醫療器材研發與產業

醫療器材研發與產業

林啟萬 臺灣大學

02-33665272; cwlinx@ntu.edu.tw

內容

• Part I

– Fast facts and Vision

• Part II

– The impacts of modern medical technologies – Some term definition

– Total Product Life cycle management – Quality system (GxP)

• Part III

– Examples

Part I

4

Stages of Taiwan Economic and Industrial Development

Industrial Policy

• FDI incentives

• Export incentives

• Industrial technology development

• Industrial park development

• Infrastructure development

• Economic deregulation, introduction of free-market

• Encouraging investment

• Strengthening of environmental protection

• Encouraging investment

• Encouraging R&D

• Information infrastructure development

• Developing knowledge-intensive manufacturing and service industries

Phases of Developm

ent

Import-

substitution light Industries (1953-1960)

Export-oriented industries and heavy industries

(1961-1980)

High-tech industries, export-oriented industries and expanded services (1981-1990)

Expansion of High-tech industries exports, and knowledge-intensive service industries

(1991～)

Innovation-driven Efficiency-driven

Factor-given

Economic growth rate

7.7%

(1953-1960)

9.8%

(1961-1980)

8.0%

(1981-1990)

5.1%

(1991-2008)

Representative

industries

Textiles / Toys / Umbrellas

Metal Manufacturing / Bicycles Electronic Components / IT Products

Semiconductors and TFT LCD

ICT and associated components

Solar power and LED

1980 1990 2000

1970 1960

1950 2010

R&D Inputs: Expenditure and Manpower

Source：Main Science and Technology Indicators, 2008/2, OECD

Notes：1. Expenditure scale, calculated on Purchasing Power Parity (PPP), is indicated by colored circular area.

2. Figures behind the country indicate R&D expenditure as a percentage of GDP(%), researchers per 1,000 employment (FTE), and R&D expenditure (Billion USD PPP) respectively.

3. The data year of Finland is 2008 (manpower of 2007), Germany, Sweden, Taiwan and

U.S.A. are 2007 (U.S.A. manpower of 2005), while China, Japan, Korea, and U.K. are based on 2006.

Finland(3.41, 15.7, 6)

Sw eden(3.63, 9.8, 12) Korea(3.22, 8.7, 36)

U.S.A.(2.68, 9.6, 369)

Austria

Taiw an(2.62, 10.0, 18)

Germany(2.53, 7.2, 69) Denmark

Singapore

Japan(3.39, 11.1, 139)

Australia

U.K.(1.78, 5.9, 36) Netherlands

Canada

Czech Republic

China(1.42, 1.6, 87) Ireland

0 5 10 15

1 2 3 4

R&D Expenditure / GDP (%) No. of Researchers / 1,000 Employment (FTE)

5

Coordination ~ from basic research to

technology development and commercialization

Type of Research

Government Funding Agencies

In R&D

University &

Government Labs.

Non-profit Research Institutes

Industries

Fundamental Research

NSC, MOE, DOH

MOEA, MOTC, MOD, COA, DOH, EPA, etc.

Technology Development

Universities, Academia Sinica, Etc.

ITRI, NHRI, NARL, INER,

CSIST, etc.

Public/

Private Enterprise

Research Laboratory Inst. for Nuclear

Energy Research, ChungShan Inst.

of S&T, National Synchrotron

Radiation Research Center, etc.

Implementation

Applied

Research

7

Short- to mid-term strategies are to encourage academic and industrial R&D, so as to enhance industrial technical capabilities and strengthen the technology dissemination

mechanism. Long-term strategy is to encourage industries to conduct cutting-edge

applied research and technology integration. NSC’s changes to I-U cooperation guidelines will include business management service-type I-U projects and international I-U projects.

1 2 3

Experimental development

Applied research

Basic research Experimental

development Applied research

Basic research

Industrial capabilities Academic

capabilities

Original technologies Cutting-edge

I-U cooperation

1

2 4 3

4

Direct government funding for academic R&D and innovation

Direct government funding for industrial R&D and innovation

5

5

I-U Cooperation

Improvement Strategies

Program to Upgrade Industrial Tech

& Enhance HR

I-U Coop Research Projects

Academic Technology Development

Programs Implement

current TT mechanisms

Bridging

Industries

University

Mutual trust, respects, win-win

Mutually cooperative model:

raise companies’ capability, develop cutting-edge technology, strengthening the management of R&D results and intellectual property

National S&T Programs - bridging resources together

University-Industry Cooperation

Biotechnology Takeoff Package

Biotechnology Takeoff Package Program (2011-2016)

Genomic medicine:

building a research center to identify disease-causing genes of regional

significance, studying pathological

mechanisms, etc.

Biotech and drug development: covers new drug screening and discovery (including

small molecules, natural products, proteins,

antibodies, vaccines) and biochips, etc.

