The Taiwan Fast Track: How US and European Approvals accelerate Taiwan FDA approval



I'm Arthur bradwood and welcome to medical devices in Taiwan leveraging C and C E and FDA our May 2018 webinar I have with me my colleague Jenny Lynn consultant in Sydney office here and Jenny's actually from Taipei and she's one of our Taiwan specialists here in Brevard biomedical and she'll be joining in with the question and answer session at the end just a bit of background about Taiwan its population about 24 million now market size a couple of years ago of getting up towards five billion dollars and growing quite strongly at something like seven or eight percent a year and it's one of Asia's most advanced markets about 70% of high-end devices are imported about 30% of those come from the United States and for those who you've been to Taiwan will know it it's an advanced country and a high level of tertiary education I mean a sophisticated health system with a very large amount of public health delivery there is a demand for the latest technology the demographics about 13% of the population are over 65 like all others it's aging and most of the care is delivered as part of public patients in Taiwan that translates into opportunity for people who want to export medical devices to Taiwan let's begin with the Taiwan FDA and the legislation the Taiwan Food and Drug Administration and regulates food drugs medical devices and cosmetics very similar to the US FDA a little bit of history at the bottom there and the regulation dates back to 1993 when the pharmaceutical Furze Act was enacted the management systems were reformed in 2000 medical devices registration really began in serious way in 2005 and in 2010 the Taiwan FDA was established under the Department of Health and in 2013 it was elevated to the Ministry of Health and Welfare and we've seen this across many Asian jurisdictions over the last few years where regulatory agencies have been effectively promoted in terms of their important importance and taken on our highest status and that certainly haven't in Taiwan Taiwan takes medical device and pharmaceutical regulations very seriously and there is a typical act and regulations and regulatory instrument structure so the act is the pharmaceutical Affairs Act of 2017 the latest version the regulations are the regulations for registration and management of medical devices and the Taiwan FDA then publishes a range of guidances such as the guidance for medical device labeling for post market activities and product specific preclinical guidances there's a range of different but documents there and the link on the screen works you will get a copy of the slides at the end and you can look at that and you can go to the guidance on the Taiwan FDA and website and to the legislation and let's just look at some key points of how regulation works in table one firstly there are a number of things you have to have to gain at Taiwan FDA regulatory approval of course the whole process is focused on safety and efficacy of the device but you must have firstly a country of origin approval if the device is not approved in the country in which it it is manufactured and the country of the legal manufacturer then you cannot proceed with a regulatory approval in Taiwan similar to the arrangements in other parts of Asia including in in mainland China you must have a country of origin approval the predicate device in Taiwan is strongly preferred you can go forward without a Taiwan predicate but makes things so much easier if there is a device already approved in Taiwan which is effectively the same or similar to your device and you can refer to it in your submission you need to have a valid manufacturing quality system certification and that's called a qsd certificate and we'll come to the detail of that later and but you need to have a valid quality system controls either as iso 13485 or the US fda registration on-orbit and we will talk about that in some detail and then you need a local market agency market agent in Taiwan a sponsor the Taiwan FDA deals with a legal entity in Taiwan you can't make an application from offshore so everything must be done through a local Taiwan sponsor that can be your distributor or you can use an independent regulatory agency and regulatory consultancy or service agent to do that and that's one of the services Brentwood biomedical officer to be able to support registrant registration in Taiwan and there are some common documents to all regulatory submissions firstly the labeling materials must be in Chinese and in English and the Chinese is traditional Mandarin script that differs from the rest of China which uses the simplified Mandarin script in Taiwan labeling has to be in traditional Mandarin script as well as in English you need a qsd certificate and for quality systems that's a certificate issued by the Taiwan FDA you need to have your preclinical testing and quality testing reports you need product information instructions for use and product information you need for high-risk devices to submit a clinical evidence report and you need on top of all of this technical documentation documentation that needs to be a formal authorization letter from the legal manufacturer appointing the local agent and the authorization letter formed part of the submission packet and finally the sponsor must have an appropriate business license to operate in Taiwan and to act as a sponsor for class three medical devices the technical documentation that's submitted must be in the standard technical dossier format that's used in in other global colonization task force jurisdiction so the the state format is mandatory for the technical dossiers for class three devices so let's begin with looking at the quality systems documentation qsd the qsd certificate this is a certificate that's actually issued by Taiwan FDA and you have to obtain it before you can proceed to the next step of product registration the product registration