China's First Generic Methylphenidate Hydrochloride Extended-Release Tablets Launched Amid Chronic Shortages for 23 Million ADHD Patients

Source: China Business Network

Reporter Cao Xueping from China Economic Herald, Hefei Report

After much anticipation, it has finally arrived.

September 2,Hefei Lifeon Pharmaceutial Co．，Ltd．(003020.SZ) announced that its first generic drug, Methylphenidate Hydrochloride Extended-Release Tablets, has officially been launched for sale.

It is reported that Methylphenidate Hydrochloride Sustained-Release Tablets, known as "smart drugs" in China, are psychiatric medications used to treat ADHD (Attention Deficit Hyperactivity Disorder, commonly referred to as "hyperactivity disorder"). In August 2005, the original drug "Concerta" was approved for marketing in China.

In recent years, the demand for extended-release methylphenidate hydrochloride tablets has continued to grow rapidly in the Chinese market. According to statistics from the Pharma Intelligence database, sales in Chinese sample hospitals were approximately 350 million yuan in 2023, and further increased to about 430 million yuan in the first three quarters of 2024. Previously, frequent stockouts of "Concerta" were reported in many hospitals across China.

In 2012, the core patent protection for "Concerta" expired. Why did the first generic version take 13 years to reach the market, given the frequent stockouts of the original drug?

Regarding this, Dr. Chen Jun, R&D Director of Hefei Lifeon Pharmaceutical Co., Ltd., told reporters from the "China Business Journal," "The core technical support for 'Concerta' is the oral osmotic pump-controlled release technology (OROS technology), which itself sets an extremely high barrier for generic production. The company's secretary also stated that there are technical and regulatory barriers for the methylphenidate hydrochloride extended-release tablets, and it is expected that there will not be any competing products of the same variety in China for a relatively long period.

Previously, there was a serious shortage.

In China, "Focalin" is imported, repackaged, and sold by Xian Janssen Pharmaceutical Ltd.

In June 2024, Xian Janssen publicly responded to the shortage of "Concerta," stating: "Methylphenidate Hydrochloride Extended-Release Tablets (Concerta) is an imported and domestically packaged drug by our company, classified as a Schedule I psychotropic substance under national control. The main raw materials for producing Concerta are subject to global regulation. Since 2023, due to various factors, the global demand for Concerta has continued to increase. Although the company plans to supply Concerta throughout 2024, the expected global demand will exceed the company’s production capacity. In the global supply plan, China has always been a prioritized market. Compared with 2023, the demand in the Chinese market this year has significantly increased. Despite the company increasing its supply, it still faces supply pressures and challenges. To alleviate the supply shortage, the company has planned to transfer the packaging process of Concerta for the Chinese market from overseas factories to the Xi'an factory to accelerate the supply speed in China."

However, the shortage of "Focalin" has not seen significant improvement.

In the past year, the Department of Developmental Behavioral Pediatrics and Child Health at Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine has issued four notices regarding the temporary suspension of "Concerta 18mg/36mg," while the Psychiatry Department of Beijing Children's Hospital has issued over five notices about shortages of certain specifications of "Concerta," with the latest notice released on June 14 this year.

In fact, behind the frequent shortages of "Concerta", there are tens of millions of ADHD patients in China.

According to the "Pediatric Expert Consensus on the Early Recognition, Standardized Diagnosis, and Treatment of Attention Deficit Hyperactivity Disorder (2020)," the prevalence rate of ADHD among children and adolescents in China is approximately 6.26%, corresponding to about 23 million patients.

Why is it difficult to replicate?

According to Chen Jun's introduction, the formulation structure of "Concerta" can be described as a "micro precision instrument." It is a capsule-shaped tablet with a diameter of less than 5.5 millimeters and a length of only 12 millimeters. Inside, it contains a three-layer core consisting of two drug-containing layers and a push layer, along with multiple layers such as an isolation layer, a controlled-release membrane coating, and an immediate-release drug-containing layer. The controlled-release membrane is a non-dissolvable semipermeable membrane that requires laser drilling to achieve precise drug release. The core purpose of this structural design is to simulate the drug release curve of a conventional immediate-release agent taken three times daily – after administration, the immediate-release layer quickly releases the drug for rapid onset, followed by sequential slow release from the low-concentration drug reservoir layer and high-concentration drug reservoir layer. The blood drug concentration achieves a small initial peak, then stabilizes or slightly decreases during a plateau phase, before gradually increasing again after 6-7 hours to reach a higher peak. This avoids the decline in efficacy caused by acute drug tolerance due to continuous release and compensates for later-stage efficacy through a higher blood drug concentration.

Chen Jun stated that this technology is based on the combination of multiple processes, such as the separate preparation of three types of particles, three-layer tablet pressing, various functional coatings, and laser drilling. Each process must be precisely controlled to ensure the coordination between upstream and downstream processes and the compatibility of the final product. Any minor issue will affect the product quality and cause it to fail inspection. During the development process, not only is repeated optimization of each process required, but long-term accumulation of production experience and adaptive modification of key equipment are also essential. "The success Lifeon Pharmaceutical enjoys today is due to nearly 20 years of industrial technical experience accumulation in the field of osmotic pump technology."

In Chen Jun's view, the special formulation structure and complex production process of "Concerta" have led to high barriers for generic replication, but the core issue lies in the extreme sensitivity of the efficacy of methylphenidate hydrochloride to the drug release characteristics of the formulation. For instance, the FDA had previously approved extended-release formulations containing methylphenidate hydrochloride, but clinical feedback indicated reduced efficacy, revealing the issue of "acute tolerance." A more unique background involves two companies whose generic versions of "Concerta" were once approved by the FDA, but after being marketed, reports emerged from patients about insufficient efficacy. This prompted the FDA to initiate an investigation. Ultimately, through pharmacokinetic comparisons and clinical efficacy trials, the FDA re-examined the relationship between the pharmacokinetics and clinical efficacy of "Concerta," concluding that the generic drugs were not clinically equivalent to the original drug, leading to the swift revocation of their approval. The original drug employs a unique drug release curve design, allowing for a rapid onset of action followed by a "recovery period" during which the concentration in the patient’s body decreases, thereby restoring the brain's ability to secrete catecholamines. Subsequently, the concentration increases again, ensuring efficacy throughout the day.

"In the pharmacokinetic comparative trial with 'Concerta', we not only provided the commonly required statistical test results for bioequivalence, such as time to peak concentration, maximum plasma concentration, and absorption, but also divided the critical period of drug action from 0 to 12 hours into three time periods that best reflect the in vivo pharmacokinetic characteristics. We separately demonstrated the bioequivalence statistical test results for these three periods, scientifically and rigorously proving the consistency between the two, ultimately gaining marketing approval from the National Medical Products Administration," introduced Chen Jun.

(Edited by Zhang Jiazhen, Reviewed by Tong Haihua, Proofread by Yan Jingning)