China Update What s new from CFDA? Attendee Questions and Answers

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1 China Update What s new from CFDA? Attendee Questions and Answers Brandwood Biomedical webinar presented by: Steven Wen, Head of China Operations Brandwood Biomedical steven@brandwoodbiomedical.com Q. We have a class IIa device in Europe which is CE marked and class II with 510(k) in USA. No clinical trial required for either region but it is not specifically listed by China. There is no predicate in China for this device type at this time. What is the best approach to use the existing clinical evaluation data to support registration? A. Unfortunately China SFDA requests any Class II or III devices to complete clinical studies in China (Path 3) unless it is listed in the exemption list (Path 1) or has a substantial equivalent device approved in China already (Path 2). That is a big challenge for everyone. CFDA will continue to update the exemption list by taking the advice from industry. The existing Class II exemption list consists of 488 devices and the upgraded version (to be issued soon) will add another 145. It may be worthwhile to work with an industry association or other channel to seek to add the device onto the exemption list. Q. Is this to determine whether the studies done outside of China are sufficient for device approval? A. In general, clinical study data from outside of China is not sufficient to get device approval in China anymore. Any new Class III & II device needs to be supported by a clinical study in China, unless it is on the exemption list or there is a substantially equivalent device approved in China already. So there are three submission paths: 1. If your product is in exemption list, there is no need to conduct clinical studies or provide a clinical evaluation report, you just need to justify your product is exactly matching the definition set in the exemption list and make a simple comparison to a marketed predicate device. 2. If your product is not on the exemption list, but has sufficient evidence on a predicate device (we also call predicate device as substantially equivalent device), then you can submit a clinical evaluation report (CER)

2 3. If your product is not on the exemption list, and without a predicate device, then you need to conduct clinical studies in China. In addition, all clinical studies need to notify local provincial level CFDA, and High risk device clinical studies need pre-approval from State level CFDA. Q. Just to clarify, the manufacturer makes the initial determination of CER sufficiency? So, once submitted to CFDA, it is possible that CFDA may not agree and thus require a study? A. That is correct. Q. If a clinical trial is needed, are there CFDA specifics about the patients required and follow-up periods or can a manufacturer propose those for negotiations? A: In general there are 3 scenarios 1. For some certain types of devices, such as drug-eluting or peripheral stents, CFDA has issued specific guidance on clinical studies which specifies the protocol design including patients needed, follow up period, end point criteria, statistical method, etc. 2. For those products without guidance from CFDA and where the risk of the device is comparatively low, the general rule (Reg. No 5) requests that the study design must show statistically significant outcomes. Of course, the design protocol can always be discussed with the CFDA reviewers to try and gain some insight into their requirements, however, the ethics committee and statisticians will often play a very important role as CFDA reviewers will essentially rely on the ethics committee and statisticians to review and approve the protocol. 3. For a number of high risk Class III device, CFDA requests pre-approval of protocol in order to avoid any dispute after the study is done. Q. Are there predefined clinical sites (meant for the trials) or can any site be selected based on personal preference? A. No, the sponsor cannot select a clinical site freely. There is a list of CFDA-accredited sites, which can be downloaded from the CFDA website. There are approximately 500 sites on this list and each site has specific departments which are capable of completing specific clinical studies; for example Beijing Tongren Hosptial Ophthalmology, Cardiac, etc. You can choose a clinical site/department according to your device s intended use and you must remember to review the validity of the site s accreditation certificate before signing the contract. Q. I heard that the clinical study needs to be finished 1 year after the laboratory testing. How do you handle longer Follow-up periods in the study that is to exceed one year? A. That is not accurate. You need to BEGIN the clinical study within one year after testing is done, not finish it.

3 Q. Meta-analyses: Given one goes for the literature pathway to justify performance and safety (PubMed, etc), is one expected to provide meta-analyses on these literature data? A. Yes. CFDA asks you to use systematic review methodology to analyze the data, such as using meta-analysis. There are more details about the concept of systematic review in CFDA s guidance and training material for CER Q. Please clarify the requirement of Product Technical Requirement (PTR)? Is this a one-time requirement that the company needs to meet during product registration review? Or does the company need to meet these PTR routinely? Even after product registration review? A. PTR is not a one-time document. It is the core piece in the submission dossier, and also serves as the protocol for local type testing. Once it is approved, the manufacturer needs to meet these requirements routinely. Any changes to the content in PTR would trigger a product change application. If there are any adverse events, injury incidents or lawsuits, the first thing CFDA or court will do is to check if your product still meets the PTR. If not, there could be significant consequence. Non-Conforming product is regarded as Non-approved products. Q. Product Technical Requirement. I understand that this will be an approved document from CFDA and the product should meet all the specifications that are listed on the PTR. Does the CFDA have any requirement on the testing capability of the company? In other words, can we outsource the testing to a contract lab or is CFDA expecting the company shall have testing capability for all of the testing outputs? A. A manufacturer has the responsibility to make sure the product meets the PTR requirement. If any of the testing in PTR cannot be performed by the manufacturer itself, such as biological testing, EMC testing, IEC testing, the manufacturer may authorise a third party to test. Q. Is the CFDA planning to use the new ISO coming next month? A. Yes, CFDA will definitely adopt the new ISO in the future, but it will take time; there could be a lag to some other countries and most likely CFDA will give a transition period for manufacturers to upgrade their system. Q. Any differences to ISO adverse events /serious AE monitoring reporting? To whom should be they reported? A. CFDA s definitions of AE and SAE are the same as other countries like U.S. or EU countries. CFDA has established a Drug & Device AE reporting center and all reports go there. Q. What is the difference between ISO and Chinese GMP? A. There are many common requirements in GMP and ISO However, GMP sets more detailed requirements to manufacturing facility, equipment, process management, etc., especially for certain types of device such as implantable or sterile devices. For example, it sets very high requirements of the clean room for implantable device.