(Integrated efforts made by National Science Council,

Ministry of Economic Affairs, Department of Health)

Hsinchu Science Park 653ha (since 1980)

Tungluo (350ha) under development

Chunan (123ha)

Hsinchu Biomedical Park

(38 ha) under development Longtan (107ha)

Ilan

preparation)

Central Taiwan

Science Park 413ha (since2003) Huwei (97ha)

Kaohsiung Science Park (570ha)

Southern Taiwan Science Park 1,038ha (since 1996)

Administrations Hsinchu :1,373 ha

Central: 1,481 ha Southern：1,608ha

Total:4,462ha

Science Parks Development

Hsinchu Southern Taiwan Central

Taiwan Total

Operational

Since

1980 1996 2003

No. of Park- registered

Companies

451 158 92 701

No. of

Employees

130,577 48,136 20,736 199,449

Gross Revenue

( US$Million)

2006

35,028 14,113 5,578 54,719

2007 35,819 17,466 8,303 61,588 2008 31,453 17,109 8,944 57,506

Science Parks Statistics

12

Strong IC Industry Development Industry output ranked 4th in the world With wafer foundries ranking 1st in the world And IC design 2nd in the world behind the US

With the IC Industry as Example

United Microelectronics Corporation (UMC), 1979

1^st 4” Wafer Fab in Taiwan

Vanguard International Semiconductor Corp. (VIS), 1994

1^st 8” Wafer Fab in Taiwan

Taiwan Mask Corporation (TMC), 1988 1^st Mask Fab in Taiwan

Syntek Semiconductor (Syntek), 1983

1^st IC Design in Taiwan

Introduction of CMOS Technology, 1976

from RCA

Taiwan Semiconductor Manufacturing Company (TSMC), 1987 1^st 6” Wafer Fab in Taiwan

Funding of technology introduction (1975~1979)

LSI Technology Development Program

(1979~1983)

Sub-Micron Fabrication Technology Development

Program (1990~1995) VLSI Technology

Development Program (1983~1988)

Deep Sub-Micron Fabrication Technology

Development Program (1997~2000)

Government Support

Year 1975 1980 1985 1990 1995 2000

Digital Life

 Establish key service middle ware to enable Connected Home and Virtual Home to provide for integrated services.

 Open up new service possibilities and business model.

Community

Audio/Video Security

ICT Internet

White goods

Service Gateway

/Home Gateway

感測器 Travel

Health

Energy Safety

Video

Mobile Game _…

Internet

Integrate individual items to enhance service

Home switch

Home NAS Control

console

Visions—ICT-Enabled Healthcare Program

Assisted Living Environment

Increase the ability of independent living

Retirement at Home

Enhanced Care giving Environment

Reduce caregivers’

burden

Long-Term Care

Employing information and communication technology (ICT), to promote caring aid and system industry at

Taiwan.

New Nang Gang Biomedical Science Park, Taipei

Sightseeing:

Lakes International

Academia center

Focus fields：

Bio-medical

translation,Core subject, graduated school, visiting program

Biotechnologies areas：VC etc

創造優質研 發科學園區

Balancing of Enviroments and economics

Create a National Biotechnology Park with a local investment up to US$

」

900million

The NSC will invest US$ 400 million to plan the layout for the park’s biomedical compound, and will be in charge of the construction of the park’s basic infrastructure and education center.

The Academia Sinica will investment US$ 500 million to build the R&D center and clinical laboratories and introduce research on new

pharmaceuticals and special biotech disciplines, such as translational medicine and genomic medicine.

Integrating incubation‐related services, providing capital, legal services,

intellectual property protection and for the development of biopharmaceutical products and medical devices.

Biomedical Technology and Product R & D Center

Hsin Chu Hospital

Industry &

Incubation Center Centers for

Disease Control

Medical industry land

營運中

開發或規劃中 Biotech Building

In line with “Biotechnology Takeoff Package”

The Creation of Biotech Incubation Center

the Supra Incubator Center (SIC)

Biotech Standard Factory Building

Finished by Q2 of 2011

36 units available for release for biomedical suppliers

• Ground Floor

6 units, for Science Park Administration Office, restaurants, banks and post office. Plus two areas of 660 m² standard factory units for rent.

• Second to Sixth Floor

34 standard factory units of 660, 330 or 181.5 m²

National Hsinchu Hospital

Completed by 2014 (200 beds)

To support the biomedical research, especially translational medicine

To serve as the regional research hospital

Biomedical Technology and Product Development Center

Base area: 33,013 m

(Medical special zone III) Site coverage ratio: 50%

Floor area ratio: 270%

Total construction cost: 30 million USD Construction scale:

6 floors

Construction area：6,510 m

Total floor area：38,888 m

Including Industry and Incubation Center

The construction will be finished by 2012

Part II

A motto for all of us

“Charity in the broad spiritual sense – the desire to relieve

suffering…. Is the most precious possession of medicine

-- Dr. Churchill, 1947”

MGH Hall way

“The Twelve Definitive Moments of Modern Medicine”

• 1941 Penicillin

• 1949 Cortisone

• 1950 Smoking identified as the cause of lung cancer

• Tuberculoisis cured with streptomycin and PAS

• 1952 The Copenhagen polio epidemic and the birth of intensive care

• Chlorpromazine in the treatment of schizophrenia

• 1955 Open-heart surgery

• 1961 Charnley’s hip replacement

• 1963 Kidney transplantation

• 1964 Prevention of strokes

• 1971 Cure of childhood cancer

• 1978 First test-tube baby

• 1984 Helicobacter as the cause of peptic ulcer

From The rise and fall of Modern Medicine, by James Le Fanu (p32)

• Genomics: “To provide biologists with the equivalent of chemistry’s Periodic Table, to characterize all the genes of an organism, including their sequences, polymorphism, structures, regulation, interaction and products.”

