Abstract
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However, despite the increase in registrations, long-standing conflicts between drug registration evaluation and pharmaceutical innovation still exist. China's regulators, the pharmaceutical industry, and health economists have all emphasized the need to adjust the existing evaluation strategy for innovative drugs, as well as the evaluation, research, and regulatory approaches for generic drugs, in order to speed up and improve the consistency of evaluation for both traditional medicine and generic medicine. A better-quality and higher-efficiency drug review and approval mechanism will improve China's pharmaceutical management.
The key reform lies in the legal system. After China enacted the Regulations on Drug Administration in 1963, which was the first drug registration approval regulations, drug administration finally began to be more regularized, 2 with the next major benchmark being the promulgation and implementation of the Drug Administration Law of the People's Republic of China in 1985. Since then, the Chinese government has introduced a series of supplementary regulations and notifications, such as the Drug Registration Administration (2002, Trial), and the Drug Registration Regulation (2007). Over time, these provisions have failed to keep up with the development of China's pharmaceutical industry, and the management quality and efficiency of the registration process have been unable to meet industry requirements, which therefore demand urgent amendment. Public comments for Drug Registration Regulation (Revised Draft) (hereinafter referred to as “Revised Draft”) were requested (through the government's legal information website) in February 2014. Whether this amendment can help transform China's drug registration, meet the industry's contemporary development needs, resolve outstanding issues, and balance the interests of all parties, is still an open question.
I. Contents and Its Changes of the Drug Registration Regulation (Revised Draft)
China's Drug Registration Regulation (Revised Draft) was adjusted—as compared to the original edition—in a number of ways, such as: general principles, basic requirements, clinical drug trials, declaration and approval of new drugs, declaration and approval of generic drugs, declaration of non-prescription drugs, supplementary declaration and approval, drug re-registration, and bylaws. All together, nine chapters and 20 articles were involved. They cover the following aspects from two perspectives: to encourage drug innovation and accelerate drug availability.
1. About the basic requirements
Article 18 states that the applicant shall provide descriptions of the patent rights status (in China) of both the applicant and others. Patent disputes are to be resolved in accordance with relevant laws and regulations. Additions were made to the last sentence, i.e., apply the relevant provisions of Patent Law of the People's Republic of China (2008) to deal with matters of drug registration management. Article 19 stipulates that applicants may submit applications for registration for patented drugs in China. State Food and Drug Administration departments shall review the drug in accordance with this Regulation; approve a registration number; and issue a “Import Drug License” or “Pharmaceutical Product Registration Certificate,” which becomes effective after the patent expires. 3 Article 22 confirms that pre-clinical studies of drugs should be carried on by a qualified organization certified by “Quality Management Practices for Non-clinical Drug Studies,” which clarifies that all the drugs must be tested by certified organizations.
Drug registration overlaps with patent law in drug regulation, and thus, the applicable legal rules need to be distinguished. Firstly, Article 18 and 19 of the Revised Draft both mention patents. According to the European and American drug review mechanisms, sufficient time should be set aside for the drug evaluation and oversight authority to review and judge the application, and the applicant needs to submit patent information together as part of the application. Secondly, 4 ICH emphasizes quality, safety, and efficacy as guiding principles in drug evaluation, which agrees with new provisions of the Revised Draft. Thirdly, in view of the excessive regulatory powers of the China Food and Drug Administration (CFDA) and unclear lines of authority, the Revised Draft focuses on services instead of over-regulation, with an eye towards transformation of government functions, which effectively limits the previous, over-expanding power of the CFDA and helps ensure that patent disputes may be settled in court, in accordance with relevant patent laws and regulations. For drugs for which others have obtained Chinese patents, an applicant can submit an application for registration two years before the expiration of the patent. Revised Draft follows the practice of the U.S. Food and Drug Administration (FDA), which means that a patent dispute does not affect drug registration. What should be noted, however, is that in order to avoid patent infringement, companies are entitled to decide launch date of their drugs.
2. About the clinical tests
Article 36 was amended to state that applicants can conduct independent clinical trials by following the standards for clinical tests, or they can entrust a drug testing institute specified in this regulation or a third party with the relevant qualifications. The latest draft amendment proposes that a third-party inspection agency could be commissioned to conduct clinical trials. Article 37, based on the original provisions, adds a clinical trial proposal, as well as related information filing and publicity requirements, all with the purpose of enhancing transparency, public scrutiny, and inquiry.
