Regulatory Trends in China's Pharmaceutical Market
OVERVIEW OF THE CHINESE PHARMACEUTICAL MARKET
China's pharmaceutical market has expanded dramatically in the past twenty years, averaging between 18 - 20% growth, significantly higher than US and European growth during that period (7 - 9%). Pharmaceutical imports have been growing at 20% since the early 1990s and currently exceed $930 million. The total pharmaceutical market is expected to grow to $23 billion by the year 2000, to become the world's largest pharmaceutical market by 2020.
These projections ignore, however, factors that interfere with Western pharmaceutical companies' chances for profit. Foreign companies' profit margins have significantly dropped from the previous five to ten years, when they were enjoying 20% sales growth and quick returns. Greater foreign and domestic competition, added to a regulatory system protective of domestic producers, has yielded an environment of limited profits to most foreign companies. New laws ban foreign-produced versions of drugs already sold in China by domestic manufacturers, allowing foreign pharmaceutical manufacturers to sell only "unique" drugs. To sidestep this law, foreign companies must enter joint partnerships with domestic ventures and manufacturers. There are now 1,800 such foreign-invested enterprises (FIEs) in the Chinese pharmaceutical market, while in the late 1980s only a dozen such partnerships existed.
The Chinese government is attempting to address foreign companies' concerns with new regulations. This year, the Chinese government decided to reorganize the monitoring and approval structure for pharmaceuticals, laying the foundation for future reforms in the pharmaceutical industry. It is important for these companies to stay informed of new market changes and regulatory reforms, many of which will affect how they do business in China.
Because China's transition to the new system remains incomplete, several problems have occurred. For example, there is a backlog in the regulatory system because of some uncertainty over which agencies are responsible for monitoring and approving certain drugs, while the staff reduction in regulatory agencies' has delayed the review of some drug applications and clinical data. In addition, the government has still not decided how to restructure the pharmaceutical regulatory system at the provincial and local levels. Although many of these local branches' regulations are very different from the central agency's, they have shown resistance to ceding their power to the central government. China's size means that it will take time for reforms to reach the lower levels of government – and some have questioned whether a unified regulatory system is even possible in a country as large and diverse as China. The government hopes central reorganization to be complete by the end of 1998.
CONSOLIDATING THE SYSTEM: THE STATE DRUG ADMINISTRATION
Two agencies previously controlled China's pharmaceutical regulatory system: 1) the Bureau of Drug Policy Administration (BDPA), and 2) the State Pharmaceutical Administration of China (SPAC).
The BDPA, an agency of the Ministry of Public Health (MOPH), filled a function similar to that of the U.S. FDA, and enforced Chinese pharmaceutical law. The BDPA's duties included implementing China's Drug Administration Act, and regulating pharmaceutical manufacturing, distribution, sale, and advertising. In addition, it approved domestic and imported drugs and biologics, and formulated and issued national drug standards.
The BDPA's jurisdiction included the National Institute for Control of Pharmaceutical and Biological Products (NICPBP), the highest authority for pharmaceutical quality control in China. Also under the BDPA's aegis, though technically an outside agency, was the Center for Drug Evaluation, responsible for many important features of the regulatory process. It conducted technical review for applications, convened and coordinated advisory evaluation committee meetings, and developed technical and scientific guidelines for drug development.
The SPAC, created in 1978 as an MOPH daughter agency, oversaw all activities relating to pharmaceutical R&D, manufacturing, sale, and distribution. Its influence waned as China began allowing private companies to control their own affairs, a policy that became a source of tension between the SPAC and the BDPA. Since 1993, the SPAC's duties have been limited to reviewing and approving the administrative protection of pharmaceutical products.
The Chinese government established the new State Drug Administration (SDA) in March 1998, to consolidate the SPAC, BDPA, and the State Administration of Traditional Chinese Medicine (SATCM; similar to SPAC but only responsible for regulating traditional Chinese medicine). By consolidating law enforcement and inspection activities, eliminating functional overlap in different agencies, and separating control over the regulatory and business operations in the pharmaceutical industry, the SDA centralized and streamlined regulatory authority. In the new organizational structure the SDA has replaced the SPAC and BDPA, and operates alongside the SATCM (now an MOPH agency) to regulate all drugs entering the Chinese market.