– E.S Lander, Science 274 (1996) 536

• Proteomics: “The biologists search for an analogy of the encyclopedia of reactions known to chemistry, the

characterization and identification of all proteins expressed within any cells at any time.

– G.H.W. Sanders, A. Manz, TIAC 19 (2000) 364

 Require rapid and affordable technologies for high

throughput, automation, miniaturization, integration micro system for minute size samples.

Breakthrough in Medicine

Home Knowledge

People

主動智慧式

症狀治療

關連式服務

整合式治療 個人化治療與預防

服務模式的演進

資訊流動的模式

被動服務

Nutrient

Ambient Devices

Hospital Clinical, Home

Company, School, Home

Monitoring, Responsive

Interpretation

Health care unit

介面標準

WHA 55.18, ASTM CCR; IEEE 2047 PHI

HL7 IEEE 1073

Telemedicine

婦女 嬰幼兒 老人

現行標準

個人化醫學

轉譯醫學

實證醫學

醫學發展趨勢與重點科技整合之關連性

Course Idea

NI LabVIEW Virtual Biomedical Instrumenta tion (VBI)

SIEMENS PLM NX,

Teamcenter

Levels of Studies

Physiology

– Molecular level – Cellular level – Tissue level – Organ level

Biophysics

– Principles – Theories – Models

Engineering (Safe, Fast, Cheap)

– Ethical issues

– Design (materials, devices, functions) – Fabrication

– Risk factors vs Benefit – Cost

Engineering Scientists

Life Scientists

Engineering

2010/12/27 Chii-Wann Lin 27

What is a

Device?

Blood Pressure

Animal electricity & Biopotential

感測電極

錯誤偵測電路 與 保護電路

導程切換 選擇器

隔離 前級放大器

自動校正 與 基線補償電路

類比數位轉換器 紀錄器

微處理機 與 周邊裝置

控制與分析程式 資料儲存記憶體

右腳驅動電路

X-ray

2010/12/27 Chii-Wann Lin 31

New Robotic Surgery Device

• Approved July 11, 2000

• Enable a surgeon to perform laparoscopic gall bladder

and gastroesophageal reflux disease (severe heartburn) surgery while seated at a console with a computer and video monitor

Da Vinci Surgical System

http://www.intuitivesurgical.com

2010/12/27 Chii-Wann Lin 32

Swallowable Camera Pill

• Approved August 1, 2001

• A swallowable capsule

containing a tiny camera that snaps picture twice a second as it glides through the small intestine.

• A technological advance in

methods of examining GI tract by visualizing inside of small intestine to detect polys,

cancer, or causes of bleeding and anemia.

Given Diagnostic Imaging System

http://www.givenimaging.com/

2010/12/27 Chii-Wann Lin 33

GlucoWatch Biographer

• Approved August 7, 2001

• A disposable component for a

wristwatch-like device designed to provide diabetics a noninvasive method to test glucose levels.

• Can alert users when glucose levels are too high or too low.

• It is intended to supplement, not

replacement of standard finger-stick blood tests diabetics perform daily.

http://www.glucowatch.com/

2010/12/27 Chii-Wann Lin 34

2010/12/27 Chii-Wann Lin 35

名詞定義

• 醫療器材 Medical device

– 藥物 Drug

• 法規 Regulation or Regulatory affairs

– 標準 Standard

• 認證 Accreditation

– 驗證 Certification

2010/12/27 Chii-Wann Lin 38

醫療器材

• Taiwan

– 我國藥事法 規範醫療器材相關法源

– 第四條定義 藥物包含藥Drugs與器材Devices

– 第十三條定義, 所謂醫療器材係指〝包括診斷、

治療、減輕或直接預防人類疾病, 或足以影響人 類身結構及機能之儀器、器械、用具及其附件、

配件、零件〞.

