LI Yan-ru, TIAN Li-juan

(School of Business Administration, Shenyang Pharmaceutical University, Shenyang 110016, China)

Biosimilars: Current Status and Countermeasures

LI Yan-ru, TIAN Li-juan

(School of Business Administration, Shenyang Pharmaceutical University, Shenyang 110016, China)

Objective To study the current status of biosimilars, and to explore strategies for the healthy development of biosimilars in China. Methods Literature review was conducted to summarize the status of biosimilars both at home and abroad. Results and Conclusion The development of biosimilars in China is not yet mature compared with the advanced countries. Support from both companies and the state is needed to promote the development of biosimilars in China.

biosimilar; current status; development strategy

Biologics (biological) refer to active substances that are produced from the living body tissue or cells such as bacteria, yeast, animal or human cells[1]. Biosimilars are biological products that are similar in quality, safety and eff i cacy to the approved biologics[2].

Since our first recombinant protein drugs-recombinant human interferon α1b was produced in 1989, the development and production of biosimilars have had a long history. Recently, due to a large number of biological drugs patent is about to expire, global biosimilar development is booming. However, because of the immunogenicity of biological drugs and some other unique characteristics, many adverse reactions might occur when the patients take the biosimilars, So in the process of the development of biosimilars, it is necessary to grasp the opportunities and meet the challenges as well.

1 Opportunities and challenges of Biosimilar development

1.1 Biopharmaceuticals occupy an important position in the f i eld of medical and biosimilars development is promising

According to the U.S. magazine Genetic Engineering & Biotechnology News, GEN published in 2012, I sorted out seven biologics among the top 20 drugs from the world’s bestselling prescription drug ranking, see Table 1.

As shown above, biologics have a large sales proportion in the drug market. Biological drugs have pharmacological activity and small toxicity and they are widely used to treat a variety of desses such as cancer, coronary heart disease, blood disorders and diabetes. They occupy an important position in the f i eld of medicine.

In recent years, a number of biological drug patents are about to expire (as shown the Table 2) and it leaves a huge prof i t margins for the development of biosimilars.

1.2 The complex structure of biological agents increases the occurrence of adverse drug reactions

In 2012, British media pointed out that Roche was suspected of concealing eight drugs adverse reactions, including five in sales in China. There were four kinds of biological drugs among the f i ve, including Herceptin, MabThera, Pegasys and Avastin[4]. Among these drugs, Avastin was approved in China in 2010，and the other three were approved in 2003. There were still some serious adverse reactions though the drugs have been tested many times. We can conclude that the danger of biological drugs on the human body needs a longer period of time to evaluate. In the process of using biosimilars, the quality difference between the original biological drugs and biosimilars might be demonstrated after a long period of clinical applications which further increases the difficulty of risk control.

The difficulties in the development of biosimilar lie in its own particularity and imitation process. Not like generic drugs, the quality of biosimilar depends on production process. Biological drugs have unique multidimensional protein structure and they are very unstable, and the stability of the non-covalent bond is easily broken by external factors, suchas heating, extending shelf life, an organic solvent, oxygen, PH variations etc. They all can cause changes in the protein structure[5]. Biosimilars are different from chemical generics in that their production process is complex. Each biologics production process is unique and different manufacturing process will produce a different product. The slight differences, such as the adhesion of inclusions on the active ingredient in the production process will affect the efficacy and safety of biosimilar[6].

Table 1 Top 20 biopharmaceuticals in 2012 global sales (prescription drugs)[3]

Table 2 Biopharmaceuticals will come off patent

In addition to the factors mentioned above, immunogenicity in production process is the most critical factor that can lead to adverse reactions. Immunogenicity refers to the ability of a particular substance to stimulate an immune response in the human body which can affect the eff i cacy of biosimilars. Almost all biological drugs can provoke antibodies[7]. The harmful immunogenicity can be manifested in two aspects, one is the drug allergies and the other is drug-resistant immune response which results in changes in the biological properties of vivo pharmacokinetic, pharmacodynamic and other aspects of toxicity. Therefore, we should try to reduce the immunogenicity in the production process.

2 The relevant provisions on biosimilars in Europe and America

2.1 EMEA biosimilar related bills

EU issued the f i rst biosimilars guidance and it introduced a draft in the area of growth hormone and insulin in1998. It enacted the legal provisions in 2003 and promulgated the Biosimilar Draft Guideline in 2005. It had enacted guidelines of nine segments from 2006 to 2010. EMA has approved 14 permit listed companies biosimilars by March 2011[8].

In 2006, EU issued technical guidelines on the quality research of biosimilars, including the production process and quality research[9]. The guideline includes two aspects: Guideline on biosimilar products containing biotechnologyderived proteins as active substance which was mainly about specific quality requirements for biosimilars and highlighted the requirements for production process, analytical methods, physical and chemical properties. Guideline on preclinical and clinical research of biosimilar products contains biotechnologyderived proteins as active substance which was mainly about the preclinical and clinical testing requirements. Preclinical studies included drug toxicology evaluation. Clinical studies included pharmacokinetics, pharmacodynamics, efficacy and safety, focusing on the immunogenicity evaluation of the drug.

2.2 FDA biosimilar related bills

2.2.1 Biosimilars draft guidance

On February 9, 2012, FDA issued Biosimilars Draft Guidance which consisted of three aspects: First, scientific evidence in demonstrating biosimilarity to a reference product, it was a method used by FDA to assess the submitted data and information and to determine whether the biosimilar was similar to the reference products. Second was the quality proof in demonstrating biosimilarity to a reference protein product. It was used to evaluate quality similarity between biosimilarand the reference product. Third were problems of biosimilars. FDA provided answers to the problems which might arise during research and development of biosimilars in the Implementation of the Biologics Price Competition and Innovation Act in 2009[10].