The SDA will have a total of about 120 employees, 60% taken from the SPAC, 20% from the SATCM, and all of the BDPA's 20 employees. The new agency will regulate and supervise the research, registration, production, market circulation/advertising, and use of the following medical products:
• Chemical drugs and antibiotics
• Traditional Chinese medicine and preparations
• Biological products
• Biochemical drugs
• Diagnostic products
• Medical devices and material
• Medical packaging material
The SDA's Director General, Mr. Zheng Xiaoyu, is the former head of the SPAC; former head of the BDPA, Mr. Shao Mingli, and former SATCM second deputy head Mr. Ren Dequan are slated to fill two of the four Deputy Director General positions.
The SDA's Department of Drug Registration is in charge of registering new drugs, biologics, generics, and imported drugs. It also issues drug standards, approves new drug clinical trials, controls "special drugs" (i.e. narcotics and radiopharmaceuticals), performs "drug re-evaluation" (although the government has not yet defined what this involves), and gives guidance to the nation's drug control institutes. The department is expected to have four divisions set up by product type: The Division of Chemical Drugs, Division of Traditional Chinese Medicine, Division of Biologics, and Division of Special Drugs. BDPA's Center for Drug Evaluation and NICPBP are likely to be incorporated under this department as well.
Other departments involved in pharmaceutical regulation include the Department of Safety and Surveillance, the Department of Market Supervision, the Department of International Collaboration, and the Department of Personnel and Education. The Department of Safety and Surveillance is made up of three divisions:
• The Division of Drug Evaluation: responsible for monitoring essential drugs and OTCs, and providing adverse event (AE) surveillance;
• The Division of Drug Research Supervision: qualifies clinical research bases and enforces good laboratory practices (GLP), good clinical practices (GCP), and good manufacturing practices (GMP); and
• The Division of Supervision of Drug Manufacturing: monitors drug manufacturing and grants hospital pharmacy preparation licenses.
The Division of Market Supervision is responsible for pharmaceuticals that have already received approval and are being sold in the Chinese market. It is responsible for the qualification of drug wholesalers and retailers, market regulations of prescription drugs, OTCs, and TCMs (crude and patent preparations); enforcement of Good Marketing Practices, providing licenses for "drug business operations" (both wholesale businesses and pharmacies); drug quality inspection, and approval of drug advertisements. Below the Division of Market Supervision are the Division of Drug Business Operations Supervision, the Division of Market Regulations, and the Division of Inspection.
The Department of International Collaboration oversees international activities, international technology exchange and collaboration, and the administrative protection of pharmaceuticals, all of which are performed by its Division of International Affairs, Division of Drug Administrative Protection, and the Division of International Liaison.
Finally, the Division of Personnel and Education provides personnel management, personnel training, pharmacist qualification examinations, and pharmacist licenses (previously, pharmacists did not require licenses). It is made up of the Division of Government Officials, Division of Personnel in Affiliated Institutions, and the Division of Education.
The pharmaceutical market has opened to foreign companies considerably since the late 1980s, when most of China's pharmaceutical regulations were written. The government plans to address this problem by revising and streamlining its pharmaceutical regulations once the new organizational structure is fully established – meaning that the current regulatory system will remain in place until about the year 2000.
A. Pricing and Reimbursement
Currently, China maintains both a national and provincial set of pharmaceutical reimbursement schedules in state-run hospitals or clinics. The central government has authorized more than 1400 pharmaceuticals to receive reimbursement from state-controlled insurance organizations. Provincial and municipal governments are allowed a 10% "local readjustment" to alter the national reimbursement list.
Most foreign companies have found the reimbursement system to be both tightly regulated and inconsistent. Because the government demands low drug sale prices for an import to be considered for the list, many companies find they do not qualify. Manufacturers often complain, however, that the drugs included on the national list are not all consistent with regulations, and hint that the process may in part be more negotiation than regulation. In addition, provincial and municipal governments' "local adjustment" often produces an almost entirely different system from the central governments'.
In an attempt to sidestep the reimbursement system, many companies enter into joint ventures with local partners, facilitating their involvement in the regulatory approval process and allowing for greater market share. The reimbursement system, however, may only marginally affect market share, as national health insurance only covers about 10 - 15% of the population: government insurance only covers 7 - 8% of the population, and local labor insurance, 13 - 20%.