3. About the registration and approval of new drugs
A normative approach for supplementary application in the drug development process is added to Article 50, and it clarifies the appropriate processing steps for changing applicants, chemicals, and biological products to make adjustments to the application before Phase III clinical trials. Moreover, from the perspective of encouraging the development and registration of new drugs, Article 66 adds: “change dosage form without changing the route of medication, and approved applications for registration of new indications will not be granted with new drug certificate; except for special formulations like targeting preparations, sustained and controlled release.” As for domestic drugs and imported drugs that are processed according to the new drug application procedures, the latest draft requires applicants to first submit a clinical application for registration, and then, after approval, submit another application to put the drug on the market. 5
4. About the registration and approval of generic drugs
Article 75 requires applicants to fill in the “Drug Registration Form.” Articles 77 and 78 are about the procedural requirements for provincial drug supervision and management departments in approval procedures. The latest draft states that the registration applications of six categories of chemicals shall, for the first time, follow the marketing drug registration. For drugs that may be exempt from clinical testing after evaluation, direct entry to the market can be approved. When drugs under registration share the same active ingredients and dosage forms as marketed drugs, but differ in size, they will be handled the same as generic drugs. 6
Generic drugs are relatively less expensive than patented drugs. Therefore, they play a critical role in the government's quest to control or reduce drug prices in order to help citizens afford medical treatment. The current Drug Registration Regulation (2007) has multiple restrictions on the application period for registering generic drugs, stating that “the applicant can only submit the application within two years before the expiry of its patent.” As analytic reports show, the generic drug industry has experienced explosive growth in the past ten years. According to the 2012 report from IMS Health in the United States, global generics' sales showed a continuous increase in 2012, while China's share of sales grew by 27.3%. 7 Large numbers of applications and pending cases, as well as rapid growth more generally, have been the biggest obstacles to marketing generic drugs in China. The two-year time limit specified in the existing Regulation effectively extends (without stating that it does) the drug patent protection period, delaying the market introduction of generic drugs. The importance of the Revised Draft lies in that it deletes the provisions requiring unexpired-patent generic drugs to declare two years before the patent expires.
The Revised Draft's requirements are more in-line with the development needs of generic drugs. However, the Revised Draft has changed the requirement of the current Regulation for on-site inspection of the production of generic drugs before approving clinical trials. On-site production inspection is now delayed to “after clinical trials and technical reviews, but before the marketing of the drugs.” In practice, prior to the results of human bioequivalence test (BE) of the generic drugs and original ground drugs, the prescription process for generic drugs cannot be finalized (since if proved not equivalent, further adjustments or re-development would be needed), resulting in a waste of resources, low efficiency, and poor inspection quality. Meanwhile, under the premise of an imperfect quality control system, bioequivalence studies are disjointed, with the technical review and drug good manufacturing practice (GMP) inspections not being truly adequate. A proposed adjustment to the Revised Draft is based on the approach of combining the technical evaluation and production-site inspection, ensuring that production-site inspection joins the process of pharmacy review done after the bioequivalence tests, which will improve the efficiency and quality of on-site inspections while helping to reduce unnecessary multiple inspections of the applicants.
In addition, there is serious mismatch between the resources available for generic drug inspection and the demand for inspections, which means insufficient funds, too-few staff on the payroll, and an overly heavy workload. In 2012, the United States introduced a new Generic Drug User Fee Amendments (GDUFA) bill, stipulating that Abbreviated New Drug Application (ANDA) applications would account for 30% of GDUFA each financial year, for both domestic and foreign companies involved in supplying generics. 8 As this principle is based on payment, it improves the access threshold and application quality. The current status of China's industry tends to accelerate the marketing of generics and allocates the limited resources to generic drugs of higher clinical value and/or meeting urgent clinical needs, in order to address public drug availability and affordability problems.
5. About supplementary application and approval
Article 116 specifies that supplementary applications for the production process that affect drug quality are to be submitted to the CFDA for approval. The intention is to meet the relevant requirements of ICH; after China joined the World Trade Organization (WTO), a need arose to achieve effective uniformity in technical requirements and forms in the field of drug registration. Taking into consideration the medication's safety and effectiveness while applying the drug evaluation mechanism unified by ICH to drug registration in China, will improve the efficiency of China's drug registration management, shorten the approval time for new drugs, reduce drug development costs, and promote China's international medical trade.
The current Regulation does not contain specific provisions for changing applicants during the clinical trial period for new drugs, which may have an impact on new drug development. The Revised Draft has amended Article 50 to include a normative approach to deal with supplementary applications, in order to handle the issue of changing applicants during clinical trials due to changed prescriptions, techniques, production sites, and/or approval document holders. If applicants must be changed during new drugs clinical trials, or changes need to be made to the production process, prescription, specifications, and/or production before Phase III clinical trials, a supplementary application form can be submitted together with relevant proof and research materials. For changes in the preparation process or specification of Chinese medicine, applicants should follow the “Supplementary Provisions on Registration and Management of Traditional Chinese Medicine.” This adjustment, from a normative point of view, eliminates obstacles in drug development and marketing procedures, enhancing efficiency in applications.
6. About drug re-registration
If the drugs to be re-registered fail to meet the examination requirements, the Provincial Drug Administration (PDA) must report to the State Food and Drug Administration (SFDA). This provision emphasizes two points: the sharing mechanism; and that SFDA is specified as the regulatory authority, in order to ensure the quality of re-registration.
