Academic Report on Singapore HSA Class D and Australia TGA Class III Medical Device Regulatory...

Academic Report on

Singapore HSA Class D and Australia TGA Class III Medical Device Regulatory Overview & Strategy

Introduction

This chapter is a modified literature review on the overview of Australia Therapeutic Goods Administration (TGA) and Singapore Health Sciences Authority (HSA) with their respective medical device regulatory route and requirements pertaining to the product known as Vivace VX-1 a Transcatheter Mitral Valve Implantation (TMVI).

Background

Due to the fact that both TGA and HAS developed, published and update their medical devices guidance documents that are available to the public for general applicability to interpret and plan according to the agency’s rules and regulations. This chapter relies heavily on the extracted information (a part or a whole portion) obtained from the respective guidance documents and reports for comparison purpose. All the source and referencing are available in the footnote. This format of presentation was chosen because the author is using the actual, updated and transferrable regulatory information to discuss and try to put into practice in the ‘real’ workplace. The author (Edwin) is hoping to build up similar comparison review so as to benefits the various small and medium enterprise in the medtech industry in Singapore and Australia lacking of full-time medical device regulatory staffs to navigate the regulatory map and to made better regulatory decisions.

Product Assessment on Vivace VX-1

The Vivace VX-1 is a Transcatheter Mitral Valve Implantation (TMVI) that involves minimally invasive procedure treatment. Currently MitraClip is another medical device that serves similar intended purpose and is being supplied in both Australia and Singapore. With the acceptance of MitraClip in both countries, Vivace VX-1 will be register in Australia first and after gaining TGA issued conformity assessment certification, the market access to European and obtain CE certification can be faster. Even though after the US FDA and Australia TGA approval status of Vivace VX-1 registration, the Vivace VX-1 is not exempted for product registration in Singapore. The regulatory reason to register in Singapore is because the medical device approval by either one of the reference agencies (US FDA or Australia TGA), may qualify for abridged evaluation which is a quicker route of assessment with lower registration fees and charges.

The registration documents are required by Singapore HSA to be structured and submitted with the Common Submission Dossier Template (CSDT) which is also adopted by the various South-East Asia (SEA) countries and therefore the successful registration of Vivace VX-1 in Singapore may path the way into South East Asia (SEA) markets.

Potential Use

The Vivace VX-1 TMVI is targeted to benefit patients with moderate to severe mitral regurgitation without undergoing open heart surgery. The Vivace VX-1 aims to further serve patients who were previously denied of surgery. In Singapore, National University Hospital (2016) reported with the introduction of procedure treatment by Vivace VX-1, a majority of old age and multiple co-morbidities patients will now have another options for palliative treatment.

Target Population

In Singapore, National Heart Centre Singapore (2011) estimated 12 per cent of patients over the age of 75 will be affected in the coming years and 50 patients every year will be expected to receive the procedure treatment based on MitraClip procedure in. In Australia, Medical Services Advisory Committee Australia (2012) estimated 2,127 patients every year based on the figure populated from MitraClip procedure.

Do Vivace VX-1 Qualifies As A Medical Device ?

To better understand whether Vivace VX-1 qualifies as a medical device. There is a need to find out the qualified answer from the respective country’s Competent Authorities and their enacted legislation act that are regulating the medical devices industry.

In Australia, the Therapeutic Goods Administration (TGA) Medical Devices Branch is part of the Australian Government Department of Health and is responsible for regulating therapeutic goods including medical devices. TGA basics (No Date) The Health Sciences Authority (HSA) Medical Device Branch is entrusted with the responsibility of regulating medical device products placed on the Singapore market. HSA (2015

EdwinNgChunPeng_RAPS_Module 4_Individual Report_2015_2016 pg. 1

As reported by TGA Regulation impact statement (2013) and HSA Regulatory Framework (2015), the current regulatory framework for both Australia TGA and Singapore HSA are based on the model endorsed by the Global Harmonisation Task Force (GHTF) now known as International Medical Device Regulators Forum (IMDRF).

As a result, both of the countries issued their legislation act incorporating similar definition of a medical device, namely:

a medical device is any instrument, apparatus, appliance, material or other article (whether used alone or in combination, and including the software necessary for its proper application) intended, by the person under whose name it is or is to be supplied, to be used for human beings for the purpose of one or more of the following:

a) diagnosis, prevention, monitoring, treatment or alleviation of disease;

b) diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap;

c) investigation, replacement or modification of the anatomy or of a physiological process;

d) control of conception;

and that does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but that may be assisted in its function by such means; or an accessory to such an instrument, apparatus, appliance, material or other article. Therapeutic Goods Act Section 41BD (1989)

In Singapore, Health Products Act Chapter 122D (2007) modified and included the following two points to suit the Singapore context:

a) disinfection of medical devices;

b) providing information for medical or diagnostic purposes by means of in vitro examination of specimens derived from the human body,

In conclusion, the Vivace VX-1 qualifies as a medical device and fall within the definition of being used on humans and for the purpose of treatment of disease known as mitral valve disease and degenerative diseases.

Medical Device Risk Classification

Both Australia TGA and Singapore HSA apply risk-based classification rules to determine the risk classes.

According to HSA Regulatory Framework (2015), there are four risk classes and risk level, namely, Class A for Low Risk, Class B for Low-moderate Risk, Class C for Moderate-high Risk and Class D for High Risk medical devices. The classification of a medical device will depend upon a series of factors, including:

a) How long the device is intended to be in use;

b) Whether the device is invasive;

c) Whether the device is implantable;

d) Whether the device is active;

e) Whether the device contains a drug or biologic component

According to the Australian regulatory guidelines for medical devices TGA ARGMD Part 1 (2011), the classification levels are Class I for Low Risk, Class IIa for Low-medium Risk, Class IIb for Medium-high risk and Class III for High Risk medical devices. The manufacturer is responsible for determining the classification of a device using a set of classification rules based on:

a) Manufacturer’s intended use of the device;

b) Level of risk to patients, users and other persons (the probability of occurrence of harm and the severity of that harm)


c) Degree of invasiveness in the human body

d) Duration of use

How Vivace VX-1 Will Be Classified

As both Australia TGA and Singapore HSA classification rules are adopted from the guidance developed by the Global Harmonization Task Force. The assessment and classification of the risk class of Vivace VX-1 will be based on their respective set of rules in their published regulatory guidelines. The Australia TGA issued Australian regulatory guidelines for medical devices TGA ARGMD Part 1 (2011) and Singapore HSA published the guidance document on the Risk Classification of General Medical Devices. (HSA GN-13 2014)

There will be more than one rule that apply as the intended purpose and features of Vivace VX-1 includes implantable, surgically invasive, long-term use, for more than 30 days, with direct contact with the heart and contains non-viable animal tissues.