requires the existence of a prior qsd for with the product within the scope and the two will be linked in the registration databases so once you get your qsd it's valid for three years it takes a while to renew the qsd so effectively after two and a half years you have to begin the renewal process again and one little nuance of the system here is that the qsd validity cycle is a different length to the device regulatory approval cycle and so the two can get out of step so the qsd still gate is is issued and has to be renewed every three years and you have to start the filing of the renewal six months before the expiry it takes 120 calendar days for the Taiwan FDA to review the application for qst and class one non-sterile and our measuring devices do not require a qst certificates similar to other self-declared devices in europe and other jurisdictions where there is no formal requirement for quality system certification there are three ways of getting a qsd the first is an abridged pathway for US manufacturers and the way that works is that you submit to the Taiwan FDA the US FDA s most recent establishment inspection report a certificate foreign to foreign government issued by the FDA verifying that the device is able to be legally supplied in the United States and and if you have it and I go one through four a close the second abridged pathway and for European manufacturers including Switzerland and Liechtenstein in the European Economic Area in those cases you did a similar thing you submit your most recent inspection report from the European notified body you supply a free sale certificate validating that the device is legally able to be sold in Europe and you supply your ISO 13485 certificate in each of these cases you submit this information to the Taiwan FDA where it's then reviewed and the qsd certificate is is issued based on this information if you are not if you do not hold a European or a US regulatory approval and quality certification then there is a third pathway which is called as the standard pathway where you submit an iso 13485 certificate if you have it and plus your full quality manual quality procedure and manufacturing flowchart and that will be reviewed by the Taiwan FDA and if all else fails you can of course submit to a direct Taiwan Quality Systems audit but that almost never happens and Taiwan FDA doesn't usually and audit outside of the country for medical devices and so these are the three ways forward and the reviewing process works a bit like this firstly you file your submission from qsd with Taiwan FDA and the Taiwan FDA then once that administers we accepted that we'll pass it to an external third-party reviewer for a technical review that takes about 30 days and the reviewer then raises any questions and passes those back to the agency whether they have passed on to the applicant the applicant is allowed 60 days to review and respond to those questions and then it goes back to the third party review who's gets another 30 days to to look at your review responses and then pass the submission back to the agency for decision yes the agency issues its own final decision the review questions will typically include matters such as wanting more detail on the nature of the process or the layout of the factory sometimes floor plans that sort of thing and so there is a substantive look at how the quality system operates and the facilities to which it controls this whole process therefore takes about 100 and 120 days to get your qsd certificate in place but it can be more complicated than that what happens in most medical device operations certainly in all but the smallest of manufacturers is that there may be more than one manufacturing plant here's a theoretical schema for manufacture it's got four different manufacturing plants and a sterilization vendor and products may move from plant to plant they may be made in one plant as product a is here or product B and here may be made possibly in two separate plants then brought together and and then sent off to a sterilization vendor externally and then brought back again and then released the question is who gets the qsd certificate because the issue is a qsd certificate is issued to a specific plant at a specific address and and the answer is typically it's the site which does the final product release the final quality release there's a kind of a pharmaceutical mindset to how this works is a very great deal of interest in the final QC release of product and that's the site that gets issued the qsd and it can be of course even more complex than that where you may have a large number of sites and the flexible manufacturing arrangement to move things around and we have in the past had to negotiate directly with the taiwan FDA on behalf of a manufacturer which had just such an arrangement and had for many years held a qsd certificate in the name of their corporate headquarters which in fact was an office block the the the Taiwan FDA raised a query on one particular round of renewal Bukh simply because the US FDA had changed the format of the establishment inspection report and listed all of the manufacturing facilities directly on the report for the first time which then raised awareness amongst the agency that there were more than one plant and covered under the qsd and eventually it was possible to negotiate with the agency to demonstrate control of the quality system from the corporate headquarters and and and effectively control of all the product release and therefore the agency was then prepared to issue a single qsd certificate for the whole organization but then you can get complicated diversions such as that but the simple principle is one qsd certificate for one set of product release and and then those products which are released at that facility are associated with a qsr distribute in the subsequent approval step so let's look at that product approval process the product registration process and Taiwan operates a risk-based