• 醫療器材 Medical device 21 U.S.C. 201 (h)

– An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any

component, part, or accessory , which is intended for use in the diagnosis of disease, or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in humans or other animals; or intended to affect the structure or any function of the body of humans or other animals; and which does not achieve any of its principal

intended purposes through chemical action within or on the body of humans or other animals, and which is not dependent on being

metabolized for the achievement of any of its principal intended purpose

• 藥物 Drug 21 U.S.C. 321 (g)

– “An article intended for use in the diagnosis, cure, mitigation,

treatment, or prevention of disease in humans or other animals; and

an article (other than food) and other articles intended to affect the

structure or any function of the body of humans or other animals”

2010/12/27 Chii-Wann Lin 40

Medical Devices vs Drugs

• MDs by Design

– 10% Clinical trials

– Feasibility, Safety and Effectiveness

• Drugs by Discovery

– 100% Clinical trials

– Dose limiting toxicity trials (phase I) – Safety and efficacy (phase II, III, & IV)

Source: FDA/CDRH

2010/12/27 Chii-Wann Lin 41

Premarket submission & Review

• Drugs/Devices (FD&C Act): requires demonstration of safety and efficacy for new drugs and devices prior to marketing.

– IND/IDE

– NDA/PMA/510(k)

• Biologics (PHS Act): requires demonstration of safety, purity, and potency for biological products before marketing.

– IND

– Biologics License Application (BLA)

• The sponsors (manufacturers) do the testing (preclinical and clinical), not FDA, to demonstrate that its product is safe, and effective for the intended use.

• FDA evaluates the test results by assuring the safety and effectiveness of the product.

Source: FDA/CDRH

2010/12/27 Chii-Wann Lin 42

1

2 3

4

5

2010/12/27 Chii-Wann Lin 43

醫療器材之管理方式

一.產品 醫療器材 須辦理查驗登記 無須辦理查驗登記 非屬醫療器材

二.品質系統 須申請GMP

無須申請GMP

一等級（Class I） 二等級（Class II） 三等級（Class III）

醫療器材優良製造規範

（GMP）

(部份品項無須實施）

醫療器材優良製 造規範（GMP）

醫療器材優良製造 規範（GMP）

無須辦理查驗登記

查驗登記 (部份品項無須辦

理查驗登記）

查驗登記 +

臨床相關資料

Source: DOH

2010/12/27 Chii-Wann Lin 44

The nature of MD Safety

• A risk management issue

• tied with device effectiveness/performance

• Throughout the life cycle of the device

Risk management

 Degree of risk

 Risk assessment of devices

2010/12/27 45

Risk/Benefit

• Two kinds of benefits: to subjects and to society

• Evaluation of Risk/Benefit ratio is subjective judgment

• Risks often underestimated and benefits overestimated

• Should take into account different subject populations

and individual differences among subjects

Conformity Assessment 符合性評估

• The systematic examination to determine the extent to which a medical device fulfills

specified requirements.

有效 Effectiveness

• In a significant portions of the target

population, the use of product for its intended use and conditions of use will provide clinically significant results

• Consist principally of well-controlled clinical

investigations (GxP)

安全 Safety

• Investigation involving in vitro studies, laboratory animals, and human subjects

• The probable benefits to health (for its intended use) when accompanied by adequate directions and

warning against unsafe use… outweight any probable risks

• Absence of unreasonable risk of illness or injury

2010/12/27 49

名詞定義

風險 Risk: The probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a

research study. Both the probability and

magnitude of possible harm may vary from

minimal to significant. Federal regulations

define only "minimal risk."

2010/12/27 50

Definition of Failure

• The nonperformance or inability of a component or systems to perform its intended function for a specified time under

specified environmental condition. It must always related to a measurable parameter or a clear indication.

– If there are no definitions for its normal functions, there will be no failure.

– It works under specific environmental conditions, temperature, lighting, ambient noise, stress level of operator, interference.

– It happens as an event or behavior that occurs at a particular instant in time. Failure may be intermittent, degradation after a long period time, drift.

• Failures in components or devices are usually listed in terms of a failure rate. The failure rate of a component or device is the probability of a failure per unit of time for the items still

functioning.

2010/12/27 51

The Definition of Reliability

• “the probability, at a desired confidence level, that a device will perform a required function, without failure,

time.”-

IEEE Standard Glossary

– required function: the function must have been established through such activities as customer and/or market surveys.

– to perform without failure: the normal operation of the

device must be defined, in order to establish what a failure is.

– to perform under stated conditions: the environment in which the device will operate must be specified.

– to operate for a specified period of time: the life expectancy of the device must be defined as well as the typical daily

usage.

Important concepts regarding

Consensus Standards for medical Devices

• Standards are voluntary not compulsory.

– Standards are organized as

• Horizontal , vertical

• National, International

• etc ..

• Regulations are mandatory.

• It requires codes (laws) to go from standards to

regulations.

