Scrip Regulatory Affairs

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1 China has made the largest modification to date of its regulations governing medical devices 1-3. The new regulations, which were issued on 31 March and are scheduled for implementation on 1 June, will introduce numerous changes that will impact both foreign and domestic device manufacturers. The new rules, which modify device regulations that were published in 2000, contain 80 articles. A number of new provisions tighten up requirements for device makers. Overall, however, they promise a clearer and faster path to market for many products and companies. At the same time as these new regulations are going into effect, China s Standardization Administration (SAC) is actively revising 600 national and industry standards, which will be completed by the end of Regulatory changes and revisions occur frequently in China and can make market entry a moving target. Nevertheless, substantial opportunities will continue to exist in the Chinese medical device market. Keeping up to speed with the shifting regulatory landscape for medical devices is key to gaining market entry. This article discusses China s device registration process. It explores new and coming regulatory changes and explains which strategies medical device companies should consider for a smooth entry in China. A burgeoning healthcare market China s burgeoning healthcare market is now the third-largest globally, up from the tenthlargest in 2009, and healthcare spending in the country is projected to grow to $1 trillion by China s robust year-on-year growth is being driven by factors such as the country s rapidly rising GDP, government initiatives that include healthcare coverage for 100% of China s 1.3 billion citizens, and an aging population for whom there are insufficient caregivers. The government s coverage goal has largely been met, at least in urban areas, and a shift in focus from coverage to quality of care is underway, including raising patient reimbursement rates (goal of 75% for inpatient procedures) and minimizing differences in quality between urban and rural healthcare systems. Medical device registration in China There are three broad medical device classifications in China: implantables, disposables, and active products. Only medical devices that are approved by the China Food and Drug Administration (CFDA) and put in the appropriate pricing formula can get reimbursed under medical insurance coverage. The reimbursement pricing process is local and involves the following three steps: 1. the distributor/manufacturer submits an application for a retail price; 2. pricing codes and recommended pricing are determined by the local medical device association (often retired CFDA and Ministry of Health employees), 3. the local medical device association gives recommendations to the local pricing bureau for a final decision. The reimbursement pricing process takes an average of days. The larger cities eg Beijing, Shanghai, Guangzhou tend to follow similar reimbursement schemes. To gain access to these reimbursement pathways you must first register your product and obtain approval from the CFDA s Center for Medical Device Evaluation. The number of guidances relevant to the product registration process has grown rapidly since the first regulations were released in There are currently over 70 registration guidelines and updates/additions are frequent. Today, domestic Class I devices (safety and effectiveness is ensured through routine administration) are registered through the local municipal department, domestic Class II devices (further control is required to ensure safety and effectiveness) are registered through provincial and municipal authorities, and domestic Class III (implantables, life support devices, and devices carrying potential safety risk) are registered through the CFDA at the national level. Foreign products of any class must be registered through the CFDA at the national level. Several documents are required for submission, and a working checklist would include, but is not limited to, the documents listed below. As a rule, country of origin requirements must be followed for specific documents. Authorization of registration EC certification - Quality System ISO (European company) CE certification of product and declaration of conformity (European company) US Food and Drug Administration 510K clearance and certificate to foreign government (US company) Focus on China Strategies for registering and testing medical devices under China s new rules Cindy Hu, Shawn Shorrock, Yuling Hu and Seth J Goldenberg discuss sweeping new regulations for medical devices in China and explain what manufacturers can do to ensure a successful entry in the Chinese market. Entrust letter of technical standard and declaration of consistency of technical standards Authentication statement (User guide) User manuals Testing reports Statement of testing for typical sample selection Letter of quality guarantee Authorization of the agent Letter of after-sale service authorization Declaration of authenticity Certification of after-sales company business license Guarantee letter from agent (registration) Guarantee letter from after-sales agent Statement of submission for applicator Declaration of clinical trial report The key steps involved in product