For Singapore, the classification rules that apply under the HSA GN-13 (2014) are as follow:

a) Rule 8: All implantable devices, and long-term surgically invasive devices intended to be used in direct contact with the heart.

b) Rule 14: All devices manufactured from or incorporating animal tissues and rendered non viable are Class D.

c) The Singapore HSA allows self-assessment with their Online Medical Devices Risk Classification Tool (2016) and after 3 online questions the result computed Rule 14 Class D which is an easier option than to go through the guidance documents.

For Australia, the classification rules that apply under the TGA ARGMD Part 1 (2011) are as follow:

a) Rule 3.4(4)(a) A surgically invasive device for long-term use to be used in direct contact with the heart, the central circulatory system or the central nervous system is Class III.

b) Rule 5.5(1)(a) Devices that contain animal tissues or derivatives that have been rendered non-viable are Class III.

In conclusion, when there may be more than one rule, the highest classification will apply. In the case of Vivace VX-1, all the rules pointed toward the highest spectrum. Therefore, the allocated risk classification will be Class D and Class III for Singapore and Australia respectively.

Risk assessment: What Is Required In A Risk Management Plan

For risk assessment, the Singapore guidance document HSA GN-17 (2014) Guidance on Preparation of a Product Registration Submission for General Medical Devices using the ASEAN CSDT stipulated the following information to be submitted:

a) Compulsory submission of a risk management report with the risk management activities conducted according to ISO 14971. A risk management report will contain details of the risk analysis, risk evaluation, risk control conducted for the medical device. The risks and benefits associated with the use of the medical device should be described.

b) This risk analysis should be based upon international or other recognized standards, and are appropriate to the complexity and risk class of the device.

c) A list of possible hazards for these devices must be prepared.

d) Indirect risks from device-associated hazards, such as evaluation of these risks against the claimed benefits of the device and the method(s) used to reduce risk to acceptable levels must be described.

e) The technique used to analyze risk must be specified, to ensure that it is appropriate for the medical device and the risk involved.

In Australia, the TGA have the TGA ACSMD (2016) Advisory Committee on the Safety of Medical Devices to seek further advise on the safety, risk assessment, risk management and performance of medical devices being supplied.


TGA ARGMD Part 1 (2011) stated that the Risk Management report have to follow the format of ISO14971 so as to comply with Essential Principles, Schedule 1 of the Regulations and section 3 of the Essential Principles with the following information for submission:

a) Risk Management Report to include the Essential Principles that would require a manufacturer to conduct a risk analysis to evaluate the known and foreseeable risks of using a device and ensuring that any undesirable side-effects are minimized and acceptable, when weighed against the benefits of the intended performance of the device

In conclusion, both Australia TGA and Singapore HSA accept the risk management process as defined in ISO 14971 with the overarching principle of applying the concept of risk-based approach to regulation and risk management to ensure that the level of regulation is proportional to the degree of risk involved and the benefits offered in using a medical device.

Labelling Requirements- Identification Of Device Labeling

In Australia, the use of Global Medical Device Nomenclature (GMDN) term and code as the device identification is required by the manufacturer as part of the conformity assessment procedures stated in TGA ARGMD Part 1 (2011). The GMDN structures consist of a single five-digit code, device category, template and preferred terms and device name. The five-digit code will have to be stated on labelling of Vivace VX-1.

The reasons for selecting and adhering the appropriate GMDN term and code are as follow:

a) Used by TGA to describe medical devices;

b) Assist in consistent assessment of devices before they are approved for supply;

c) Assist in ongoing monitoring of devices once they are available for supply

To obtain the correct GMDN term and code for Vivace VX-1.There is a need to join as a paying member and subscribe to the GMDN agency to access the database or even pay for creating a new term and code. For a company with annual medical device sales of less than 0.5 Euro million, the membership fee is 200 Euro with subsequent annual fee at 100 Euro GMDN Agency (No date).

In Singapore, the GMDN term and code is not mandatory for medical device product registration. However it is an added-values to Singapore HSA to include any given GMDN code or the Unique Device Identification (UDI) during reporting of adverse event.

Labeling Requirements- Translation Requirements

In Australia, under the Therapeutic Goods Order No. 37 (1991) the general labelling requirements have to be fulfilled in English language. This is aligning to Singapore HSA GN-23 (2014) labeling requirement for medical devices that product labeling and such must be in English.

In conclusion, the English language labeling requirements will apply across the board for Australia TGA and Singapore HSA labeling and label definitions, in which the HSA GN-21 (2015) Guidance on Change Notification for Registered Medical Devices defines label as:

a) Label (as set out in the Health Product Act): in relation to a health product or an active ingredient, means any written, printed or graphic representation that appears on or is attached to the health product or active ingredient or any part of its packaging, and includes any informational sheet or leaflet that accompanies the health product or active ingredient when it is being supplied.

In the same context, the Therapeutic Goods Order No. 37 (1991) defines label as:

a) Label is a display of printed information provided on or attached to a therapeutic device;

b) if the therapeutic device is within one of more levels of packaging, that level of packaging or any of those levels of packaging; or

c) Information that is sealed within a package, but does not include a label which is intended to be returned by the consumer to the supplier or manufacturer as a record of purchase.