Different Levels of Standards

• International Standard Organizations, ISO

• International Electrotechnical Commission, IEC

• The Association for The Advancement of Medical Instrumentation, AAMI

• American National Standard Institute, ANSI

• Commission of European Nationals, CEN

• Others ..,NFPA,UL,CENELEC,BSI,JISC,CNS, ASTM,

NCCLS, FCC, ADA, OSHA, NIOSH, NBS, PMA, VA,,

SAMA,HIMA,CGS……

New activities

• Pharmacogenomics

• eHealth

• Personalized medicine

2010/12/27 Chii-Wann Lin 55

http://law.moj.gov.tw

2010/12/27 Chii-Wann Lin 56

2010/12/27 Chii-Wann Lin 57

Part III

From Quality System Point of View

Continual improvement of the quality management system

Customers (and other

interested parties)

Requirements

Customers (and other interested parties)

Satisfaction

Management responsibility

Resource management

Measurement, analysis and improvement

Product

realization Product

Output

Clause 5

Clause 8 Clause 6

Input

Clause 7

Value-adding activities Information flow

2010/12/27 Chii-Wann Lin 61

Quality Systems

Adverse Even t Reporting

Engineering

Toxicology Biocomp atibility

Statistics Review S ciences

Study D esign

Forensic

En gineerin g Ep idem iology

Reuse Sterility

Env ironm ent EM C

Sh ock Vibration

Post-M arketing Surveillance

End of Life

M ode of Action D esign

Clinical Sciences

Risk A n alysis

Hazard A n alysis

Human Factors

Total Product Life Cycle of MD

Request for Designation

Clinical Trial

GCP

(ISO 14155/ICH E6)

Premarket Registration Class I, II, III, AC

Manufacture

GMP/QSD (ISO 13485)

AE Reporting Recall

Standards Recognition ISO/ASTM…

Consulting Window

Testing

GLP/GTP

Taiwan DOH

Advertisement

US FDA Life cycle

2004

2007/2002

2007

1999 1973

(2000 reclassification) 2001

2002

200 0

上市前審查要點

由工研院量測中心 李子委主任提供

10 steps toward market

• 各國上市前審查規定

• 確定產品Intended Use

• 相關產品分類分級

• 選擇所使用的技術

• 蒐集類似品的技術資料

• 風險分析與評估

• 確定產品分類分級

• 產品指引與採認標準

• 產品系統相關組件規格舉例

• 安全與功效評估資料

65

STEP 1: 各國上市前審查規定

國別 上市前審查 審查基準 採認標準

中華民國 第二、三等級

查驗登記

醫療器材查驗登記準則

體外診斷醫療器材查驗登記審查須知

衛生署醫療器材採認 標準

美國 510(k)

PMA

Substantial Equivalence/FDA Special Controls

PMA+QS Inspection

FDA Recognized Standards

EU+EFTA Technical File Review

AIMD/MDD/IVDD Essential Principles Annex II: Full QS

EU Harmonized Standards

Australia Technical File Review

Essential Principles Recognized

Standards Canada Technical File

Review

Essential Principles Recognized

Standards

Japan 醫療機器承認審

查

413 醫療機器基本要件基準 34 醫療機器承認基準 3 醫療機器審查指南

JIS, ISO

66

醫療器材安全與功效評估方法

1. Substantial Equivalence 2. Safety

3. Effectiveness

4. Essential Principles of Safety and

Performance of Medical Devices

67

Substantial Equivalence

• A device is SE if, in comparison to a predicate device it:

 has the same intended use as the predicate device; and

 has the same technological characteristics as the predicate device; or

 has different technological characteristics, that

 do not raise new questions of safety and effectiveness, and

 the sponsor demonstrates that the device is as safe and

effective as the legally marketed device.

68

STEP 2: 確定產品Intended Use

69

STEP 3: 相關產品分類分級

Sec. 862.1345 Glucose test system.

(a) Identification. A glucose test system is a device intended to measure glucose quantitatively in blood and other body fluids.

Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia, and idiopathic hypoglycemia, and of pancreatic islet cell carcinoma.

葡萄糖試驗系統是測量血液及其他體液中葡萄糖(定量)之器材。此 量的測定是用來診斷及治療各種碳水化合物代謝疾病，包括糖尿 病(diabetes mellitus)、低血糖症(hypoglycemia)及高血糖症

(hyperglycemia)。以及胰島細胞癌(pancreatic islet cell carcinoma)

(b) Classification. Class II.

70

STEP 3: 相關產品分類分級

71

STEP 3: 相關產品分類分級

Sec. 878.4800 Manual surgical instrument for general use.

(a) Identification. A manual surgical instrument for general use is a nonpowered, hand-held, or hand-manipulated device, either reusable or disposable, intended to be used in various general surgical procedures. The device includes the applicator, clip applier, biopsy brush, manual dermabrasion brush, scrub brush, cannula, ligature carrier, chisel, clamp, contractor, curette, cutter, dissector, elevator, skin graft expander, file, forceps, gouge, instrument guide, needle guide, hammer, hemostat, amputation hook, ligature passing and knot-tying

instrument, knife, blood lancet, mallet, disposable or reusable aspiration and injection needle, disposable or reusable suturing needle, osteotome, pliers, rasp, retainer, retractor, saw,

scalpel blade, scalpel handle, one-piece scalpel, snare, spatula, stapler, disposable or reusable stripper, stylet, suturing apparatus for the stomach and intestine, measuring tape, and

calipers. A surgical instrument that has specialized uses in a specific medical specialty is classified in separate regulations in parts 868 through 892.