II. Future Trends Analysis of the Drug Registration Regulation
Aiming at continuous improvements in evaluation efficiency, quality, and scientific basis, China's Center for Drug Evaluation focuses on meeting the clinical needs of the pharmaceutical industry while enhancing the availability and affordability of medicine for the public. Future trends for China's drug evaluation are to further strengthen innovative drug evaluation, continue to explore the evaluation and management of generic drugs, strengthen information disclosure and communication, and constantly improve the quality assurance system.
China's medicine industry has grown rapidly, but patent issues during drug registration are becoming serious. It is therefore imperative to learn from (and, as applicable, introduce) foreign policies in dealing with such issues. Since the patent linkage system in the United States and Canada is more mature and established than that in China, both jurisdictions can teach lessons to China.
The provisions from Article 18 and 19 in the current Regulation constitute the preliminary drug linkage system in China. Article 19 from the Revised Draft deleted the requirement to “apply for registration within 2 years prior to the patent expiration,” reduced unpredictability and uncertainty in registration, and protected the interests of registered applicants. Some scholars have advocated learning from the patent rating system specified in the U.S. FDA's Orange Book, requiring original drug applicants to provide supplementary patent information for registration and also establishing information sharing in the registration approval and patent mechanisms, for the protection of both the patent-holders of originator drugs and the legitimate interests of generic drug manufacturers. 9 Other scholars, however, believe that implementing a similar “drug linkage system” may lead to excessive patent protection for foreign drugs and may also delay the marketing of generic drugs, which could hinder Chinese citizens' timely access to medicines and health benefits. 10 The Revised Draft has made changes and adjustments for practical issues, and other changes are still under discussion. China's current patent linkage system is another form of evaluation, by which CFDA conducts evaluations through patents and the ownership status of the drugs to be registered, evading examination by a no-infringement statement. Possible future trends of China's Drug Administration include no longer being involved in judging whether the drugs to be registered are infringing patents or whether the patents are valid, which means canceling the Administration's relevant judicial and administrative functions.
Drug review forms an important link between drug research and marketing, and is essential for the healthy development of the pharmaceutical industry. Taking into account the current status of drug examination in China and the unreasonable system and mechanism that cause a backlog of cases, there is clearly an urgent need to speed up the examination process. In practice, the workforce and technical reserves of China's drug evaluation center are not sufficient enough to deal with over 7,000 applications each year. For example, in 2013 alone, China Center for Drug Evaluation handled 7,529 new registration applications (as counted by registration numbers). 11 Although the new drug examination institutes can be focused on the task and thereby reduce the backlog, simply throwing more resources (in this form) at the problem is not a viable long-term strategy. Rather, to comprehensively address this challenge, in the future, it will be necessary to center around clinical needs and industry demand; optimize resource allocation; and regularize examination fees, all with the purpose of improving both the quality and efficiency of the drug approval management system.
Referring to the U.S. FDA and the EU approach, if a pharmaceutics preparation is not approved as a new drug, then its raw material drug production should not be allowed. The goal is to reduce the time and resource cost of repeated review of the drug substance. If the enterprise files for registration again, it only needs to approve production of the preparation at the same time as approving production of the drug, which will accelerate drug review.
The global pharmaceutical sector is dominated by generic drugs, but the development of the generic drug industry in China is hindered by imperfect regulations, delaying generic drugs introduction to the market. Imperfect regulations mean the system of “two evaluations for one registration.” The current Revised Draft still has not changed this element, retaining the requirements for generic drugs to be approved before carrying out the bioequivalence tests; however, in practice, the security review mechanism has effectively ruled out the risk of human trials, thus providing little reason for a subsequent drug review.
In addition, the generic drug registration process is divided into two stages of review and evaluation, which not only undermines the integrity of drug development, but also delays the market introduction of new drugs. In comparison, U.S. clinical trials for generics adopt a “filing system” approach. Mandating only “one evaluation for one registration” not only saves time by combining on-site inspection with technical review and GMP inspection to optimize the prescription process for generic drugs, but also enhances the efficiency of generic drug access. With the discussions about the Revised Draft and reform for generics sector, some scholars believe the Chinese government should guarantee the availability of health insurance and basic medical care 12 among AA hospitals and AAA hospitals in addition to primary health care institutions, encouraging them to increase generics coverage when bidding and purchasing. 13
Conclusion
Aimed at improving the evaluation quality and efficiency, China's Drug Registration Regulation (Revised Draft) has not been officially issued, but it can be inferred that amendments involving clinical tests, registration and approval of new drugs, registration and approval of generic drugs, registration of non-prescription drugs, registration and approval of supplementary application, and new regulations will be applied in the new round of drug registration management—such as the possibility of changing applications of new drugs during clinical trials, removing the relevant restrictions on generic drugs, and reforming patent regulations and policies. While learning from successful foreign experiences and enhancing its own established system, drug registration management in China needs to pay close attention to the supervision of traditional medicine and ethnic medicine, promote the re-evaluation of vaccination regulation, and improve consistency in generic drug evaluation.