Registration Requirements- In-Country Representation

In Australia, medical device must be registered and included on the Australian Register of Therapeutic Goods (ARTG) before they can be sold. A sponsor is responsible for applying to the TGA to have their therapeutic good included on the (ARTG). TGA Role of the sponsor (2015)

The definition of a sponsor in relation to medical devices as stated by the Therapeutic Goods Act 1989 (2016) are as follow:

a) a person who exports, or arranges the exportation of, the goods from Australia; or

b) a person who imports, or arranges the importation of, the goods into Australia; or

c) a person who, in Australia, manufactures the goods, or arranges for another person t manufacture the goods, for supply (whether in Australia or elsewhere);

but does not include a person who:

d) exports, imports or manufactures the goods; or

e) arranges the exportation, importation or manufacture of the goods;

on behalf of another person who, at the time of the exportation, importation, manufacture or arrangements, is a resident of, or is carrying on business in, Australia.

In Singapore, higher risk medical devices must be registered and included on the Singapore Medical Device Register (SMDR). A Registrant is responsible to register higher risk medical devices by applying for marketing clearance with HSA before placing such device products on the Singapore market. HSA Product Registration (2014)

The definition of a Registrant as stated in HSA GN-24 (2014) are as follow:

a) A Registrant, in relation to a registered medical device, is the person who applied for and obtained the registration of the medical device under the Health Products Act (Act);

b) A Registrant do not have to be licensed under the Act, however the registrant is required to register with HSA to facilitate product registration applications in Medical Device Information Communication System (MEDICS) e-Services.

In Singapore, based on HSA GN-02 (2011), Product Owner means a person who sells a medical device under his own name, or under any trade-mark, design, trade name or other name and who is responsible for designing and manufacturing, there are licensing to be applied based on the activity performed by that person in relation to medical devices. The three type of licensees are as follow:

a) Manufacturer’s license- any person who manufactures medical device in Singapore;

b) Importer’s license- any person who imports medical device into Singapore;

c) Wholesaler’s license- any person who supplies medical devices by wholesale (which include export) in Singapore.

Registration Requirements- Documentation required for submission of a device registration application

In Australia, TGA ARGMD Part 1 (2011) pointed out that the appropriate conformity assessment procedures to register Vivace VX-1 is the Part 1 (Full Quality Assurance Procedures) with Clause 1.6 (Examination of Design) with the Declaration of Conformity legislative reference as Schedule 3, Part 1 clause 1.8. For Manufacturing medical devices overseas for import into the Australian market. The overseas medical device manufacturers are required to obtain a TGA Conformity Assessment Certificate before the medical device can be included on the ARTG, and therefore be supplied into the Australian market. TGA Manufacturing medical devices (2016)

The summary as stated by TGA ARGMD Part 1 (2011) are as follow:

a) Part 1, Full quality assurance procedure encompasses design, production, packaging, labelling, and final inspection of a medical device;


b) Manufacturer must implement a full quality management system (that is, all clauses of ISO 13485 including clauses 7.3 and 7.5.2) and arrange for the quality management system to be audited by the

TGA or EU Notified Body. The TGA or EU Notified Body also assesses the manufacturer’s technical documentation for the medical devices, including clinical evidence.

c) This conformity assessment procedure can be applied to all devices that they manufacturer.

d) Part 1, Clause 1.6, Examination of Design Involves an examination of the design dossier for medical devices to which the manufacturer has applied a Part 1 conformity assessment procedure.

e) The technical documentation for the Class III and AIMD device (also referred to as a design dossier) must be submitted for examination to assess the compliance of the device with the Essential Principles.

f) This must be done in conjunction with Part 1 assessment of the quality management system; by either the TGA or the same EU Notified Body.

The requirements as stated by TGA ARGMD Part 1 (2011) are as follow:

a) A manufacturer applies this procedure to Classes AIMD, Class III, Class IIb, or Class IIa medical devices by implementing a full quality management system that takes into account the regulatory requirements for the: design, production, packaging, labelling, final inspection processes and implementation of an ongoing monitoring system.

b) A certificate will be issued by the TGA or an EU Notified Body if the quality management system is satisfactory. The certification will declare that the quality system conforms to the requirements of: Part 1 of the TGA regulatory requirements or Annex II section 3 of the EU Medical Device Directive (MDD) 93/42/EEC or Annex 2 section 3 of the EU Active Implantable Medical Devices Directive 90/385/EEC (AIMDD).

c) The assessment is against the requirements of the Australian legislation or the EU Directive. The assessment will include audit of the quality management system (all clauses of ISO 13485 or equivalent standard) and an assessment of the manufacturer’s technical documentation for the devices, including clinical evidence. The conformity assessment certification remains valid only if it is subject to periodic and satisfactory surveillance audits. Changes to the quality system that broaden the scope of the quality system or substantially alter the approved system, design or production arrangements may require further assessment or approval by the conformity assessment body. Once a manufacturer has obtained conformity assessment evidence under this Part they must then prepare an Australian Declaration of Conformity in accordance with clause 1.8 of Schedule 3 of the Regulations.

In Singapore, HSA-GN-15 (2014) documented that Vivace VX-1 (after fulfilling some criteria) are eligible for either the Abridged Evaluation Route or the Full Evaluation Route. The Guidance documents applicable to the product registration documentation requirement are as follow:

a) GN-17: Guidance on Preparation of a Product Registration Submission for General Medical Devices using the ASEAN CSDT Common Submission Dossier Template

b) GN-18: Guidance on Preparation of a Product Registration Submission for In Vitro Diagnostic (IVD) Medical Devices using the ASEAN CSDT

c) Annex 2 for GN-17 and GN-18 List of Configurations of Medical Devices to be Registered

d) GN-16: Essential Principles Checklist Template

e) GN-15: Letter of Authorisation Template

f) GN-20: Guidance on Clinical Evaluation (if applicable)

The requirements for the 2 different route are stated below:

Abridged Evaluation Route:

a) Eligibility Criteria- A medical device that has obtained at least one reference regulatory agency approval for a labelled use identical to that intended for marketing in Singapore at the time of submission will qualify for the abridged evaluation route.


b) Submission Requirements for Abridged Evaluation Route: Letter of Authorisation, Annex 2 for GN-17 and GN-18: List of configurations of medical devices to be registered, Proof of approval by reference regulatory agency, Common Submission Dossier Template (CSDT).