(b) Classification. Class I (general controls). The device is exempt from the premarket

notification procedures in subpart E of part 807 of this chapter, subject to the limitations in 878.9.

72

STEP 3: 相關產品分類分級

Sec. 862.1660 Quality control material (assayed and unassayed) .

(a) Identification. A quality control material (assayed and unassayed) for clinical chemistry is a device intended for medical purposes for use in a test system to estimate test precision and to detect systematic analytical deviations that may arise from reagent or analytical instrument variation. A quality control material (assayed and unassayed) may be used for proficiency testing in interlaboratory surveys. This generic type of device includes controls (assayed and unassayed) for blood gases, electrolytes, enzymes, multianalytes (all kinds), single

(specified) analytes, or urinalysis controls

(b) Classification. Class I (general controls). Except when used in donor screening tests, unassayed material is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to 862.9.

Product Code: JJR, electrolyte controls (assayed and unassayed) 510(k) required

73

STEP 4: 選擇所使用的技術

74

STEP 5: 蒐集類似品的技術資料

510(k) Summary and Decision Summary

Product Code: NBW

Sec 862.1345 system, test, blood glucose, over the counter

Product Code: LFR

Sec. 862.1345 glucose dehydrogenase, glucose

Product Code: JQP

Sec. 862.2100 Calculator/data processing module for clinical use.

(a) Identification. A calculator/data processing module for clinical use is an electronic device intended to store, retrieve, and process laboratory data.

(b) Classification. Class I (general controls).

The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in 862.9.

Product Code: CGA

Sec. 862.1345 glucose oxidase, glucose

Product Code: JJX

Sec. 862.1660 single (specified) analyte controls (assayed and unassayed)

75

STEP 6: 風險分析與評估

• 820.30 ( c ) Design input:

– "Each manufacturer shall establish and maintain procedures to ensure that the design requirements relating to a device are appropriate and address the intended use of the device, including the needs of the users and patient."

• 820.30( f ) Design verification:

– Each manufacturer shall establish and maintain procedures for verifying the design input. Design verification shall confirm that the design output meets the design input requirements.“

• 820.30( g ) Design validation:

• Design validation shall ensure that devices conform to defined user needs and intended uses, and shall include testing of production units under actual or simulated use conditions. Design validation shall include software validation and risk analysis, where appropriate.“

76



同類產品使用經驗

 期刊、雜誌、新聞

 產品回收

 顧客回饋



FDA

 FDA Guidance

 510(k)/PMA Database

 FDA Recognized Standards

 Medical Device Recalls

 Medical Device Alerts and Notices

 MedSun: Medical Product Safety Network

 Medical Device Reporting



Emergency Care Research Institute, (ECRI) http://www.ecri.org



Institute of Safe Medical Practices (ISMP)



UK MHRA

蒐集醫療器材的風險資訊

77

 產品

 Method: GLUCOSE DEHYDROGENASE

 User: Lay persons

 Over the Counter

 血糖機

 主分類：862.1345 Glucose test system, Product Code: NBW, system, test, blood glucose, over the counter, Class II, 510(k) required, GMP required

 次分類一：862.1345 Glucose test system, Product Code: LFR, Glucose Dehydrogenase, Glucose, Class II, 510(k) required, GMP required

 次分類二：862.2100 Calculator/data processing module, for clinical use (衛生署：無), Product Code: JQP, Class I, 510(k) exempt, GMP required

 採血針

 878.4800 Manual surgical instrument for general use, Product Code: FMK, lancet, Blood, Class I, 510(k) exempt, GMP required

 品管液

 862.1660 Quality control material (assayed and unassayed), Product Code: JJX,

Single(specified) analyte controls (assayed and unassayed), Class I, 510(k) required, GMP required

STEP 7: 確定產品分類分級

78

 Format for Traditional and Abbreviated 510(k)s - Guidance for Industry and FDA Staff, 2005

 21 PART 809 In Vitro Diagnostic Products for Human Use Labeling Requirements - In Vitro Diagnostic Devices

 Guidance on Medical Device Patient Labeling; Final Guidance for Industry and FDA

 Write It Right, Recommendations for Developing User Instruction Manuals for Medical Devices Used in Home Health Care, 1993

 Assessing the Safety/Effectiveness of Home-use In Vitro Diagnostic Devices (IVDs); Draft Points to Consider Regarding Labeling and Premarket Submissions

 Review Criteria Assessment of Portable Blood Glucose Monitoring In Vitro Diagnostic Devices Using Glucose Oxidase, Dehydrogenase or Hexokinase Methodology, 1996

 Draft Guidance for Industry and FDA Staff - Total Product Life Cycle for Portable Invasive Blood Glucose Monitoring System

STEP 8: 產品指引與採認標準：血糖機

79

 ISO 15197 In Vitro diagnostic test system – requirements for in vitro whole blood glucose monitroing systems intended for use by patients for self testing in

management of diabetes mellitus, 2003

 ISOC30-A2 Point-of-care blood glucose testing in acute and chronic care facilities