registration, along with a best-case timeline under the current regulations, are shown in Table 1. However, extended registration timelines are common (eg 6-12 months for Class I, months for Class II, months for Class III) and the regulatory situation is very dynamic, with frequent regulatory changes. In vitro diagnostics In vitro diagnostics (ie tests/devices that can detect infections, diseases, or conditions) have additional requirements, such as mandatory in-china clinical trials at two to three CFDAapproved sites in which at least 1,000 cases and comparison to approved products (if appropriate) are required. The CFDA will also require an audit of quality systems and type testing with separate registration of the device and reagents. All testing must be done on three separate batches of reagents. Not including the clinical trials, this process can take 18 months. The current main guidelines for IVDs in China are: In Vitro Diagnostics Reagent Registration and Management Method (Interim), SFDA No 229, 19 April,2007; Requirements for the Format of Application Documents in IVD Reagent Registration, SFDA No 609, 30 September 2007; In Vitro Diagnosis Reagent Clinical Study Technical Guidance, SFDA No 240, 28 April 2007; and In Vitro Diagnostics Reagent User s Manual Drafting Guidance, SFDA No 240, 28 April Informa UK Ltd April

2 Table 1. Sample product registration steps & timeline Key Steps Class I (working days) Class II/III (working days) Draft product specification/standard Test sample ready N/A Performance test N/A Submission preparation 5 5 CFDA submission 5 5 Evaluation in queue Supplemental notice issued Wait for second review completed Center for Medical Device Evaluation approval & transfer to CFDA Strategies for success in medical device testing Testing standards As part of the registration process, device manufacturers are required to write standards specific to their product (see Table 1) and then file for validation testing by the CFDA. It is critical to carefully follow existing testing standards in creating your Draft product specification/ standard document, based on both national standards (GB; eg GB ) and industry standards (YY). Additional national or industry standards are, in many cases, designated as recommended standards (YY/T or GB/T). Company-drafted product standards are designated with YZB and are confidential, but are referenced in the CFDA database. GB national standards are based on, but not equivalent to, global ISO standards (with some divergences). A careful understanding of the differences between these standards is important. For example, Risk Assessments and Chemical Characterization as defined by ISO :2009 are not generally interpreted in China the same way as they are by other international regulatory bodies. A checklist approach still trumps testing plans based on characterization of your raw materials, but progressive raw material suppliers in China actively work with the testing labs to support finished-product device manufacturers. Note that a test plan based on risk, which leverages characterization or risk assessments, will not be successful if key tests are excluded. An experienced local representative is crucial to testing success. A thorough gap analysis of the testing standards should be undertaken early on in the process, even during initial testing for the US or European markets. For example, Chinese testing labs frequently require earlier time points for implantation CFDA administrative review & approval License printing TOTAL working days working days testing than most labs would typically employ. Adding a few time points to an existing test could decrease the time to enter the Chinese market by six months or more and result in significant cost savings. Testing centers Your device will undergo testing at one of the 10 major CFDA-accredited testing centers (see Figure 1) or at one of 44 affiliated testing institutes (primarily at universities) that the CFDA uses to subcontract out testing work. The typical testing process involves three key steps: submit your medical device and standard for review; upon acceptance of your standard, the testing lab will request samples (note that in many cases there will be a request for too many samples and it is usually acceptable to push back here; likewise over-testing applying standards that are too stringent for the product may also occur, and it is best to consult an expert here about the best path since you may need to balance time and cost for repeat testing versus time to market); and testing is completed (can be 6-9 months) and a final test report issued, with a designation of Pass or Fail. Failed reports will typically not include a great amount of detail about why a failure occurred. Good relationships and dialogue with the testing lab is crucial, as is sending a representative to the testing lab, one who has been thoroughly briefed on the performance of and functionality of your device. Performance testing results can vary across Chinese testing labs as well as in comparison to foreign testing results. Overlap in some lab testing areas, however, allows medical device manufacturers some flexibility regarding which testing center in China performs the required testing. Note that for both biological and type testing, the situation can often be dynamic. Biological safety testing, for