c) Common Submission Dossier Template (CSDT) with the following requirements:

a) Executive Summary

b) Essential Principles Checklist and Declaration of Conformity (Refer to GN-11 for the Declaration of Conformity template)

c) Device Description

d) Summary of Design Verification and Validation Documents

− Summary of Preclinical Studies including the sterilization validation and shelf life studies, if applicable- Clinical Evidence – Clinical Evaluation Report

e) Proposed Device Labelling

f) Risk Analysis

g) Manufacturer Information− Name and address of the manufacturing site(s)− Proof of Quality Management System – Eg: ISO13485 Certificate, Conformity to US FDA Quality System. Regulations or Japan MHLW Ordinance 169− Manufacturing Process – Flow Chart

Full Evaluation Routes:

a) Eligibility Criteria- A medical device that has not obtained any prior approval from any of HSA’s reference regulatory agencies at the point of application will be subject to the full evaluation route.

b) Submission Requirements for Full Evaluation Routes: Letter of Authorisation, Annex 2 for GN-17 and GN-18: List of configurations of medical devices to be registered.

c) Common Submission Dossier Template (CSDT) with the following requirements:

a) Executive Summary

b) Essential Principles Checklist and Declaration of Conformity (Refer to GN-11 for the Declaration of Conformity template)

c) Device Description

d) Detailed Information of Design Verification and Validation Documents − Full reports of Preclinical Studies including the detailed sterilisation validation and shelf life studies if applicable − Clinical Evidence – Clinical Evaluation Report including publications and full reports of the studies referenced in the clinical evaluation report

e) Proposed Device Labelling

f) Risk Analysis

g) Manufacturer Information − Name and address of the manufacturing site(s) − Proof of Quality Management System – e.g. ISO13485 Certificate, Conformity to US FDA Quality System Regulations or Japan MHLW Ordinance 169 − Manufacturing Process – Flow Chart

Registration Requirements- Submission Platform

In Australia, TGA Business services (2015) stated that Sponsors have to use the online services to complete the registration applications. The Sponsors need to apply a client identification number (Client ID) and also apply to access to the online TGA: electronic Business Services (eBS) system. Beside managing therapeutic good registration applications, the Client ID and access to eBS system are required for the following activities:


a) Supply in Australia

b) Manufacture

c) Import into Australia

d) Export from Australia

e) Submit clinical trial notifications (CTNs)

f) Notify about adverse events or recalls.

g) View and cancel current Australian Register of Therapeutic Goods (ARTG) entries

h) Generate certificates online.

In Singapore, MEDICS e-Services can be created and login either with a SingPass or HSA PIN, a CRIS company account and a Registrant's Account. According to MEDICS e-Services (2015) the Medics allow the following transactions:

a) Dealer's Licence & Registrant's Account

b) Product registration

c) Export-Only Unregistered Medical Devices

d) Certificates

e) Withdrawal

f) Amendment for Dealer's license / Submission of update of Class A Medical Device Exemption List

g) Amendment for Registrant's account

h) Cancellation

i) Change Notification for Registered Devices

j) Change of Business Information

k) Renewal of dealer's licence

l) Retention of SMDR device listing

m) Global Update of Applicant Details

n) Assignment of Importer Wholesaler Ship and Management of View Access to Importer and Wholesaler

Costs: Fees and Charges Associated With Initial Regulatory Compliance

In Australia, the TGA operates on a 100% cost-recovery basis and collects its revenue primarily through annual charges, and application, evaluation, audit, conformity assessment, application audit and assessment fees. Fees are charged for applications, assessments, and audits for new medical devices. Fees are also payable when there are changes that the TGA needs to assess. TGA ARGMD Part1 (2011)

TGA Fees and charges (2016) reported the breakdown of the costs for Vivace VX-1 (Class III medical device) as follow:

a) Application fee- $1,265 AUD to include a medical device in the ARTG


b) Application audit assessment fees- $1,265 AUD for a medical device that is a prosthetic heart valve

c) Application audit assessment fees- $3,700 AUD for Level 1 - verification of sponsor's application and evidence of conformity (for application based on a Europe certificate)

d) Application audit assessment fees- $6,790 AUD for Level 2 - Level 1 activities plus review of evidence of conformity (for application based on a Europe certificate)

e) Medical device clinical trial- $345 AUD for Clinical trial notification (CTN)

f) Medical device clinical trial- $17,600 AUD for Clinical trial exemption (CTX) evaluation

g) Application fee for conformity assessment procedures- $900 AUD for all type of conformity assessment procedures

h) Initial assessment fee of conformity assessment- $28,600 AUD for Full quality management system inspection: Schedule 3, Part 1

i) Initial assessment fee of conformity assessment- $56,300 AUD for Design examination: Schedule 3, Clause 1.6

j) Surveillance inspection fee- $8,320 for Full quality management system surveillance inspection: Schedule 3, Part 1

In Singapore, Importers and wholesalers of medical devices in Singapore are required to meet GDPMDS (Good Distribution Practice for Medical Devices in Singapore) requirements, the objective of which is to ensure the quality and integrity of medical devices throughout the distribution process. The GDPMDS certificate is issued by third party certification bodies accredited by the Singapore Accreditation Council, and is valid for three years with an annual site audit, in accordance with international ISO practice. The cost of applying and maintaining the GDPMDS certification fees varies between third party certification. HSA About GDPMDS certificate (2012)

The HSA Fees and Charges (2015) reported the Product Registration and Applicable Evaluation Fees for Vivace VX-1 (Class D medical device) as follow:

a) Dealer's Licence Fees- $1,000 SGD for a new application for an Importer licence

b) Dealer's Licence Fees- $1,000 SGD for a new application for a Wholesaler licence

c) Application fee- $500 SGD payable for product registration

d) Evaluation fee- $5,700 SGD for Abridged Evaluation Route

or

e) Evaluation fee- $11,400 SGD for Full Evaluation Route

Costs: Fees and Charges Associated With Ongoing Regulatory Compliance

TGA Fees and charges (2016) reported the breakdown of the ongoing costs for a Class III medical device as follow:

a) Application audit assessment fees- $6,790 AUD for Considering submissions to the Secretary in relation to a proposed suspension of a kind of medical device from the ARTG.

