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• 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)
DenmarkSingapore
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 4R&D Expenditure / GDP (%)
No
. o
f R
esearc
hers
/ 1
,000
Em
plo
ym
en
t (F
TE
)
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
3 4
4
Direct government funding for academic R&D and innovation
Dire
ct g
overn
men
t fun
din
g fo
r in
du
stria
l R&
D a
nd
inn
ova
tion
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 102 ha(in
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
1st 4” Wafer Fab in Taiwan
Vanguard International Semiconductor Corp. (VIS), 1994
1st 8” Wafer Fab in Taiwan
Taiwan Mask Corporation (TMC), 1988
1st Mask Fab in Taiwan
Syntek Semiconductor (Syntek), 1983
1st IC Design in Taiwan
Introduction of CMOS Technology, 1976
from RCA
Taiwan Semiconductor Manufacturing Company (TSMC), 1987
1st 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 m2 (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 m2
Total floor area：38,888 m2
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
WH
A 5
5.1
8,
AS
TM
CC
R;
IEE
E 2
04
7 P
HI
HL7
IEEE 1073
Te
lem
ed
icin
e
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 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, under stated conditions, for a specified period of 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
QualitySystems
AdverseEvent Reporting
Engineering
Toxicology
Biocompatibility
Statistics
Review Sciences
Study D esign
ForensicEngineering Epidemiology
Reuse Sterility
Environment
EM CShock Vibration
Post-MarketingSurveillance
End ofLife
Mode ofAction
D esign
ClinicalSciences
RiskAnalysis
HazardAnalysis
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
2000
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) http://www.ismp.org/
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) Sampling rate: 8000 Hz
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) Sampling rate: 11025 Hz
NO wheezing pattern
RS length(ms)
Wheezing (ms)
Wheezing/RS (%)
1878.5 0 0
Wheezing Analysis - Result - Wheezing
Wheezing
RS length(ms) Wheezing (ms) Wheezing/RS (%) Source
NO.1 1829.3 452.79 24.75
http://lib.cpums.edu.cn/jiepou/tupu/atlas/www.vh.org/adult/provider/internalmedicine/LungSounds/Sounds.html
NO.2 1547.6 452.79 29.25 http://faculty.etsu.edu/arnall/www/public_html/heartlung/breathsounds/contents.html
NO.3 1841.3 87.07 4.72 同上
NO.4 958.8 179.96 18.76 http://www.uinet.or.jp/~ishiyasu/lungsound/index_en.html
NO.5 3753.2 684.989 18.25 http://www.dramatic-asthma-relief.com/?hop=bahuguna
NO.6 1712.3 512 29.90 http://solutions.3m.com/wps/portal/3M/nl_BE/Littmann/stethoscope/education/heart-lung-sounds/
disease
dia
gno
sis + -
+ 5 1
- 1 6
Sensitivity: 83 %
Normal
RS length(ms) Wheezing (ms) Wheezing/RS (%) Source
NO.1 2303.5 0 0 http://lib.cpums.edu.cn/jiepou/tupu/atlas/www.vh.org/adult/provider/internalmedicine/LungSounds/Sounds.html
NO.2 1978.9 0 0 同上
NO.3 1526 0 0 http://solutions.3m.com/wps/portal/3M/nl_BE/Littmann/stethoscope/education/heart-lung-sounds
NO.4 1057.6 72.56 6.86 http://faculty.etsu.edu/arnall/www/public_html/heartlung/breathsounds/contents.html
NO.5 1618.5 0 0 同上
NO.6 1736.5 0 0 同上
NO.7 1878.5 0 0 http://www.stethographics.com/index.html
Wheezing Analysis - Result - Normal
disease
dia
gno
sis + -
+ 5 1
- 1 6
Specificity: 86 %
3. 植入式神經電刺激晶片在治療下背痛之研究
主要臨床適應症
• 背部手術後综合症(Failed Back Surgery
Syndrome,FBSS)
• 複雜區域性疼痛综合症(Complex Regional Pain Syndromes, CRPS)
• 幻肢痛/殘肢痛(Phantom/stump limb pain)
• 周圍缺血性疼痛(Chronic ischemic Pain)
• 慢性難治性心绞痛(Chronic Refractory Angina)
• 其他: 神經根病(Radiculopathies), 蛛網膜炎(Arachnoiditis), 带狀疱疹後神經痛(Post Herpetic Neuralgia）
Indications for Advanced Pain Therapies
Neurostim Pain Therapy
• Failed Back Syndrome (FBS) • Complex Regional Pain
Syndrome • Arachnoiditis
• Radiculopathies • Peripheral Ischemic Pain(PVD)
• Neuralgias
Neurostim Pain Therapy or Intrathecal
Pain Therapy • Failed Back Syndrome
• Complex Regional Pain Syndrome • CRPS
• Arachnoiditis • Painful Neuropathies • Spinal Cord Injury
• Post-Herpetic Neuralgia • Phantom Limb Pain
Intrathecal Pain Therapy
• Diffuse Cancer Pain • Failed Back Syndrome • Axial Somatic Pain
• Osteoporosis • Arachnoiditis • Visceral Pain
• Head, Neck Pain
Courtesy E. Krames, M.D.
Neuropathic pain Mixed pain Nociceptive pain
總計畫
4. 個人化醫療之生物晶片 Biochip for Personalized Medicine
TB高通量篩檢應用–TB protein Array
Method ELISA SPR ELISA SPR
Antigen Combi-9 Combi-9 Observed
Sensitivity 0.9 1 N/A 0.862
Specificity 0.57 0.89 N/A 0.857
PPV 0.68 0.91 N/A 0.862
NPV 0.84 1 N/A 0.857
側向導流與積體化SPR整合晶片設計
<100um
Guided layer
Sensor chip
Support accessory
Waveguide
Au
substrate
NC
Sample pad
Adsorption pad
Step 1
Step 2 spin 1000 rpm
Step 3
Step 4
Absorption pad :
-nitrocellulose，cellulose acetate
Polymer substrate:
-visible substrate (PVC, PDMS，PC…) Filter membrane :
-nitrocellulose，cellulose acetate
5 cm
Related links
• Integrating the Health Enterprise, IHE: http://www.ihe.net/
• AAMI - Association for the Advancement of Medical Instrumentation http://www.aami.org/
• IEC - International Electrotechnical Commission http://www.iec.ch/
• FDA-CDRH - U.S. Food and Drug Administration, Center for Devices and Radiological Health http://www.fda.gov/cdrh/
Homework
• Follow the 10 steps toward market and apply the ideas toward one of my exemplar cases (pick one):