example, may be accepted from certain reputable foreign labs it helps if they have a presence in China also but even if foreign lab results are accepted, the CFDA may still require that a subset of biological safety testing be performed at a CFDA testing center. Raw materials Most of the pressure of testing is put on finished products; however, it is possible to leverage raw material testing that has been completed overseas in globally recognized laboratories. In the US, raw materials can be submitted to the FDA in a master access file (MAF) format that can be utilized by many medical device manufactures who use that raw material in their device, which can relieve the finished product manufacturer from repeat testing 5. In China, the MAF process does not currently exist and, thus, any raw material testing that the finished product medical device manufacturer wants to leverage should be presented to the testing lab to determine if it is appropriate or if additional testing will be required locally. It is difficult to bridge a change in raw materials and meet the CFDA requirements without additional testing; a new registration may even be required depending upon the scope of the change. Summary: tips for successful testing careful planning and execution of the testing process is key to success; utilize in-country expertise, preferably a third-party agent with experience and relationships in China; draw on the expertise of your raw material suppliers; leverage the competition between test centers; overlap in testing lab capabilities allows some flexibility regarding what testing center performs testing; and utilize foreign test reports, where possible. Expect a dynamic environment... build in flexibility... choose your partners wisely. Recent regulatory changes Regulatory changes regarding medical device clinical trials, registration, testing, marketing, and post-market monitoring in China have been changing rapidly over the past year and a half. Even more changes are being introduced by the new laws that were issued on 31 March and will go into effect 1 June (see final section below). Additional key areas of regulatory changes are summarized in Table 2. 2 April Informa UK Ltd 2014

3 Figure 1. Ten main testing centers for medical devices in China Center Main testing capabilities 1. Medical Device Quality Surveillance and Test Institute Biological materials, artificial organs and tissue engineering 2. Beijing Medical Device Quality Surveillance and Test Institute IVD, radiotherapy equipment 3. Dental Materials Quality Surveillance and Test Institute in Dental materials Peking University 4. Shanghai Medical Device Quality Surveillance and Test Institute Anesthesia and respiratory equipment, surgical instruments, etc 5. Jinan Medical Device Quality Surveillance and Test Institute Medical polymer materials, sanitary materials 6. Shenyang Medical Device Quality Surveillance and Test Institute X-ray diagnostic equipment (including CT) and accessories, medical refrigerated products 7. Tianjin Medical Device Quality Surveillance and Test Institute Orthopedic materials and equipment, medical equipment of physical therapy 8. Wuhan Medical Device Quality Surveillance and Test Institute Ultrasonic diagnostic equipment. 9. Hangzhou Medical Device Quality Surveillance and Test Institute 10. Guangzhou Medical Device Quality Surveillance and Test Institute Optical equipment, medical laser equipment, medical equipment of deep hypothermia therapy Dental equipment, disinfection equipment, etc Informa UK Ltd April

4 Table 2. CFDA medical device guidelines: key regulatory changes Draft release date Area covered Key point(s) Number & effective date 29 December 2008 (Trial measures) Medical device adverse event (AE) monitoring system Device companies and regulatory bodies within China are both responsible for building an effective AE collection and reporting system Goal is to have a functioning platform in place by the end of 2014, with one year of review and testing prior to official release in 2015 Will require significant changes throughout the China healthcare system 24 September 2012 Medical device labeling Text of labels and packaging for medical devices sold in China must also be in Chinese 30 October 2012 Human genetic materials Collection of human tissue, cellular, or chemical material and data derived from them will require regulatory review and clearance Agent collecting the material must be a legal entity in China Electronic transmission of data derived from human materials also regulated 10 December 2012 Device classifications New classifications system; some devices change classification category System based on classification as active device, passive device, or in vitro diagnostic (IVD) device 19 December 2012 Testing for active medical devices 20 March 2013 Medical device license reregistration 20 March 2013 Priority review for innovative medical devices 22 March 2013 State Food and Drug Administration officially becomes China Food and Drug Administration 22 May 2013 Medical devices supplementary review 2 July 2013 Class II clinical trial regulations 9 July 2013 Medical device testing guidance 9 July 2013 Clinical trial data management 22 September 2013 Penalties for regulatory violations 30 September 2013 Class III clinical trial regulations 12 November 2013 Amendments to 2007 