drug enterprises, but it also has a certain hint effect on the generic drug enterprises, especially the first generic drug. According to FDA regulations, generic drugs can be declared as early as the NCE-1 day, that is, the first day of the fifth year after the new drug is approved, that is, the first day of the fifth year after the new drug is listed on the market, which is one year less than the NCE time, so it is called the NCE-1 day. This time is usually considered to be the first imitation day. If all generic drug companies are fully prepared, they will rush to submit their ANDA data to FDA on this day. Once the data is accepted, their first imitation qualification will be confirmed.

(3) Orange Book (OB) system

The Orange Book, "Drugs with Therapeutic Equivalence Evaluation Criteria" (Approved Drug Products withTherapeutic Equivalence Evaluation), is published by the FDA and provides a detailed and complete list of approved drugs, as well as information on the patents and exclusivity periods involved in the drug. According to the provisions of the Hatch-Waxman Act, the original research and development enterprises must provide patent information at the same time when submitting the application for new drug marketing Application (NDA) to FDA. When the new drug is approved, the corresponding patent will be registered in the orange book, providing reference materials for future generic drug companies to develop generic drugs, conduct ANDA, or patent litigation. Patents that can be included in the orange book include patents that directly point to drugs, such as compounds, products, crystal forms, etc., and can also include therapeutic methods. In general, metabolite, packaging and process patents are not included.

(4) The ANDA system

Before the passage of the Hatch-Waxman Act, there was no difference in the approval procedures for generic drugs and new drugs, which were required to undergo the same safety and effectiveness tests as new drug registrations, making it almost unprofitable to produce generic drugs. After the passage of the bill, when applying for the listing of generic drugs, the applicant only needs to carry out bioequivalence test when submitting ANDA, that is, to prove bioequivalence with the reference preparation, without submitting other data, which greatly reduces the cost of generic drug enterprises, thus speeding up the listing of generic drugs and reducing the medical expenses of patients. Since the implementation of ANDA, the generic drug industry in the United States has developed rapidly. FDA has received more and more generic drug applications, and the number and sales of generic drugs approved for listing have also increased year by year. For example, from 2011 to 2015, the generic drug market in the United States has increased from US $51.3 billion to US $76.2 billion (ex-factory price, excluding rebates and discounts).

(5) Patent Challenge System

According to the Hatch-Waxman Act, generic drug manufacturers must submit one of the following four statements when submitting an ANDA in accordance with the provisions of the Orange Book:

Paragraph I statement (PI): The drug is not patented;

Paragraph II statement (PII): The drug has a patent, but the patent has expired;

Paragraph III Statement (PIII): FDA is not required to approve the generic drug before the relevant patent expires;

Paragraph IV Statement (PIV): Patents related to the applied generic drug are invalid (Strategy 1) or generic drugs are not infringing (Strategy 2).

If Chinese generic drug companies want to compete for the first generic drug market in the United States, they must first understand and study the relevant drug patent legal protection system in the United States; secondly, they must focus on the patent evaluation of the target drug, and choose the appropriate generic drug application according to the actual balance of interests; once again, they need to improve the quality of themselves and their products. It is believed that with the continuous improvement of R & D and technological innovation capabilities of Chinese pharmaceutical companies, the continuous optimization of R & D project management capabilities, the continuous clarity of product positioning capabilities in drug segmentation fields, and the determination of Chinese pharmaceutical companies to implement the internationalization process of "going out", Chinese pharmaceutical companies can slowly narrow the distance with large foreign generic drug companies and get a share of the first generic drug market in the United States.

Source:http://www.y-lp.com/pages/Article.aspx?id=5146254912593177197