b) Application audit assessment fees- $430 AUD for Variation to an ARTG inclusion entry if the entry is incomplete or incorrect.

c) Miscellaneous- $430 AUD for Application for consent of Secretary to importation into Australia, supply for use in Australia, or exportation from Australia of a medical device that does not conform to the essential principles

d) Changes Fee to conformity assessment- $17,200 AUD for Full quality management system inspection: Schedule 3, Part 1

e) Changes Fee to conformity assessment- $33,900 AUD for Design examination: Schedule 3, Clause 1.6


f) Review of certificate of conformity assessment fee- $50,900 AUD for Design examination re-assessment: Schedule 3, Clause 1.6

g) Annual charges of $1,200 AUD are charged to the sponsor TGA for retention of product listing in the ARTG

In Singapore, applying a Registrant's account to register medical devices on behalf of product owners do not incur charges. For the others fees and charges, HSA Fees and Charges (2015) and HSA Target Processing Timelines (2014) reported the breakdown of the ongoing costs and the target turn-around-time [TAT] for a Class D medical device as follow:

a) Annual Retention Fees- $120 SGD for per Class D Medical Devices listed on SMDR

b) Dealer's Licence Fee- $1,000 SGD for annual renewal for an Importer licence

c) Dealer's Licence Fee- $1,000 SGD for annual renewal for a Wholesaler licence

d) Licence amendment Fee- $150 SGD for any amendment to approved Importer licence

e) Licence amendment Fee- $150 SGD for any amendment to approved Wholesaler licence

f) Change Notification Fee- $0 (No fees applicable for Notification Changes) [TAT: Immediate]

g) Change Notification Fee- $500 SGD for Administrative Changes [TAT: 30 working days]

h) Change Notification Fee- $2,800 SGD for Technical Changes [TAT: 90 working days]

i) Change of Registrant Fees- $800 SGD for any changes of approved Registrant

Timelines Of Device Registration Process

In Australia, the TGA application instructions (2015) reported the industry-agreed time frames for assessments for conformity assessment certification are target times only and are not legislated. While the TGA will attempt to meet target times, it may not always be possible (e.g. when onsite inspections are required as part of a QMS certificate application assessment).

The TGA endeavours to meet industry-agreed time frames for assessments for conformity assessment certification. All time frames are given in TGA working days and start from the date the e-Business application fee is received. A working day is any day other than a weekend, a public holiday in the Australian Capital Territory, or when the TGA is waiting on information requested or waiting for payment of fees.

The assessment timeframe with documentation that are of good quality, application that is well-structured, no omissions in the submission, and that fees are paid promptly are as follow:

a) Target time frames of 90 working days for Full Quality Assurance System(QMS) certificates (for Part 1 only)

Additional of 60 working days if ACMD advice required

b) Target time frames 120 working days for Design Examination certificates (for part 1, Clause 1.6)

Additional of 60 working days if ACMD advice required

In Singapore, HSA Target Processing Timelines (2014) reported that HSA shall endeavour to meet the target processing timelines for all submitted applications. Applicants should ensure that the dossiers are complete before submission. Incomplete submissions and untimely responses to queries will result in unnecessary delays to the registration process and thus, will have a negative impact on the target processing timeline . The target turn-around-time (TAT) for applications commences from the date of receipt of the application and does not include ‘stop-clock time' due to input requests for clarifications and additional information. The target turn-around-time (TAT) are as follow:

a) 310 Working Days for Class D Full Evaluation Route


b) 220 Working Days for Class D Abridged Evaluation Route (with One reference agency approval [USA FDA PMA or Australia TGA]

c) The Vivace VX-1 is excluded from being registered via Expedited Class D Registration Evaluation Route because it is an implantable device that is in direct contact with the central circulatory system (direct contact with the heart)

Post-market Requirements- Post-market Monitoring

In Australis, TGA have it own diligence check on the environmental scanning to collect and review of scientific and medical literature, media reports and regulatory news to identify safety issues that require further investigation. TGA rely on primary source of Information by Media, industry, governments, other countries regulatory bodies, academia and even consumers. In Singapore, the HSA’s Vigilance and Compliance Branch conduct the various post-market surveillance related activities; Adverse event monitoring, Risk assessment and management, Risk communication and regulatory research, Environmental scanning for potential issues relating to health products’ safety, quality and efficacy, medical advertisement and compliance monitoring.

TGA ARGMD Part 3 (2011) reported that once a medical device has been included in the ARTG the device must continue to meet all the regulatory, safety and performance requirements and standards that were required for the approval. For Post-market monitoring, TGA mandated annual reporting of problems for Class III medical devices Sponsors have to provides three consecutive annual reports to the TGA following inclusion of the device in the ARTG. The Annual reports are due on 1 October each year. Reports should be for the period 1 July to 30 June. The annual report must include all complaints received by the manufacturer relating to problems with the use of the device that have been received by them over the year. Complaints received by the manufacturer relating to the use of the device, including its supply under a different name, in other countries where the device is available must also be included.

In Singapore, there is no annual report of problem for Class D registered medical device. The HSA required Manufacturer/Product owner and registrant to uses a number of post-marketing risk assessment approaches to ensure the continued safe use of medical devices. These measures include reporting to healthcare professionals and the mandatory reporting of adverse events by manufacturers and registrant is an important part of the post-market surveillance system.

For Singapore, the Post-market monitoring activities includes change notification on any technical/ review/ administrative change, as defined in GN-21 Guidance on Change Notification, made to registered medical and have to require approval from the HSA prior to supply of these medical devices. The manufacturer/ product owner shall assist the Health Sciences Authority with any request for information on registered medical devices. The product owner shall provide post-market support and assistance to the registrant for medical devices registered under this listing.