classification with three classes and class 1 2 and 3 and from low-risk through to high-risk for class 1 devices they still have to be registered but it's a declaration statement only for class 2 devices of moderate risk and there is a need to submit technical data and for class 3 devices which are higher risk the technical data have to be in a sted format and you submit a large quantity of data essentially so let's look at the reviewing timelines for class 2 devices and applications are submitted to the FDA the agency takes about two weeks to administrative leox eped and allocate the submission to a reviewer and then at that point the clock starts and T FDA has 75 calendar days to conduct its first round of review the T FDA will then issue formal review questions to the applicant and the applicant has 60 days proximately to respond to the t fda there's a tight timeline on preparing your response just 60 days you submit your response and the t FDA is then allowed another 65 days to finalize the application and come to a decision there's a single round of review with a relatively short time to provide your review responses that class two devices for class three same process only the timelines are slightly different so the application is submitted to T two T FDA again until we review an acceptance process and then this time T FDA is allowed one hundred and five calendar days to conduct their review you get your questions and again you get sixty days only to respond and then goes back to T FDA and this time they have ninety five calendar days to finalize the application now one thing about Taiwan FDA is it is pretty good with deadlines and they they measure themselves closely against their deadlines and they do by and large meet these deadlines or come in under them and and certainly in a review process if you're slow with your responses you're going to get reminders and things will move along according to the clock and the pre market submission document and I like this this is set out for class 1 class 2 class 3 and devices which are completely new in design structure or material or a combo or a combination so for class 1 devices it's a self declaration you must hold the preclinical and quality control testing on file and you're labeling must require comply with requirements and for class 2 devices and class 3 and you need the said the common document set that we refer to earlier in the presentation plus the qsd certificate and for class 2 devices you will need to have a technical file and the clinical evaluation may be required to be submitted sometimes the agency will civically request that for us and CEO proved devices if the device has both a u.s. and the CEO provable then you are exempted from requirement to submit preclinical and QC testing reports so this speed things up quite a bit the review goes much more quickly and there's much less technical data essentially though the the agency relies on the existence of prior us and CEO proof devices for approval for quest two devices and will wave the review of the tech much of the technical content of the submission so that can give you a fast-track approval for Class two devices for class three devices though there is always a full review based on submission of a summary technical file in the state format including a clinical evaluation report and the submission of an essential principles checklist and Taiwan and uses the essential principles of the global harmonization task force and as they're essential principle checklist for devices which may be completely new to Taiwan with completely new design or structure and all material then there may be a need to or a more detailed review with a full technical file including clinical valuation report to be reviewed and that doesn't happen very often but it's completely new technology the agency will take a deeper look so just looking at how the these US and EU approvals allow exemption proof link from preclinical and QC testing reports if you have either an FDA registration and you can show evidence of that or you and you have an EC certificate then as I said just now the the agency then allows you to file an application without the preclinical testing and the clinical report and they will simply go forward on the basis of an administrative review of the existing overseas approvals and for class 3 the ght F step format is mandatory and just for those of you who might need a reminder this is what it looks like there's the contents list from the ght F and so you want to see the overall descriptions the essential printable checklist a risk analysis summary an overview of design and manufacturing information the preclinical product verification testing and the clinical evaluation report for addition plus the labeling in both English and traditional Mandarin and the clinical evidence let's just take a look at acceptance of clinical data in Taiwan and the use of international data it's a question that often comes up this Taiwan require trials to be done in Taiwan will they accept international data and the simple answer is that Taiwan generally accept international data the regulations say like it does in the rest of China and in other parts of the world that the clinical data are acceptable from anywhere subject that they are compliant with GCP equivalent to the local Taiwan GCP and since Taiwan effectively uses GCP based around ISO one four one five five then all advanced jurisdictions are going to have acceptable TCP and secondly applicant applicability of the data to Taiwan usage in terms of the population density genetic scan as well as clinical practices and other cultural factors all of that is in the regulation and that can be problematic in some other jurisdictions with acceptance of international data but in practice it is very rare that I want to require local clinical data they were if there is international data they will accept it and the the in theory if there are local region or regional differences