drug registration regulations YY is carried out strictly EMC test is needed in local test center for active devices Absence of change declaration streamlines process Minor changes to model, specs, or standards: abbreviated dossier accepted (technical documents pertaining to change only) Major changes (to scope of application, structure, design, performance, function, materials, or basic principle of product): Submit as new registration Creates a priority review process for innovative medical devices (domestic and foreign products) Defines innovative medical device SFDA reorganized, elevated to ministry level, and renamed CFDA All information for supplementary review must be given to the CFDA at once, and within 60 days of the supplementary review request being issued Expanded list proposed of Class II medical devices exempt from clinical trial data during the registration process Sets CFDA internal standards for testing and testing timelines Includes provision on return of testing samples For manufacturers, CFDA can now mandate sampling/resampling at any time Long-term goals for improving the management of clinical trial data in China, including unified data management rules, creating an accessible registry of trials, and building a trial database Describes the punitive damages that can be sought for violators of CFDA regulations, including fines, seizure of property, etc Also describes the hearing process that will be used to determine if disciplinary action is warranted when violations are identified Many new classes of higher-risk Class III products, particularly implantables, added to list of those requiring clinical trial data (eg pacemakers, stents, artificial heart valves, 3D-printed orthopedic implants, etc) Manufacturers must submit a clinical trial application (CTA) with the CFDA before starting trials Supplementary CTA application is required if significant changes made to the study protocol CFDA will begin to accept generic applications two years prior to patent expiration Opinion 205, August 2013 Notice 280, April 2013 Order 361, December 2012 Order 151, January 2014 Notice 9, December 2013 Order 13, March 2014 Center for Medical Device Evaluation Notice 1, June 2013 Order 211, October 2013 ; closed for comment 13 December April Informa UK Ltd 2014

5 26 November 2013 IVD products Detailed definition of subcatalog for IVD products (6840) Order 242, 2013 Takes effect 26 May December 2013 Medical device inspection and good manufacturing practices (GMP) standards 26 December 2013 Good supply practices (GSPs) for medical devices 13 March 2014 Five main categories of noncompliance 31 March 2014 CFDA regulations for supervision and regulation of medical devices Updates GMP device standards that became law in 2011 Revisions touch on all aspects of GMP regulations, including organization and responsibilities, facilities and equipment, personnel and training, sales, and post-market responsibilities Lays out a set of standards for management of the distribution process for medical devices Will be first GSPs for medical devices in China Refers back to ISO (ISO GSPs for medical devices) Strengthens the responsibility requirements of the sponsor, investigators, and sites Campaign initiated by the Department of Medical Device Supervision, which was created during CFDA restructuring Aims to address prevalent and serious acts of misconduct in areas of registration, manufacturing, and distribution See details below Inspection guidance released 13 January 2014 Order 7, January 2014 Notice 24, March 2014 State Council Order 650, 2014 Takes effect 1 June 2014 New CFDA regulations on the horizon Over the past three years, the CFDA has been working on a large rewrite of the medical device regulations issued in 2000 that will have a significant impact on both foreign and domestic product registrations. The latest regulations that are set to come into force on 1 June were approved by the State Council on 12 February 2014 under State Council Order 650. In a statement, the CFDA explained that it was revising the regulations toward five main goals: 1) to strengthen the regulation of medical devices and implement measures that assure corporate responsibility of medical device manufacturers selling their products in China; 2) to place a focus on high-risk products and establish traceability systems by improving processes pertaining to medical device adverse event monitoring, reregistration, and recalls; 3) to actively explore and improve the way regulatory mechanisms can both encourage innovation and promote the healthy development of the medical device industry; 4) to encourage and support the participation of all sectors of society in these goals; and 5) to safeguard the public health by identifying and prosecuting misconduct in all areas of medical device development, including registration, manufacturing, distribution, and promotion. There are numerous changes that will impact imported device manufacturers. First, the CFDA will become the singular authority for medical devices and will no longer share responsibility with import control (AQSIQ, Administration of Quality Supervision, Inspection, and Quarantine), which issues the China conformity certificate (CCC). For Class I medical devices, a welcome change will be a decrease in regulatory requirements, in that filing the product with