2.2.2 Biosimilar user-fee act

In 1992, the U.S. congress established a system for enterprises to pay fees for new drugs and biologics license application (prescription drug user fee, PDUFA)[11]. PDUFA should be awarded the legal effect every five years. Last updated PDUFA bill made it clear from October 2012 to September 2017 FDA should charge a fee from biological companies for a drug review according to the Biosimilar user-fee in order to promote public health and safety administration[12].

The role of the Biosomilar user-fee Act on biosimilar circulation regulation is to provide funding support for the FDA review of biosimilar drugs. The United States has numerous generic drugs and it stipulated 180 days exclusivity period for first generic drugs. However, with the rapid development of generic drugs, the pressure on the review increases. In order to alleviate pressure on the review of drugs while ensuring the safety of biosimilar, FDA charged a fee from companies. To ensure the participation of the United States Biosimilars supply companies to comply with quality standards, FDA conducted a pharmaceutical manufacturing practices (cGMP) on-site inspection every two years for domestic and foreign enterprises. At the same time, biosimilars production process was rigorously reviewed to minimize adverse effects.

3 Status and strategies of biosimilars in China

In recent years, the biopharmaceutical industry in China has maintained a rapid growth. According to the NDRC data, the output value of bio-pharmaceutical manufacturing industry in China reached 159.21 billion Yuan in 2011, an increase of 23.5%. Most of our biological drugs are biosimilars, although the overall development of the industry is quick, there are still many problems.

3.1 Main problems for the biosimilar development in China

3.1.1 Biopharmaceutical companies have weak technology innovation foundation

Technological innovation is the core for biosimilar development. Companies should try to complete the change from imitation to innovation on the basis of improving the similarity between the original drugs and biosimilars. But at present, among the industrialized 21 kinds of genetic engineering drugs and vaccines in China, only three kinds have intellectual property rights and the rest are tracking imitation of foreign products. This is mainly due to low development investment in R&D leading to the weak foundation for the development of biosimilars. We still have a long way to go to catch up with the world level on technological innovation.

3.1.2 Low industry concentration for biological drug company, severe small-scale duplication of investment

The overall scale of China’s biological companies is small and enterprises can’t compete against the international companies. Biological companies are facing the problems of small scale, low industry concentration and serious product homogeneity. In recent years, with more biological drug patents becoming expired, a host of companies simultaneously choose the same reference monoclonal antibody drugs to imitate. This repeated investment of small scale domestic enterprises cause a huge waste of resources, which results in the low prof i t margins for biosimilars. It is diff i cult for enterprise to form a patented product. Once the market changes, companies will be unable to cope with the f i erce competition in such a situation.

3.1.3 Biological enterprises weak anti-risk capability

As the high-tech industry, the initial investment for biosimilars is relatively high. It has long product development cycles and larger risk. But the scale of China’s biological companies mostly is small and medium, and their single financing channel leads to the shortage of fund for R&D. As a result, they can not have the big market share, and the lowlevel repetition and low prof i t make it diff i cult for enterprises to develop.

3.1.4 Lacks of a clear policy

There are no relevant definitions about biosimilars in China; the 2007 edition of “Drug Registration” Article XII declared that biologics drug application should be in accordance with the new drug application. Our “Twelfth Five-Year Plan”proposed to focus on the development of the biological industry in China, but we still do not have the relevant def i nition of biosimilars, nor related f i les. The development of national policies and regulations is the guide for industry; the government should make relevant provisions of biosimilars as soon as possible so that enterprises can better develop.

3.2 Strategies for the development of biosimilars

3.2.1 Strategies for biological enterprises

Biological companies should actively expand f i nancing channels and strengthen cooperation with research institutions to have source of innovation. At the same time, enterprises can have appropriate restructuring plan to enhance the competitiveness. Among them, the key point is to improve the similarity between biosimilar and reference product. The current development strategy of biosimilars should focus on the following three aspects: Post-transcriptional modif i cation, the three-dimensional structure and protein aggregates. For post-transcriptional modification, LC-MS-NMR (liquid chromatography-mass spectrometry-nuclear magnetic resonance spectroscopy) technology has a good prospect in the future. For the three-dimensional structure, YunQiao enterprise developed matrix protein conformation ELISA technique (PCA-ELISA) system which could have a sensitive and rapid analysis of three-dimensional conformation of protein drugs at the molecular level[13]. Protein aggregation is the main reason for the enhanced immunogenicity. Therefore, reducing the amount of protein aggregates becomes the main way to reduce the immunogenicity. We usually monitor the f i nished product purity and polymer level with molecular exclusion (SEC -HPLC) and high performance liquid chromatography, sodium dodecyl sulfate-polyacrylamide gel (SDS-page)/SDS-capillary electrophoresis (CE-SDS) during the production process, and reduce its immunogenicity[14].

3.2.2 Government should strengthen support for the development of biosimilars

Due to the long development process and high output of biosimilar, government should intensify support for biosimilars. First, it should make clear plan of biosimilar development and formulate specific regulations to speed up the approval. We can learn from Europe and America to enact regulations and guidelines for biosimilar and establish a specialized drug approval system. Second, the standard threshold should be improved to prevent biosimilars “blowout” phenomenon. Relevant departments can get the original research product of foreign patent expiration in advance and establish a test method to detect different products and corresponding reference materials.

China, as a big country of generic drugs, is facing a good opportunity to develop biosimilars. If the guideline principles of biosimilar could be enacted soon, biosimilars industry will certainly achieve major breakthroughs in the future.

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Author’s information: TIAN Li-juan, Professor. Major research area: Social pharmacy. Tel: 15840095857, E-mail: tianlijuan_8 @126.com