in in the indication or in the population or in the clinical practices you will need to do some local trials but in practice this is what this almost never happens there are guidances and on clinical data there's a QA on handling of clinical data data from overseas countries and a couple of other guide sister listed on the webpage and they're easily found on the Taiwan FDA website let's move to labeling and product labeling yes it must be in traditional Mandarin there is a specific requirement that warnings contraindications precautions and the side-effects are identified on the labeling either in black or in a red box as shown here on the screen and the labeling must identify both the manufacturer and the sponsor and the Chinese product name must not include any Western letter or number or some other symbol it has to be only traditional Mandarin characters and the model number and overall specifications must also be identified on the label so here's the whole process in summary for device registration in Taiwan for class one devices there is no requirement for a and C a qsd certificate there is no requirement for a country of origin approval there is no requirement to submit technical or clinical data or a technical file you do need to hold a certain number of administrative documents and products provided sterile or for and some other class Wan devices also require a qsd and but there are they are the exceptions to the rule but generally Class Wang devices are simply self declared and the manufacturer must hold the evidence that they comply with regulations very similar to what goes on in Europe in Australia and in other jurisdictions that use a ght TF regulatory model for Class two devices you must have AK USD and you must have a country of origin approval and generally you need to submit preclinical testing QC testing reports and clinical evaluation reports although if you have both European and FDA approval you can skip that part the technical file does not have to be in a state format and again the administered documents have to be held and then for class three you need the whole set qsd country of origin approval all preclinical and data and a clinical evaluation report a technical file in the stead format and again the administer of documents and registrations have to be renewed and as I said before the qsd is on a three-year renewal cycle the product registration is on a five-year in your cycle so they do get out of step a product registration is granted for five years and again the rear edge astray ssin needs to be submitted within six months prior to the registration certificate expire expiration date not with not not more than six months but within that six month period you need to file the registration and certificate and renewal the qsd three years of validity and the re registered registration must be submitted at least six months prior to the registration certificate or expiration date so you need to manage your calendars and not forget to get back to the agency with appropriate renewals at the right times otherwise you'll find that you've got lapses in registrations and/or qsd delegates and you have to start all over again now what happens if you get a product variation firstly technical variations and administrative variations two different types a technical variation is where there is a change of an intended purpose or an indication for use in the device an administrative variation is when you've got a change of a product name change of manufacturer or sponsor information a change of the instructions for use or an additional removal of a model number and specification two types and and those variations and you need to file a submission back to the agency for for review of the of the variation and the technical variation of course and also review some technical information administrative information not and maybe we can have a little bit of a discussion of that in the question answer session in the moment as to how this process works there are some changes coming along in Taiwan and we just like to review those briefly there is a new medical device management act which has been put through and there are some changes to be implemented under that new act firstly the definition of manufacturer has been expanded and now includes legal entities that design and place devices on the market under their own name so in other words the act now explicitly uses the concept of a legal manufacturer as used in other jurisdictions so that's really a clarification it's always been interpreted that way but it's now quite explicit in the act the there is a new category of medical sorry an expansion of the definition of medical device dealers and that's now expanded to legal entities that lease service or repair medical devices so organizations that do that in Taiwan are now explicitly included within the scope of the operations of the act there is as we are seeing across most of the East Asian and Southeast Asian jurisdictions and in an implementation of good distribution practice most of these economies rely on a substantial proportion of imported medical devices and manufacturers are expected to establish good distribution practice in particular tracking systems for supplying sourcing and the records of the distribution of the devices so they can be tracked through the supply chain and for the purposes of things like recalls for example and there is a new online registration process for class Wan devices being implemented and which which will mean that some class Wan devices in the beginning not all will be changed over to an electronic listing with a simplified application and you will be required to update that annually to maintain your registration variability validity so moving over to online submissions for class one devices and there are some cases where you don't require a license and that's been expanded in the new Act to include to be explicit about licenses not being required for clinical trials