The central government has also enacted price control measures in the pharmaceutical industry. In addition to placing more price controls on imported drugs in 1997, the government granted high profit margins to innovative drugs: 25 - 30% for Class I drugs, and decreasing profit margins for II, III, IV, and IV, with IV given the least. The system, however, excludes marketing expenses from profit calculations.
B. Pharmaceutical Classification
Under Drug Administration Articles 21 and 22 (July 1985), "new drugs" are those that have never been produced in China before, and for which a new indication, a change in the route of administration, or a change in dosage form is to be adopted. New drugs are classified into five categories:
• Class I: new pharmaceuticals that have not been approved in any country (i.e. new drugs reported but not specified in foreign pharmacopoeia);
• Class II: products currently in process of being approved by a major regulatory agency (i.e. the FDA, European Community, Japanese government) but not specified in foreign pharmacopoeia;
• Class III: preparations made of two or more compounds;
• Class IV: synthetic products of natural compounds, approved drugs, and modified formulas that have long been approved and in use in international markets; and
• Class V: adopted drugs with a new indication.
Please note: these classifications refer only to locally manufactured new drugs; imported drugs as a whole are treated as a separate class.
Currently, no single agency oversees all pharmaceutical cases. The SDA regulates Classes I, II, III, and imported drugs, but provincial governments deal with Classes IV and V. In addition, the government is in the process of creating a legal distinction between prescription drugs and over-the-counter drugs (OTCs). In the past, confusion between the two caused some consumers to obtain prescriptions for OTCs, which has led to prohibitive reimbursement costs for the government.
Two separate regulatory processes exist: one for imported products, and one for locally manufactured products, irrespective of the sales company's location. Both processes require the company to submit a registration data package. For imported drugs, this package replaces the import drug permit required by Chinese regulatory authorities. While similar to the US FDA's requirements, the volume and content of information necessary is significantly less.
The registration data package must include:
• Application form
• Technical data
• Chemistry, manufacturing, standard, and analytic methods, stability, and quality control
• Non-clinical pharmacology and toxicology
• PK/PE, local clinical data
• 3 different batches of samples
• Locally manufactured drugs: 3 batches bulk, 3 batches finished
• Imported drugs: 3 batches final product
• Free sales certificate (for imported drugs)
Most of the documentation, such as the manufacturing methods and non-clinical pharmacology/toxicology data, need only a brief Chinese summary attached to the English version. Increased attention to product quality requires complete translations into Chinese of the standard/analytic methods and stability data.
Under the current system, while Class I product manufacturers may apply to the CDE directly, most other manufacturers need to submit an application to the provincial department of health, which then forwards it to the Center for Drug Evaluation (CDE). A CDE advisory committee performs a full review of the drug, identifies possible deficiencies in the application, and sends them back to the manufacturer for response. Because the CDE may need to communicate with the manufacturer concerning its application, this process may be lengthy. Only after the committee has reviewed the application at one of its biannual meetings does it forward the document to the BDPA. If an investigational new drug (IND) is involved, the BDPA is authorized to make a decision; if a new drug application (NDA) is involved, only the MOPH may decide whether or not to approve the application.
Imported drug applications, however, travel through a different bureaucratic process. The manufacturer must first send the packet of applicant materials to the MOPH's International Cooperation Center, pharmaceutical division. Within this division, the Imported Drug Evaluation (which is comprised of many of the same members in the CDE's review committee for locally manufactured drugs) reviews the application. The committee may order the manufacturer to conduct a local registration/clinical verification study (described in the Clinical Investigation section below). Once the manufacturer has submitted a report on its study to the committee, the BDPA will make the final approval decision.