the CFDA will be sufficient, instead of having to go through the full registration process. It is not clear exactly what will be needed for this filing requirement, but it should significantly speed up the time to market for Class I products. For other classes of products, however, requirements may become more stringent. Class II and Class III devices, for example, will now require clinical trial data unless they are on the exemption list; in May 2013 the CFDA published for comment a draft list of Class II medical devices that are exempted from clinical trial data requirements 6. The current list of exempted products which the CFDA is seeking comment on includes over 500 Class II products and over 100 Class III devices. The new classification system will also adopt a risk-based model that could see the downclassification of many products that historically have been up-classified to Class III in China, but there are also several product types that have been added to a draft list of Class III products that will now require clinical trials and will become effective with the new regulations on 1 June (see Table 3), something that foreign companies were able to avoid when they had data from studies conducted outside of China. Thus for those companies that do fall into the Class III categorization, there is a higher probability of clinical trials being required, unless the product class is included on the clinical trial exemption list. For Class III devices there will also be increased focus on quality management systems, including the potential for onsite audits by CFDA officials. Additional changes include an increase in the time a product license is valid, from four years to five years, which coupled with the smoother registration requirements discussed above (and the reregistration simplifications issued at the end of last year, see Table 2), should significantly decrease the burden for companies after a product is on the market, assuming it does not undergo any significant revisions after approval. While there are numerous positive changes and a clearer layout of the expectations for documentation, the home country approval requirement has not been removed as some had hoped and this must still be met. This has historically been a challenge for US manufactures who receive approval in Europe first; however, with the increasing burden of approval in the EU this advantage will most likely fade. Lastly, to help support expanded CFDA oversight, a new registration fee for medical devices (yet to be defined) will be required and may run into thousands of US dollars. In spite of the recent regulatory changes in China, and in some cases due to these changes, the country has been and will continue to be a significant market opportunity for medical device manufactures around the world. Overall, these new medical device regulations could provide a clearer and faster path to market for many products and companies. References 1. China Food and Drug Administration (CFDA) press release, 17 February 2014, 2. CFDA, Regulations for the Supervision and Administration of Medical Devices, as amended (in Chinese), 31 March 2014, xinwen/ /31/content_ htm 3. CFDA, Regulations for the Supervision and Administration of Medical Devices (2000), State Order No.276, 4 January 2000, cn/ws03/cl0767/61641.html. Informa UK Ltd April

6 Table types of Class III medical devices will soon be required to undergo clinical trials before approval in China (draft) Product type 1. Implantable pacemaker/defibrillators 2. Implantable blood pumps 3. Perfusion systems 4. Intracranial stent support and delivery systems 5. Fully bio-absorbable stents and delivery systems 6. Artificial heart valves 7. Tissue-engineered medical devices containing live cells 8. Artificial organs 9. Absorbable fixation products for long bones 10. Orthopedic nano-implants 11. 3D-printed orthopedic implants 12. New orthopedic implants with no predicate in China 13. Drugs or biological products containing oral bone filling material 14. Drugs or biological products containing oral absorbable collagen/gelatin products 15. New vascular staplers with no predicate in China 4. Le Deu F, Parekh R, Zhang FN, Zhou GB, Health care in China: Entering uncharted waters. Multinationals are flocking to take advantage of the opportunities, but long-term success is by no means assured. McKinsey & Company, November 2012, and_services/health_care_in_china_entering_ uncharted_waters 5. US Food & Drug Administration. Master Files: Introduction to Master Files for Devices (MAFs), updated 18 March 2014, MedicalDevices/DeviceRegulationandGuidance/ HowtoMarketYourDevice/PremarketSubmissions/ PremarketApprovalPMA/ucm htm. 6. Goldenberg S, CFDA expands list of Class II medical devices exempt from clinical trial data. China Regulatory and Industry Monthly, June 2013, www. namsa.com/resources/news-and-events/newsletters Cindy Hu is director, China Regulatory, at NAMSA, a medical research organization that provides regulatory, laboratory, clinical, and compliance services to medical device and healthcare product manufacturers. Shawn Shorrock is director, Global Regulatory, at Solvay Specialty Polymers; Yuling Hu is manager, Regulatory Affairs and Quality Assurance, at NAMSA. Seth J Goldenberg is senior principal scientist at NAMSA. [email protected]. 6 April Informa UK Ltd 2014