samples and gifts for purpose of self use devices shown at trade exhibitions devices used in research offered by charities and medic medical devices and supplied for maintenance and repair purposes only in other words their parts all of these activities do not require TFT a license and finally a post market surveillance and has been stepped up in the new act where there is now a requirement for medical device dealers to provide safety monitoring report periodically and notify adverse events where where a device has got a potential to compromise safety of the human body and take corrective preventive action so if you've got a safety issue that the Rises that's something that's notified from the agency and and corrective actions required so I think we'll stop at that point and thank you for your attention and we'll now move to questions and maybe I can start with the first question Jenny and just ask a little bit about variation submissions and how they work compared to primary submissions yes so as Arthur mentioned earlier there are two types of variation submissions one is administrative and the otherwise technical generous speaking if you made changes to ifu it really depends on what sort of changes that has been made if it just front size of fun type or it's just the general format changes not normally it will be considered as administrative changes but um we seeing that if manufacturers wanted to add our model numbers it depends out whether the there is any changes to your technical contents if there is normal HP FDA would require preclinical testing and QC reports so what what level documents that is required actually depends on whether you have technical changes to to your product or product specifications okay and what are a time line does it take to do and administrative compared to a technical review so typically for administrative our variation is shorter than our reviewing of technical variations but PFD a does not have like a strict timeline for for the differences but from our experiences administrative these are always always factor roughly how much it's it's about two months for administrative and our for the technical review it will be well it depends on what sort of file changes are made yeah yeah so it could be shorter or longer but essentially administrative reviews go through in a couple of months technical review is a bit longer but there are no formal timelines for these changes these variation reviews thank you okay and we have a bunch of other questions here let me just see we've got a question here from Danica who just want some clarification around the timing of review sorry renewal of qsd and product license submissions the the difference between prior to and within the six month time frame can we just clarify that so qsd submissions you need to submit at least six months out yes so that means that you can actually submit eight months beforehand before you what about product renewals will they they only accepted within the six month window is that what happens so you can't submit any earlier than six months yeah so I hope that's clear so qsd submit as early as you like product renewals will only be accepted within the window of time six months before the renewal thank you so I hope that's clear Danica so we have a question from Devin when does the new medical regulation changes just which we just mentioned the new Act when does it all go into effect yeah so actually it doesn't it has a FDA hasn't announced the implement implementation date so at the moment we still don't know when it will be implemented okay what what in your experience is the practice I know that they've changed things very often but how long does it typically take them to announce and implement a regulatory change in Taiwan well it takes a while because they have to go through all the legislative UN and you know they have to approve and then executive UN so it's a long process the long process so it might take a little while yet so it's been the the the Act has been announced but it's going to take a while to implement yet so I would imagine what that's going to be some months away at least okay and you know this time one's considering accepting MD SAP in the future ask Pete with an MD separate certificate be something that will be useful for Taiwan regulatory purposes I don't know if the agencies mention that no there is no relevant information of our MD s ap are to be used to by T FDA but yeah this is something that maybe we're not sure whether they would accept the adventure yeah I know I know that the Asian harmonization working party is having a look at MD SAP and I think there's a certain amount of disquiet about the value of n deceitful for jurisdictions in this region and so I'm not i think the answer Pete is that not anytime soon I would be surprised to see MD Sapp entering into the formal regulatory framework in Taiwan in the near future so sure she asks while submitting audit reports from the notified body in Europe is it necessary to submit Kappa plans for the mitigation of non-conformities identified in the report yes yes normally the third party reviewer will request it if there is any nonconformity or items on the report yet we have we factually are being requested by the FDA about this before so normally this is typically would be requested okay so so you'll need to provide your audit report and expect to get questions about any non-conformities would it be sensible to simply submit them the Kappa plan at the beginning with your with your in to be pre-emptive yes that would be our recommendation so the best thing to do is actually supply both at the beginning so yes so be pre-emptive you provide your your inspection report plus any close out of of non-conformance a partner asks Riv Deeks considered as medical devices in Taiwan yes it is yeah regulated under the same process so essentially just another type of medical device okay and how are they classified it is essentially classified as the