Generics are usually more affordable than original drugs, yet equivalent in quality and effectiveness. To create moderate competition and increase the availability of medicines, both China and the United States give incentives to the first generic drug that has successfully challenged the patent of the brand-name drug.
When it comes to patent, the patent linkage system is significant for resolving the patent disputes between the generic drug and the brand-name drug. The US established the patent linkage system through the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Amendments.
China built up the patent linkage system in 2021 by enforcing the Measures for Implementing the Mechanism for Resolving Drug Patent Disputes in the Early Stage (Interim), which is largely modelled on the Hatch-Waxman Amendments.
The patent linkage systems in China and the US both feature patent statement by the generic drug applicant, stay period for the generic drug application in patent dispute, and market exclusivity for the first generic drug that successfully challenges the brand-name drug.
But in detail, the definition, registration process, the starting date and the lengthy of market exclusivity, and some other regulatory requirements differ in China and the US.
1. Definition of the First Generic Drug
In the US, first generic drug is the first generic drug product that the Food and Drug Administration (FDA) permits a manufacturer to market in the country.
In China, first generic drug does not have an official definition written in the existing regulations. In the industry, it usually means that the generic drug developed by a Chinese company and first granted with marketing authorization by National Medical Products Administration (NMPA). *Generic drug only refer to the generic version of a chemical drug only, not including biosimilars.
2. First Generic Drug Registration Process
2.1 Process in China
In China, the patents relevant to brand-name drugs are registered on the "Patent Information Registration Platform for Drugs Marketed in China (hereinafter referred to as the platform)". When submitting the first generic drug application, the applicant shall make one of the Type I-IV Statements, notify the marketing authorization holder (MAH) of the statement, and provide corresponding evidence. If the MAH is not the patentee, the MAH should notify the patentee of the statement.
Type I: There is no relevant patent registered on the platform;
Type II: The relevant patent on the platform has expired or been invalidated, or the generic drug applicant has acquired permission from the patentee to exercise relevant patent rights;
Type III: There is a relevant patent on the platform and the generic drug applicant promises not to sell the drug product until the patent expires;
Type IV: The relevant patent on the platform shall be invalidated, or the generic drug is outside the protection scope of the relevant patent.
The first generic drug application with Type I or Type II Statement will be approved after passing the technical review. The application with Type III Statement, if having fulfilled the technical requirements, will be approved after the relevant patent expires and the market exclusivity ends. First generics approved with any of the first three statements will not get market exclusivity.
If objecting to the generic applicant's Type IV Statement, the patentee or a party of interest can file a lawsuit or apply for an administrative ruling by China National Intellectual Property Administration (CNIPA) within 45 days after the Center for Drug Evaluation (CDE) discloses the generic application. The court or CNIPA will rule on whether the technology solution of the generics falls within the protection scope of the corresponding patents.
In the case of a lawsuit / administrative ruling, the patentee or the party of interest shall submit a copy of the on-file/acceptance notice to CDE and notify the generic drug applicant within 15 workdays after the court puts the case on file or CNIPA accepts the appeal.
After CDE receives the copy, NMPA will set a 9-month stay period, during which the generic drug won’t be approved. The stay period can only be initiated for only one time, starting from the date when the case is put on file or the ruling is accepted by CNIPA. During this period, CDE will not stop the technical review of the first abbreviated new drug application (ANDA).
First generics that succeed in challenging the patent will enjoy 12-month market exclusivity. Success in challenging the patent means the applicant should meet both conditions:
1) After the generic drug applicant submits a Type IV Statement, the relevant patent is annulled in reply to the applicant's request;
2) The generic drug succeeds in getting marketing approval.
2.2 Process in the US
In the US, the applicant shall include one of the Paragraph I-IV Certifications in the first generic drug application.
Paragraph I (PI): The patent information has not been listed in the Orange Book;
Paragraph II (PII): The listed patent in the Orange Book has expired;
Paragraph III (PIII): The generic drug will not go to the market until the patent listed in the Orange Book expires;
Paragraph IV (PIV): The patent listed in the Orange Book is invalid, unenforceable, or is not infringed by the generic drug application.
The applicant shall also notify the brand-name drug sponsor and holder of the patent certification. The first generics approved with PI, PII, or PIII certification will not get market exclusivity.