 ISOH04-A6 Procedures and devices for the collection of diagnostic capillary blood specimens

STEP 8: 產品指引與採認標準：血糖機

80

 General Principles of Software Validation; Final Guidance for Industry and FDA Staff

 Guidance for Industry, FDA Reviewers and Compliance on Off-The-Shelf Software Use in Medical Devices

 Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices; Final

 Guidance for Industry - Cybersecurity for Networked Medical Devices Containing Off-the-Shelf (OTS) Software

 Guidance for Industry: Wireless Medical Telemetry Risks and Recommendations

STEP 8: 產品指引與採認標準：血糖機

81

 CLSI/NCCLSAUTO2-A2 Laboratory Automation: Bar Codes for Specimen Container Identification

 CLSI/NCCLSAUTO3-A Laboratory Automation: Communications with Automated Clinical Laboratory Systems, Instruments, Devices, and Information Systems;

Approved Standard

 CLSI/NCCLSAUTO4-A Laboratory Automation: Systems Operational Requirements, Characteristics, and Information Elements; Approved Standard

 CLSI/NCCLSAUTO5-A Laboratory Automation: Electromechanical Interfaces;

Approved Standard

 CLSI/NCCLSPOCT1-A2 Point-of-Care Connectivity

 CLSI/NCCLSGP19-A2 Laboratory Instruments and Data Management Systems:

Design of Software User Interfaces and End-User Software Systems Validation, Operation, and Monitoring; Approved Guideline - Second Edition

STEP 8: 產品指引與採認標準：血糖機

82

 CLSI/NCCLSLIS02-A2 Standard Specification for Transferring Information Between Clinical Instruments and Computer Systems; Approved Standard-Second Edition

 CLSI/NCCLSLIS03-A Standard Guide for Selection of a Clinical Laboratory Information Management System

 CLSI/NCCLSLIS04-A Standard Guide for Documentation of Clinical Laboratory Computer Systems

 CLSI/NCCLSLIS05-A Standard Specification for Transferring Clinical Observations Between Independent Computer Systems

 CLSI/NCCLSLIS06-A Standard Practice for Reporting Reliability of Clinical Laboratory Information Systems

 CLSI/NCCLSLIS07-A Standard Specification for Use of Bar Codes on Specimen Tubes in the Clinical Laboratory

 CLSI/NCCLSLIS08-A Standard Guide for Functional Requirements of Clinical Laboratory Information Management Systems

STEP 8: 產品指引與採認標準：血糖機

83

 CLSI/NCCLSLIS09-A Standard Guide for Coordination of Clinical Laboratory Services within the Electronic Health Record Environment and Networked Architectures

 CLSI/NCCLSAUTO8-A Managing and Validating Laboratory Information Systems;

Approved Guideline

 CLSI/NCCLSAUTO 10-A Autoverification of Clinical Laboratory Test Results;

Approved Guideline

 CLSI/NCCLSAUTO11-A IT Security of In Vitro Diagnostic Instruments and Software Systems; Approved Standard

 CLSI/NCCLSAUTO9-A Remote Access to Clinical Laboratory Diagnostic Devices via the Internet; Approved Standard

 CLSI/NCCLSLIS01-A2 Standard Specification for Low-Level Protocol to Transfer Messages Between Clinical Laboratory Instruments and Computer Systems

STEP 8: 產品指引與採認標準：血糖機

84

STEP 8: 產品指引與採認標準：血糖機

SOFTWARE

ELECTRICAL SAFETY

85

FDA EMC Program

http://www.fda.gov/Radiation-EmittingProducts/

RadiationSafety/ElectromagneticCompatibilityEMC/default.htm

• Electropollution: http://www.electropollution.org/

86

Human Factors

• AAMI/ANSI HE74:2001 Human Factors Design Process for Medical Devices

• ISO 62366: 2007 Medical devices -- Application of usability engineering to medical devices

• FDA Guidance:

– Guidance on Medical Device Patient Labeling; Final Guidance for Industry and FDA Reviewers

– Write It Right: Recommendations for Developing User Instruction Manuals for Medical Devices used in Home Health Care

– Labeling requirements from Device Advice

– Medical Device Use-Safety: Incorporating Human Factors Engineering into Risk Management

– Human Factors Points to Consider for IDE Devices

– Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices; Guidance for FDA Reviewers and Industry (see Verification and Validation Section)

87

STEP 8: 產品指引與採認標準：採血針

STERILITY

BIOCOMPATIBILITY

ASTM F899-09, Standard Specification for Stainless Steel for Surgical

Instruments

88

STEP 8: 產品指引與採認標準：品管液

• CLSIC24-A3 Statistical quality control for quantitive measurements procedures (FDA Recognized)

• ISO 17511: 2003 In vitro diagnostic medical devices -- Measurement of quantities in biological samples -- Metrological traceability of values assigned to calibrators and control materials (EU IVDD Harmonized)