classification catalog it is well it is similar to what is how medical devices is classified are similar similar to the US aar the time what I want classification system essentially been developed based on the US FDA is approached a classification correct so there is a classification catalog and IVD classifications in Taiwan are going to be pretty much the same as they are in the United States and what about combination products chi-ching asks are there any regulations specific to combination products in Taiwan normally it it depends on the intended purpose and the the function of the combination product it it can be considered as medical device in Taiwan but there's a separate review from the pharmaceutical Department to review your drug component so normally it would takes a longer time to to review your product registration if you do have a drug component so there would be the same sort of principle that's in most jurisdictions that you look at the primary mode of action yes and so so if its primary mode like a drug-eluting stent it's still a stent so it's a medical device and whereas some other things which may be primarily something with the drug delivery device where the primary means is actually getting the drug in there he's going to be regulated as a drug okay so so the primary mode of action determines which Pathak goes through but the medicines are subject to review as well if you've got a drug medicine combination device makes a connection okay thank you so we have did you see other questions here question here from Danica do spare parts required traditional Chinese labels so if you're supplying spare parts how do they have to be labeled do you know that the spare parts well it depends on whether the spare part is included in in the registration certificate normally you will have well he also depends on the size of the spare parts obviously something you can't have to label on really small parts but if your device includes the spare parts and you know the main device you will require the labels for all parts yes so so so part of the typically supplied as accessories as well as service parts would normally be shipped with local labeling yeah so the answer is essentially yes I think yeah okay let me just see what other questions we got here miss Tenny there is a question about new medical device from turning cars yes again Danica Danica thank you you have plenty of questions for us class one device registrations if a class one certificate is already available and we have a new class one device that can use the license are there any registration activities required I'm interpreting that is can we group registrations particular class one devices it so again we had to look at the classification catalog if they belong to the same group in that catalog then yes it can be listed on the same on certificate okay so that's for class one devices is that does that apply for all classes or just class one all classes so you can group if if the devices fit the description the catalog then you can put them all on one registrations yeah okay so they can be grouped now Diane has just come up with a question saying can we explain a bit more about classic is it closer to USFDA or Europe I think we just talked about that it's it's a class it's a catalogue based system and so it's not like the European system which uses risk rules it's a catalog based system which essentially is it's almost a copy of the US FDA's 21 CFR classification regulations in other words you'll see the same devices and the same sort of descriptions and with a Taiwan classification number yeah so that's how it works so I hope that explains it to you Diana essentially it's a it's a close copy of what's done in the United States and I think that's probably all of the questions and I don't think we've missed any oh one final one Thank You Danica a third question from you in variation submissions do all changes to instructions for use need to be submitted for review yes so I just mentioned earlier typically if you normally changes to ask you will require notification to DFT FDA however if it's just the format change like type front type front size then it doesn't require notification to the APA actually RPI dv/dt FDA has a notice of changes that is not so the notice of changes which are not required notification but essentially this is only for the format of a few not really like if you have the technical changes that indication or any of the actions of the medical device or any addition of addition of product specifications and these are typically required shows are so-called technical contents of the ifu requires a variation submission tiding the format changing all that etc does not okay that's that clear thank you okay well I think at that point we'll we'll draw to a close thank you all for your attention and for being our audience today we do these webinars approximately monthly usually around the third Wednesday of the month depending on where you are and which time zone you're in of course and look out for what's coming up we have webinars coming up over the next couple of months on global clinical evidence requirements on what's going on here in Australia with regulatory reforms and acceptance of things other than seee where the TGA is now actively looking at accepting US FDA approvals as the basis for an Australian registration and we'll also be looking at implementation of nd SAP and and how that is used around the world and particularly in the asia-pacific region so thank you again for your attention thank you Jenny for your expertise and it's it's it's a fascinating regulatory system the Taiwan FDA is quite sophisticated I love going to Taipei and see what goes on is it really is a technologically advanced country in Taiwan it's a fascinating place and thank you all and we'll see you next week miss area we'll see you next month thank you so back again on the third Wednesday of June you

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