Currently, the MOPH's regulations for "Western drugs" requires the following to be investigated during the product application process:
• Name of drug, purpose, and reason for selection
• Chemical structure or composition
• Technology and manufacturing conditions
• Quality assessment
• Pharmacodynamic data and literature
• General pharmacological investigations
• Acute toxicity
• Long-term toxicity
• Toxicity of a topical new drug
• Impact of each ingredient on the efficacy or toxicity of a compound preparation
• Mutagenicity tests
• Reproductive toxicity
• Carcinogenicity tests
• Drug dependence data
• Pharmacokinetic investigations on animals
• Preliminary stability tests on drug substances and their singular or compound preparations
• Quality standard of drug used for clinical investigation
• Drug sample
• Clinical investigation plan and pre-clinical review
• Clinical pharmacokinetic investigation
• Bioavailability or dissolution tests
• Stability test results and dates of expiration
• Protocol and remarks of production quality standards
• 3 - 5 sample batches produced in succession with analytic reports
• Clinical reports and summary
• Samples of packaging material, labeling material, and package insert
Regulatory authorities have recognized the need to consolidate and streamline the local registration study. There has been a movement towards a more scientifically based estimation of small sample size, and in some cases, regulatory authorities are becoming more flexible by waiving additional tests for the product if it is in the same therapeutic area as a product that has already been approved. The government is also planning to assign the same evaluation committee members for both imported and locally-manufactured products. Additionally, the government will assign cases randomly to committee members to encourage objectivity, and increase data exchangeability so that drug imports may be used for products manufactured locally. Finally, because China is trying to encourage new drugs – especially Class I drugs – to enter the market, authorities are planning to establish a "special meeting" system to speed up the approval process. In this potential system, the drug's sponsor or CRO could call an additional CDE advisory committee meeting, rather than wait for one of its regular biannual meetings. The sponsor may only call this meeting once the necessary registration information has been submitted, and the sponsor/CRO must pay an average of $20,000 to finance the meeting (to recover the hidden costs paid at the biannual meetings).
D. Clinical Investigation
Although China is beginning to accept foreign clinical data, almost all new drugs entering the country must conduct domestic testing in some form. Currently, Classes I, II and III drugs must undergo Phase I, II and III trials, although some Class III products are exempt from Phase I trials. Some Class IV and V products, and all new imports must be tested through a single-phase clinical verification/local registration study, lasting about 6 - 8 months. After these tests are complete, imported drugs must undergo an initial two-year trial/review, involving periodic comparative studies with locally manufactured products.
Regulatory authorities have set several standards for domestic registration study:
• The study must be comparative, with randomized, double-blind, parallel groups.
• The minimum sample size is usually 60 samples per group (120 total).
• Open-label studies must be evaluated on a case-by-case basis.
• For ethical reasons, active controls over placebos are preferred for the control group.
• Clinical and/or surrogate endpoints should be used for efficacy endpoints, depending on the drug (i.e. blood pressure reduction, intraocular pressure reduction, etc.)
• Data concerning both clinical and laboratory adverse events should be collected at the safety endpoints.
These standards pose several problems to clinical trials. First, they establish a uniform testing requirement without considering drug or disease specifics, nor are they sensitive to ethnic factors in testing. In addition, the requirements for statistical analysis are not well defined, and often involve basic hypothesis testing methods such as the t-test and chi-square test. This lack of statistical standards may result in inconsistent results, especially because investigators who control statistic design and analysis are not required to consult the drug sponsor or an independent statistician. The small sample size requirement does not allow for the statistical power to detect significant, if any, differences in the two test groups. And finally, simple hypothesis testing is inadequate for an active control equivalency trial, and cannot allow investigators to determine population effects, the study's stated intent.
Pharmaceuticals manufactured domestically must undergo a separate clinical trial procedure. Companies planning to manufacture domestically must submit:
• One drug sample that is the exact product the company intends to manufacture;
• Drug stability data; and
• Information stating the drug to be an OTC or a generic prescribed product.
The Chinese government has also attempted to simplify the clinical trial procedure for foreign companies by harmonizing its clinical standards with those accepted internationally. It has begun to increase its acceptance of foreign clinical data, for example, and in March 1998 adopted the Good Clinical Practice (GCP) standards under ICH guidelines. The new GCP standards are intended mainly for drug registration-related clinical trials in China, and comply with the country's existing drug administration laws. About 95% of China's new GCP is currently compatible with ICH; the incompatible 5% is mainly due to procedural differences. The outline of regulations below represent a condensed but similar version of the ICH guidelines (Source: L. Su, RAPS '98):
• General Provisions
• Pre-requisites of the Conduct of a Clinical Trial
• The Rights of Study Subjects
• Clinical Trial Protocol
• Investigator's Responsibilities
• Sponsor's Responsibilities
• Records and Reports
• Data Management and Statistical Analysis
• Handling of Investigational Products
• Quality Assurance
• Multicenter Trials
o Declaration of Helsinki
o Essential Documents
Under China's GCP, health authorities must assign all investigational centers and approve all clinical trials for new drugs. The Chinese government has given permission to 50 - 60 hospitals and medical centers where clinical trials may be held. In addition, each study must be conducted at a minimum of three different sites, and of these, one must be in North China and one in South China. Furthermore, a foreign company may not apply for approval to conduct a clinical trial itself; it must instead determine a Chinese company to apply on its behalf as a sponsor. Finally, appropriate sample sizes will be determined on a case-by-case basis.