• ISO 18153: 2003 In vitro diagnostic medical devices -- Measurement of quantities in biological samples -- Metrological traceability of values for catalytic concentration of enzymes assigned calibrators and control

materials (EU IVDD Harmonized)

89

System Performance

precision CV<5%

Linearity/ Result range 10~600mg/dL Hematocrit effects 10-70 %

comparisons to laboratory glucose method

Plasma equivalent

Reference method: YSI 2300 STAT PLUS

Bias ±10%

Interference Acetaminophen

ascorbic acid, bilirubin cholesterol, creatinine, dopamine, ephedrine

ibuprofen, L-dopa, methyl dopa,

salicylate, tetracycline, tolazamide, tolbutamide, triglycerides, uric acid. Preservatives

Accuracy 100% in Parkes error grid region A and B.

95% of the readings in ＜75mg/dL, ±15mg/dL or ＞75 mg/dL,

±15%

Operating humidity 10~90%RH

Altitude ≦10,000 ft

User study Layperson use

STEP 9: 血糖機規格舉例

90

Meter specification

Power source One replaceable 3.0V Li battery

Temperature reading Accuracy of thermistor is target ±1℃

Test time 5 seconds. Automatic measurement start after complete fill of test strip

Measurement unit mg/dL or mmol/L Storage temperature -10~60℃

Operating temperature

10~40℃

Data transfer interface

Via USB Cable

Reapplication time Completely filled within 1 second.

STEP 9: 血糖機規格舉例

91

Strips

Code Card needed

Sample size 0.6μL

Lancet specification

Dimension 28G

Material Stainless

Sterilization method Gamma- ray

SAL 1 x 10^-6

Packaging 50 pcs, 100 pcs, 200 pcs

Control specification

Reagent composition Glucose, PEG, Benzoic acid

Operating condition Operating temperature:20 to 25℃

Shelf life 2 years

Use life time 3 months after opening

Container PE

Glucose level with tolerance

STEP 9：試片、採血針與品管液規格舉例

92

 臨床前測試



Lab test



Bench test



Animal test



Good Laboratory Practice

 臨床測試



Good Clinical Practice



Clinical Protocol

STEP 10: 安全與功效評估資料

1. Real time index for ECG Home

care product

Introduction

• Sudden Cardiac Arrest is a major public health problem around the world.

• In most case, the mechanism of onset is a ventricular tachycardia (VT) that rapidly progresses to ventricular fibrillation (VF).

• VF is the breakdown of the organized cardiac electrical activity.

One-third of these patients could survive with the timely employment of a defibrillator .

• A pivotal component in Automated External Defibrillators

(AEDs) is the detection of VF.

Time-Delay Algorithm(1)

1. Measurement Conditions:

Sampling Rate = 360 (Hz) 2. Preprocess ECG signal

3. Set t = 0 , Select Time-Interval = 0.5 (sec.) 4. x( t ) = 2 , x( t + 180 ) = 8

5. M(2,8) = M(2,8) + 1

6. t = t + 1 , repeat step 4~step5

Phase Space(40*40): M matrix ECG signal intensity: X(t) , where t is time

2 8

Results:

Normal

VF

d=0.05

d=0.18

即時無線心電圖智慧分析模組

資料庫

(檔案名稱)

MIT-BIH

(106)

CU

(01)

CU

(02)

病徵 PVC VF VT

正常 1507 203 949

錯誤判讀 36 10 36

鑑別度 97.6% 95% 96.2%

異常 520 1474 48

正確判讀 513 1474 47

漏失 7 0 1

靈敏度 98.6% 100% 97.7%

2. 智慧型隨身心肺音偵測與訊號分析系統

Smart sensing material for monitoring of personal

respiratory/cardiac sounds

智慧型隨身心肺音偵測與訊號分析系統

Smart sensing material for monitoring of personal respiratory/cardiac sounds

• 開發薄型貼片式集音器收集心肺音

• 建立即時心肺音診斷系統

• 應用於居家隨身之氣喘診斷

 完成差動式雙貼片式集音器之初步開發

 完成可攜式心、肺音擷取分析系統 (可專利)

 完成Real-time wheezing analysis Toolkit (Using in PC, PDA) (可專利)

成果

Microphone Hardware

Real-time diagnosis

工研院研發之 軟質駐極式麥 克風

集音器

訊號擷取 介面開發

分析系統

喘鳴音自動分 析與監測

系統應用特色

同時偵測心音與 肺音

Measurement system

- Real-time analysis (Normal)

Case 2: (No.6) Wheezing (wheezing_3M.wav)

Wheezing pattern

High Correlation Coefficient ( >0.9)

RS

length(ms)

Wheezing (ms)

Wheezing/RS (%)

1712.3 512 29.90

Case I: (No.1) NORMAL (Bronchial.wav)

NO wheezing pattern

RS

length(ms)

Wheezing (ms)

Wheezing/RS (%)

1878.5 0 0