For PIV certification, one possibility is that the sponsor or holder may not initiate litigation and the first generic drug applicant gets FDA approval. The approved drug will be given 180-day market exclusivity.
The other possibility is that the sponsor or holder files an infringement suit against the generic drug applicant within 45 days of the PIV notification. In this case, FDA will postpone the approval for the generic application for 30-month stay period. For the first generic drug that wins the litigation and FDA approval, it will get the 180-day market exclusivity.
3. Comparison Summary
Commonalities and differences of first generic drugs in China and the US are summarized as below:
Comparing First Generic Drug in China and the US
Patents for registration
Chemical drugs (except drug substances): active substance compound, drug recombinant with active substance and medical use.
*NOT including intermediate products, products of metabolism, crystal shapes, methods of preparing and manufacturing the drugs, testing methods, etc.
Chemical drugs: patents for drug substance (active ingredient), drug product (formulation or composition), and/or approved method (usage or indication) of using the approved drug product.
*NOT including patents for manufacturing method of drug substances, intermediates, or products of metabolism.
Whether the original drug has been approved in the market
Irrelevant to the acknowledgement of the first generic drug
Irrelevant to the acknowledgement of the first generic drug
MAH of the first generic drug
The MAH is usually a Chinese company. The draft of Regulations for Implementing the Drug Administration Law requires the MAH and the manufacturer should both be in China or both outside China.
The MAH can be based in any country/region
Patent statement/certification for the first generic drug get market exclusivity
Stay period for the first generic drug application in patent dispute
9 months starting from the date when the case is put on file or the ruling is accepted by CNIPA
30 months starting from the date when brand-name drug sponsor / patent holder brings up an infringement lawsuit against the generic applicant
Market exclusivity for the generic drug with Paragraph IV certification that wins the patent dispute
12 months starting from the approval date
180 days starting from the date when the generic drug goes to the market
Patent dispute resolution mechanism
Both jurisdictional and administrative proceedings can trigger stay period
Only jurisdictional proceedings can trigger stay period while Patent Trial and Appeal Board (PTAB)'s patent invalidation proceedings can't
4. Analysis on Market Exclusivity for First Generic Drug
4.1. The qualification for market exclusivity
China's conditions for market exclusivity are stricter than those in the US.
In China, a generic drug has to be the first that successfully challenges the patent and the first that gets NMPA approval. If a generic drug applicant satisfies only one of the two "firsts", it cannot get market exclusivity.
In the US, the first generic drug with lawfully maintained paragraph IV certification that gets approval can enjoy market exclusivity. If two and more applicants challenge the patent on the same date, all of them will get market exclusivity as long as one of them win the patent dispute.
4.2. The effect of market exclusivity
Both China and the US stipulate that no generic drug of the same kind should be approved during the market exclusivity period of the first generic drug. But the starting date and the length of market exclusivity differ.
In China, market exclusivity starts on the date when the first generic drug gets NMPA approval and lasts for 12 months, which is longer than the 180 days in the US, because the 12 months also includes the time to prepare for commercial launch. Chances are that the patent litigation has not been finished when the 9-month stay ends and NMPA approves the generic drug. In such case, the generic company may launch the drug at the risk of infringing the patent with the purpose of not wasting the market exclusivity starting from the approval.
In the US, even if the first generic drug gets FDA approval, the generic company probably won't seek at-risk launch when the lawsuit is ongoing. This is because the US market exclusivity starts at the date of commercial launch.
4.3. The loss of market exclusivity
China currently has no regulation on annulling market exclusivity. In the US, the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) specifies the six scenarios where first generics will lose market exclusivity.
1) The first generic drug is not commercially launched within 75 days from the date of FDA approval; or the final ruling from the court (subject to the later date);
2) The first generic drug application is withdrawn by the applicant;
3) The paragraph IV certification is changed to other types;
4) The first generic drug does not receive tentative approval;
5) The first generic drug applicant reaches an anti-competition agreement with another generic drug applicant, the brand-name drug's MAH, or the patent holder.
6) The patent expires.
In general, both China and the US try to encourage the development of first generic drugs while protecting legitimate patents. China's patent linkage system has been implemented for more than a year and may need to improve itself, for example, by setting rules for first generic applicants to change patent statements.