Post-market Requirements- Post-market Vigilance

For Post-market Vigilance activities TGA ARGMD Part 3 (2011) stated the following requirements, The purpose of medical device vigilance is to improve the health and safety of patients, users, and others by reducing the likelihood of adverse events being repeated. This can be achieved by:

a) Adverse event (AE) reporting- Reports regarding deficiencies in labelling, instructions or packaging, defective components, performance failures, poor construction or design of medical devices marketed in Australia. Primary Source of Information by Sponsors.

b) Adverse event reporting with Device Incident Report (DIR) using Incident Report Investigation Scheme (IRIS)

c) Safety Alert by sponsor voluntarily that is not considered to be a recall

d) Safety Advisory

e) Urgent Medical Device Recall for Product Correction-

• Involve temporary removal from the market or from use

• Permanent removal of deficient medical devices from the market or from use

f) Urgent Medical Device Recall


g) Pharmacovigilance audits- A medical device manufacturer's adverse event records are inspected as part of the Quality Management System (QMS) assessment. Primary Source of Information by Manufacturers

h) Reporting on vigilance activities- TGA report on the monitoring and evaluation of information related to the safety and efficacy of marketed therapeutic products through a variety of means. Information is shared with the public and with health professionals through the Medicine Safety Updates (MSU) and through safety alerts published on HSA website. HSA have also established mechanisms to alert the public to recalls of therapeutic products, to provide the public with adverse event data associated with medicines and medical devices and to provide the public with an early warning communication system to advise of potential safety issues for medicines and medical devices.

In Singapore, HSA-GN-05 (2013) reported that the mandatory reporting of Adverse Event AEs by medical device dealers is an important part of the post-market vigilance system. The objective of AE reporting and others relevant activities are to improve protection of the health and safety of patients, users and others by disseminating information that may reduce the likelihood of, or prevent repetition of AEs. This can be achieved by:

a) Mandatory Reporting for Adverse event with reporting Form MDAR1 for reporting of adverse events not related to clinical trial using the email, fax or postal mail submission to Compliance Branch Vigilance, Compliance and Enforcement Division.

b) Medical Device Alerts by HSA-The Medical Device Alert aims to increase the awareness of specific medical device safety issues or events amongst healthcare professionals. The articles also serve to encourage medical device adverse event reporting, which forms part of HSA’s post-market safety surveillance programme for medical devices. The alert is distributed to all physicians, dentists and pharmacists.

c) Dear Healthcare Professional or Dear Doctor letter containing suggested actions, advisory note, recommended actions to be taken to manage important new medical device issues such as new warnings, other safety information, or important changes to the prescribing information (labelling). It is often issued to communicate risk to medical device users typically in response to an adverse event or to provide additional information to enable safer and/or effective use of medical device to healthcare practitioners. HSA GN-09 (2016)

d) Field Safety Notice (FSN) is used to communicate to device users in relation to a Field Safety Corrective Action (FSCA), it includes the product identifier of affected units and a field for the consignee to acknowledge the understanding of the contents of the FSN. HSA GN-10 (2016)

e) Medical Device Field Safety Corrective Action taken to reduce a risk of death or serious deterioration in the state of health associated with the use of medical device, including the return of the medical device to its product owner, replacement or destruction of the medical device, any action regarding the use of the medical device that is taken in accordance with the advice of its product owner, the clinical management of any patient who has used the medical device, the modification of the medical device, the retrofitting of the medical device in accordance with any modification to it or any change to its design by its product owner, the making of any permanent or temporary change to the labelling or instructions for use of the medical device and any upgrade to any software used with the medical device, including any such upgrade carried out by remote access. HSA GN-10 (2016)

f) Field Safety Corrective Action reporting with Form MDRR1 for Notification/Preliminary reporting of FSCAs that require initiation in Singapore, with Form MDRR2 for Follow Up/Final reporting of FSCAs that require initiation in Singapore and Form MDRR3 for reporting of medical device related post-market information. HSA GN-10 (2016)

g) Medical Device Recall notification with time frame of within 24 hours before carrying out any recall. The report required are as follow: Preliminarily report have to be submitted containing as much of the recall detail within 24 hours from the commencement of the recall and a final report is to be submitted to HSA within 21 days from the date of commencement of the recall. HSA GN-02 (2015)

In conclusion, both TGA and HSA have developed agreements and documents to promote a harmonised approach to medical device regulation around the world by modelling and customizing the various GHTF models. As a result, the timeframes for submitting adverse event reports are similar:

a) 2 Days for serious public Health threat

b) Within 10 Days Of Becoming Aware Of A Death Or Serious Injury

c) Within 30 Days Of Becoming Aware Of An Event That Might Have Led To Serious Injury Or Death


Both TGA and HAS have emphasized and often shared regulatory information on implementation of Post-market surveillance systems, adverse incident reporting programs and vigilance activities. Memorandum of Intention of Cooperation (2002). Therefore, the best practise in methods and ways in fulfilling the Post-market requirements can be shared among TGA and HSA and to localized to each country specific needs and then be transferred to the Manufacturer and Sponsor (TGA) and Product Owner and Registrant (HSA) to implement them.

Insurance and Reimbursement

In Australia, according to HTA Medicare Benefits Schedule (2011) reported that where a medical device is considered for reimbursement, the TGA approval process must be completed before the reimbursement decision is finalize. The listing, registration or inclusion on the ARTG is generally a requirement for any medical device to enable it to be listed for reimbursement under an Australian Government funding program known as the Medicare Benefits Schedule (MBS). During the review stage, the Department of Health and Ageing will work with Medical Services Advisory Committee (MSAC) to undertake an assessment on the medical devices for Medicare Benefits Schedule (MBS) listing and inclusion.

International Society for Pharmacoeconomics and Outcomes Research (ISPOR) (2016) reported that the Medical Services Advisory Committee (MSAC) will also assist the Prostheses List Advisory Committee (PLAC) to manage the Australian Prostheses List (PL) which comprises over 10,000 implantable devices eligible for reimbursement by private health funds. Whereas MSAC reviews and determines the listed price of services provided in the delivery of tests or devices, the PLAC does not determine the reimbursement benefit for the medical technology itself. Implantable medical devices are reviewed by the PLAC and a benefit is assigned for the device itself. (Note: MSAC determines the fee for the clinician to implant the device).