4 Secondly, GMP incorporates regulatory requirements in addition to the quality requirements, for example, it requests the inspection process and testing result should comply with not only the manufacturer s own specifications, but also the CFDA approved Product Technical Requirement. Another example is that it requests the product manual and labeling should comply with not only the manufacturer s own design, but also CFDA s regulation for manual and labeling, which is Reg No 6. Look out for a future webinar on the requirements of China GMP! Q. For a China contract manufacturing company, are GMP requirements applicable? And will CFDA audit the site? 1. Firstly, we need to understand that there are two types of site audit; the first is a QMS audit for registration, which applies to manufacturers both domestic and foreign. During the review cycle, CFDA may come to complete a one-time audit of the site QMS system (ISO 13485). The second is a GMP audit that is only for domestic manufacturers to apply for the manufacturing license post-registration. In other words, local manufacturers may accept two audits. GMP audits include initial audits and annual follow-up audits. 2. On the other hand, the current policy of CFDA is that if the legal manufacturer is a foreign company, then a Chinese factory cannot be registered as the manufacturing site (contract manufacturer or OEM). The same applies in that if the legal manufacturer is a Chinese company, a foreign factory cannot be registered as the manufacturing site. This is due to the difficulty with which CFDA would have in classifying the device as either local or foreign. 3. One common work-around for this situation is to ship the Chinese manufactured products back to the legal manufacturer s country to put on the labeling and then ship the relabelled devices back to China. In this case, the product will be registered as a foreign device and may cause CFDA to visit the legal manufacturer to complete an overseas QMS audit (in which GMP does not apply). Another option is to let the Chinese manufacturer act as the legal manufacturer (with the device labelling to include something similar to Manufactures for XXXX ). In this case the device would be registered as a local device, with CFDA to complete both a QMS and GMP audit. Q. What specifically needs to be compared between predicate and subject device regarding manufacturing processes (i.e. basic processes, such as machining, marking, cleaning, etc., or steps such as milling, turning, passivation, laser etching, etc. requiring more in depth comparison)? A. There is a template of a comparison table issued by CFDA, which includes manufacturing process and other items. CFDA does not specify what level of detail is required as part of this manufacturing process comparison. Personally, I think only a high level description of manufacturing process is needed here, as there is no need to dive into significant detail in this comparison table.

5 However, in the submission dossier of the subject device, you need to provide a separate document to introduce manufacturing process. More comprehensive details may be entered in this document. Q. How deeply should ethnic differences should be addressed? A. CFDA Guidance on Clinical evaluation does not specify how to consider ethnic differences. It just states If the ethnic difference may impact the device safety or effectiveness, the sub-set data of Chinese patient shall be established. If you think ethnic difference would not affect the safety or effectiveness, you need to justify it by providing supporting materials. Q. If one goes with the literature pathway: should the ethnical difference be covered by the literature also? A. Yes, see above. Q. Regarding ethnic differences, what if we provide a detailed justification for why ethnic differences will not affect the results of the clinical data collected outside of China? Could that be sufficient? A. Yes, if you are confident the ethnic differences will not affect the results of the clinical data, you can provide detailed justification materials. However, it is preferred to extract the Chinese patient data (if any) from overseas studies to form a sub-set data. There is no need to repeat this for any other ethnicities. Q. Any specific requirements for Software MD? A. There are no particular requirements for software, all general rules apply to software as well. Q. For a medical device that emits ionizing radiation (or a CT product) - does EMC testing to IEC nd edn require that testing to be done with the X-ray on? A. Yes. According to the IEC/EMC standard, the testing needs to be done while the working mode is turned on. In case of X-ray or CT, you need to turn on the scan while testing. Q. Can you explain the CFDA position on wireless technology? Does the device and radio technology (Bluetooth, X, MBAN, Zigbee) require approval from SRRC in the host while submitting application for the device FDA review? A. Yes, there are multiple approvals pertaining to radio (wireless) or network functionality from other government authorities; for example, the SRRC s license of radio band verification. In addition, if your radio connects to public network, like GPRS, you also need the network-entering permission from MII, similar to a cell phone. Therefore some types of devices may need 3 (or even more) licenses from CFDA/MII/SRRC etc. During CFDA review cycle, some reviewers may ask you to present the license from SRRC/MII. Some will not, since they lack that knowledge.

6 Q. Why did CFDA change their position on modular submissions from SRRC for a radio versus having to test in the host medical device? A. I am not sure if I understand this question correctly. When applying for SRRC s radio license, SRRC requests you to provide the detailed model number to be listed on the license. If your radio module is independent (for example, detachable to the host medical device) and has its own model number, you can certify only the radio module. If the radio module is integrated with the host device and has no individual model number, the whole device needs to be tested with the device model number listed on the SRRC radio license. I hope this answers the question! Q. Can we confirm that radios in medical devices require in host testing from SRRC and/or CFDA? A. Same as above, if your radio module is independent (for example, detachable to the host medical device) and has its own model number, you can just certify the radio module. If the radio module is integrated with the host device and has no individual model number, the whole device needs to be tests, with the whole device model number to be listed on the SRRC radio license. Q. Will increased regulations on distribution and marketing potentially reduce the % markups on imported devices? A. It is hard to say, because distributors of locally made devices also need to follow the rules. That is a challenge for everyone. In general, multinationals and some big local distributors have more well-established quality systems than smaller local companies and in theory should adapt to the new distribution requirements (GDP) more efficiently. New, foreign companies entering the Chinese market should choose qualified distributors, such as China-Pharm.