Because of the extent to which the government controls clinical trials, companies should also make sure they develop a strong relationship with their principal investigator (PI). Many PIs have a seat on the review committee, granting them power in determining the trial specifications and its duration. Meeting regularly with its PI to discuss data management, and "shadowing" the PI to confirm that the data is handled properly will avoid misinterpretation of local trial results, and thereby hurry the process.
LEGAL REFORM: INTELLECTUAL PROPERTY RIGHTS
Currently, China is revising its intellectual property law to help companies maintain control over their products, such as a proposed law to protect business secrets. Many of these legal reforms affect the pharmaceutical industry, such as China's January 1993 patent law, the first product patent protection made available to pharmaceuticals. Previous to the 1993 patent law, chemicals and pharmaceuticals were only covered by "process protection." Now, patent law offers twenty-year product patent protection, although patent protection is distinguished from administrative protection (granting market exclusivity rights to pharmaceuticals).
Patent applications are submitted to the Patent Bureau, whereas administrative protection applications are submitted to the SDA (previously, SPAC was responsible for handling administrative applications). If patent holders are granted administrative protection, for example, the product will gain 7 1/2 years of market exclusivity (i.e. the SDA will not approve domestic generics during this period). Administrative protection is granted automatically if:
• The product received patents in its country of origin between January 1, 1986 and December 31, 1992;
• The product was not formerly qualified for patent protection under the pre-1993 Chinese patent regulations; and
• The product was not sold on the Chinese market prior to submitting the administrative protection application.
Guaranteed protection is slowly being phased out, however, and foreign companies will soon have to trudge through the application process for the traditional 20-year patent.
Foreign companies without guaranteed administrative protection can combat the long delays with the help of a 1994 loophole in regulations. This loophole permits local companies to manufacture and sell a product before the patent holder receives administrative protection. Foreign companies may use a local company as a proxy, who in turn may register a copy of the product with the MOPH. Because drug patent details are published while administrative protection is in process, illegal copies may easily be manufactured as generics (70% of the Chinese pharmaceutical market).
Currently, local governments – notoriously susceptible to corruption – have the authority to issue manufacturing permits to medical factories and distributors. Proposed policy would transfer this authority to central government agencies, in the hopes of yielding stronger patent protection for domestic and foreign high-tech pharmaceuticals.
The central government will also improve local governments' intellectual property law enforcement, by requiring them to crackdown on companies that lack proper licenses, transfer or lease licenses to drug counterfeiters, or use contractors that fail to meet proper requirements.
Registered product protection is another item on China's legal reform slate. The 1993 Product Quality Law, for example, prohibits producers and sellers from counterfeiting products or falsely applying quality marks to its products, such as certification marks, famous brand marks or marks of excellence. It also prohibits producers and retailers from falsifying the product origin, or using another factory's name and address. Violators face severe punishments and are liable for damages.
Furthermore, China's State Intellectual Property Office (SIPO) is revising patent law to emphasize domestic and international property rights, and benefit new fields, such as microelectronic technology and biological engineering. SIPO expects to receive 100,000 patent applications a year by the year 2000, and expects this figure to increase to 150,000 every year until 2010.
Foreign companies registering products in China should understand the regulatory system and process clearly. Because China's regulatory environment is still in transition, and language and cultural barriers may delay the process, it is important for foreign companies to increase their presence in China, and to build relationships (guanxi) with local medical professionals and government officials. In this way, companies can gain an "insider's view" into the regulatory process, and – because much of the approval process is negotiated (i.e. over whether certain clinical tests are needed) – gain clout to expedite drug approval. China's pharmaceutical market offers vast opportunities for foreign pharmaceutical companies, but requires both a conditioned relationship with the country and a long-term commitment to products not already produced in China.