TGA Administration of the Prostheses List (2016) reported that under Section 72-1 of the Private Health Insurance Act 2007 (the PHI Act), private health insurers must pay at least the minimum benefit accorded to each prosthesis listed on the List:

a) for which an insured person has appropriate cover;

b) that are provided as part of an episode of hospital treatment or hospital-substitute treatment; and

c) for which a Medicare benefit is payable for the professional service associated with the provision of the prosthesis.

d) Medical device sponsors and suppliers apply to list prostheses on the Prostheses List so they will be reimbursed by private health insurers. By doing so they gain access to the private health market. The activities involved in processing applications and maintaining listings on the Prostheses List include:

TGA Administration of the Prostheses List (2016) stated that since 15 January 2009, the application fees have been $600 to apply to list a new prosthesis, $200 to initially list a new prosthesis, and $200 each six months to maintain a listing.

Singapore is unlike Australia where there is no specific private health insurance/ Government reimbursement regarding Medical Devices to be used by the end-customers. But Singapore Economic Development Board (2016) reported that Singapore Government is providing universal coverage for Singaporeans with multiple layers of care.

ASEAN Briefing (2016) reported the Overview of Healthcare Plans in Singapore:

a) Medisave Medisave is a national medical savings scheme which lets individuals set aside part of their income into their Medisave Accounts. Every employee can contribute eight to 10.5 percent of their monthly salary to cover future personal or immediate family’s hospitalization, day surgery and certain outpatient expenses.

How much an employee can contribute depends on their age group. Savings can be withdrawn to pay the hospital bills of the account holder and their immediate family members, in line with the financing framework.

b) MediShield Life- On November 1, 2015 MediShield was replaced was MediShield Life, which will offer the following: if a patient is faced with a large hospital bill, the plan offers better protection and higher payouts, which will ease payment demands (Medisave/cash) on patients Full coverage for all Singapore Citizens, including Permanent Residents, which covers aging citizens and those with pre-existing conditions.

c) Lifelong protection- MediShield is administered by the Central Provident Fund (CPF) Board and is essentially a basic healthcare plan. Additionally, it covers selected and expensive outpatient treatments, such as dialysis and chemotherapy.


d) Medifund- Medifund was set up by the Government as an endowment fund to help Singaporeans in need. It offers security for patients who face large bills and financial difficulties in paying them after obtaining government subsidies, MediShield Life, private Integrated Shield Plans, Medisave and cash.

e) Eldershield- The ElderShield plan was set up for people of old age and is an affordable severe disability insurance scheme which provides basic financial protection to those who need long-term care. It takes the form of a monthly cash payout to help cover out-of-pocket expenses that arise for the care of a severely-disabled person.

Summary Comparison

Even though the TGA required full assessment of detailed technical documentations as compared to HSA less tedious product registration documentation and templates. The documentation required for product registrations for both HSA and TGA are very identical mainly because Australia TGA is one of the Global Harmonization Task Force (GHTF) now known as International Medical Device Regulators Forum (IMDRF) founding members and Singapore HSA model their regulatory framework and requirements with the GHTF model. The ISO 13485 Quality System is accepted by both HSA and TGA. The submissions documentations of the Technical an Design Dossier are similar in nature because HSA accept Common Submission Dossier Template (CSDT) and TGA accept the Summary TEchnical Document (STED) which consist of identical components. There is no country of origin approval requirement and the type testing requirements for both HSA and TGA can be conducted in-house or in an accredited testing facilities which are only upon request by the regulatory authority.

The following charts are the summary and comparison of regulatory requirements for Singapore HSA and Australia TGA.

Countries Competent Authority/Regulatory Bodies

Classification Quality System Regulation Premarket Evaluation Common Regulatory

Areas

Singapore HSA

Health Sciences Authority (HSA) Medical Device Branch Health Products Act (Chapter 122D) Year 2007 Health Products (Medical Devices) Regulations Year 2010

Class D HSA GN-13 (2014)Rule 8 (direct contact with the heart) Online Medical Devices Risk Classification Tool (2016) –Rule 14 (animal tissues)

GDPMDS (Required) Basic standard (Submission) (horizontal standard) ISO 13485, ISO 14971 etc + Group standard (Submission) (semi-horizontal standard): ISO 10993, ISO 11135 etc

Abridged Evaluation Route or the Full Evaluation Route + ASEAN Common Submission Dossier Template (CSDT)

Follow Closely with GHTF [Now IMDRF]- Pre-market Evaluation Model

Australia TGA

Therapeutic Goods Administration (TGA) Medical Devices BranchTherapeutic Goods Act (Chapter 4) Year 1989 Therapeutic Goods Regulations Year 1990 Therapeutic Goods (Medical Devices) Regulations 2002

Class III TGA ARGMD (2011) Rule 3.4(4)(a) (direct contact with the heart) Rule 5.5(1)(a) (animal tissues)

Manufacturer must Implement a full quality management system (all clauses of ISO 13485 and arrange for the quality management system to be audited by the TGA

Part 1 (Full Quality Assurance Procedures) + Clause 1.6 (Examination of Design Global Medical Device Nomenclature (GMDN) Codes required for assessment of devices before they are approved for supply


Countries Costs associated with initial and ongoing regulatory compliance

Timelines (After Submission Until Approval)

Clinical trials Costs and Scheme

Singapore HSA

Overall Cost: US$4,600 to US$8,800 Application fees: $500 SGD| Evaluation Fees: Abridged- $5,700 SGD/ Full- $11,400 SGD| Annual Retention Fees: S$120 SGD

220 Working Days for Abridged | 310 Working Days for Full Evaluation Route

Nil

Australia TGA

Overall Cost: US $82,000 Application fees: $1,265 AUD, Application audit assessment fees: Level 1 - verification of sponsor's application and evidence of conformity- $3,700 AUD, Level 2 - Level 1 activities plus review of evidence of conformity- $6,790 AUD, Application for conformity assessment- Application fee- $960 AUD, Full quality management system inspection: Schedule 3, Part 1- $28,600 AUD, Design examination: Schedule 3, Clause 1.6- $56,300 AUD, Surveillance inspections - conformity assessment- $8,320 AUD | Annual Retention Fees: $1,200 AUD

330 Targeted time frames (Working Days)

There are two schemes under which clinical trials involving unapproved therapeutic goods may be conducted in Australia, the Clinical Trial Notification (CTN) Scheme and the Clinical Trial Exemption (CTX) Scheme. Clinical trial notification (CTN) @ $345.00 AUD / Clinical trial exemption (CTX) evaluation @ $17,600 AUD


Countries Adverse Event Reporting Post Approval Studies (PAS by US FDA) Example: Clinical, Animal or Laboratory Studies

Post Market Surveillance Compliance to QMS (Complaint Handling and Reporting to regulatory authorities)

Singapore HSA

2 Days- Serious for Public Health Threat

Within 10 Days Of Becoming Aware Of A Death Or Serious Injury

Within 30 Days Of Becoming Aware Of An Event That Might Have Led To Serious Injury Or Death

TGA uses Global Medical Device Nomenclature (GMDN) Codes for ongoing monitoring of devices.GMDN and UDI are added values to Singapore HSA during reporting of adverse event

HSA review stages are during Pre-Market application. Multiple Input Requests will be issued for full clarifications and additional information

Post-market Monitoring- Report On Demand Basis Adverse event (AE) reporting, Field Safety Notices (FSN), Medical Device Alerts, Medical Device Recall,Field Safety Corrective Actions (FSCA) Pharmacovigilance audits

Australia TGA

Addendum Report Submission May Be Required TGA review stages are during Pre-Market application. Multiple Request for Information (S41JA) will be issued for full clarifications and additional information (Application Audits apply for High Risk Class)

Post-market Monitoring- (1st 3 Years After Inclusion in ARTG) Yearly Report Monitoring [1st October Every Year] Adverse event (AE) reporting,Incident Report Investigation Scheme (IRIS), Safety Advisory or Alert, Urgent Medical Device Recall for Product Correction, Urgent Medical Device Recall Pharmacovigilance audits


Key Points and Conclusion

The registration pathways for Australia will be longer than Singapore because of the lead-time to obtain a TGA Conformity Assessment Certificate to supply in Australia. Adding further to the lead time is the substances of animal tissues that will requires demonstration of compliance with risk-management procedures, controls on sourcing, collection and handling of animal origin materials and validation of inactivation processes for viruses and transmissible agents. Even after the Conformity Assessment Certificate have being issued, the TGA have the right, entry and inspection powers to enter the US manufacturing premises (outside Australia) to check for compliance and regulatory matters. The plan to use the Class D Abridged registration route will be depending on either US FDA Premarket Approval (PMA) or TGA approval in the event of approval is delayed or denied.

With the Unique Device Identification (UDI) going to be implemented in US FDA and China CFDA soon, the device traceability effort and post-market surveillance effort will be more comprehensive for Singapore HSA as there is also the TGA Global Medical Device Nomenclature (GMDN) to follow.

There are legal obligation to furnish accurate declaration during pre and post market to HSA and TGA especially in term of the submission of the Essential Principles and Evidence of Conformity because any intentional misrepresentation constitute criminal offences in Australia and Singapore for the manufacture/product owner and sponsor/registrant.

In Australia, there are Criminal Offences under S41MA and Civil Penalties under S41MAA of the Therapeutic Goods Act 1989, for persons who import, supply or export medical devices that do not meet the Essential Principles for safety and performance. In Singapore, any false declaration in Essential Principles and Evidence of Conformity is an offence under the Health Products Act (Cap. 122D) and may result in the cancellation of registration of the above medical devices under Section 37(1) of the Act.

The device registration license validity is unlimited (lifetime) for US FDA and South Korea MFDS (KFDA), five years for China CFDA and Australia TGA and one year for Singapore HSA. The one year validity in Singapore seemed to be a disadvantage factor but in fact, the HSA have an auto renewal of device registration license scheme annually and looking at the cost factor, the annual retention fees is only $120.00 SGD to maintain the medical devices listing on SMDR. Conversely, the cost of maintaining product license and TGA Conformity Assessment Certificates required for recertification is in the range of $17,200 AUD to $33,900 AUD, more fee will be occurred for changes to the Full quality management system inspection: Schedule 3, Part 1 or the Design examination: Schedule 3, Clause 1.6. Conformity.


Because of the higher cost, there is a business objective and a need to sell more Vivace VX-1 and hopefully the Vivace VX-1 can be approved for reimbursement under Australian Government funding program known as the Medicare Benefits Schedule (MBS). There is a need to also get the Vivace VX-1 to be approved and listed as one of the implantable devices in the Australian Prostheses List (PL) in order to be eligible for reimbursement by private health insurers (funds). The Government’s reimbursement model and private health insurers’ structure together with the solid clinical evidence and demonstration of significant cost decrease and high clinical/economic value should allow Vivace VX-1 to obtain the higher payout especially for the Medicare Benefits Schedule (MBS).

Beside higher regulatory and compliance cost in Australia. TGA have some cost saving measure like the Annual Charge Exemption (ACE) scheme allows for the exemption of annual charges ($1,200 AUD ) until a product first generates turnover. The scheme allows sponsors to enter their products on the ARTG in advance of their marketing with no annual charge. Annual charge exemption scheme (2016).

This prepared report and the recommendations were not intended to be exhaustive .During pre-market, the key to success for placing any high risk medical devices in any countries are highly dependent on the quality and qualification of the manufacturer, it is crucial especially in the area of design transfer in ensuring that the design of the medical device can be correctly translated into production specifications (product development to manufacturing) The support of the local representations (sponsor and registrant) are equally important for post-market compliance and follow up. The key ingredient is to choose the right standards, guidance and regulatory guidelines to follow and be in touch with the regulatory bodies and authorities to address any ambiguous areas. In the course of researching, the author depend heavily on the guidance documents and sincerely hope that the extracted portion will allow a holistic and high level understanding for the readers.

End of Report


Reference

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End of References


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