Ekram_Galeti_Thesis_Final_Presentation

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Commercialization and Quality Requirements in
Biomedical Wearable and Implantable Devices
Ekram Galeti(223951)
Final Thesis Presentation
02 May 2012
Department of Biomedical Engineering
BME-1806 Masters Seminar
Thesis Supervisor: Professor Heimo Ylänen
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•Objective of Thesis
•Market and Application
•Commercialisation
•Quality Requirements
•Good Practices
•Discussions
•Conclusion
Commercialisation and Quality Requirements in Biomedical
Wearable and Implantable Devices
Outline
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Biomedical Wearable Devices
• used for diagnosis/ treatment of the patients
• Medical Device Data Systems(MDDS termed by FDA)
Biomedical Implantable Devices
• General Implants
• Active Implants
• Implants with medicinal products
Objective of Thesis
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4Commercialisation and Quality Requirements in Biomedical
Market and Application
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Biomaterials
• orthopaedics, cardiovascular applications, dental applications, wound healing
purpose(sutures), opthamalics, gastrointestinal, plastic surgery, and drug
delivery systems
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Biomaterial Implant industry is going to be worth
$22.8 billion in USA with CAGR of 13.6%, while in
EU $17.7 billion with CAGR of 14.6% and global
worth of US $58.1 billion by 2014
Cardiovascular is expected to grow at compound
annual growth rate(CAGR) of 14.5% from 2009 to
2014, where the market value in 2008 was
$9.8billion[1]

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Orthopaedic Implants
• osteoporosis, osteoarthritis, bone cancer, and patients who have undergone
accidents/trauma
• for bone cancer, surgeons opting for “limb-sparing surgery”
• screws, plates, and other accessories
Dental Implants
• self-esteem, oral health, smile factor, ease in eating for old people
dental Implant shall rise from $3.5 billion in 2011to $7
billion in 2020 with CAGR of 10%
penetration of 25% - 30% in US population[2]
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Active Implants
• diabetics, treating eye disease such as glaucoma, neuro-simulator for patients
with nervous disorders, and are used in heart rhythm management
• Future: wireless transmitting, monitoring of patient and implant, control of
treatment
Each year, in USA alone 325,000 deaths occur
due to sudden cardiac arrest(SCA)[3]
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• patients who suffer from chronic diseases such as heart, epilepsy, related to
nervous system, diabetic’s detection, pulmonary measurements, and
rehabilitation purpose
• ambulance services to transmit data to hospitals
• Active Implants can be connected to wearable devices for computing and data
transmission
Biomedical Wearable Devices
It is estimated that 1 in every 25 children aged between
6months to 5years experience febrile seizures[4]
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Commercialisation
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Commercialisation in Medical Industry
USA has largest Healthcare service sector with revenues approximating $1.75
trillion while Medical industry sector accounts market of $110 billion(EU $80
billion) and is estimated to grow due to rapid development in technologies and
increase in population with diseases[5]
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Figure: Product development check point

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• Market Research Methodologies
• Primary Information
• Secondary Information
• Market Segmentation Approach
• sizing of Market
• pricing
• stage of introduction of treatment, driving forces, hurdles
• treatment costs
• future growth of Product
Market Research
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• Market Assessment Techniques
• SWOT Analysis
• PESTEL Analysis and impact on business
• Fish-Bone Analysis
Market Research
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Figure: Fish-Bone analysis for company competence to start a venture in Biomedical Wearable and Implantable devices

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• Drivers
• aging population, cosmetics, increase in chronic diseases, dental industry
• government grants and venture investment
• identification of existing referral chain system in treatment of disease
• Hurdles
• regulatory system
• buying power of third parties
• late reimbursement by third parties
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Market Research
Figure: referral chain of hip replacement Implants

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• Patents: Utility, Novelty, Non-Obvious
• protection from infringement
• monopoly in the market for certain period of time
• Limitation of patentee:
• Territorial limitations
• Time limitations
• Limitation in scope
• Inventor’s can seek patent:
• USPTO, EPO, WIPO
Intellectual Property(IP) , Patenting, Licensing
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Figure: process for filing a patent

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• Licensing:
• no capital
• unable to reach market
• to develop in large scale
Intellectual Property(IP) , Patenting, Licensing
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Figure: classification of grants of rights to produce and sell

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• design as per the market/customer specifications
• literature review of success and failures of existing devices
• failure of products due to non-feasibility in development stages
• listing down milestones and risks
• involvement of multi-disciplinary teams
• Early planning and designing the NPD process can:
• reduce the time of approval at regulatory agencies
• increases successful progress of NPD at different stages
• minimize the costs involved
• ensures quality and safety in every stage of NPD
an final product
New Product Development(NPD)
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Figure: Medical device project proposal list

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• Early identification of product lines to stay alive in market(very important for
SME’s)
• Short-term and long-term plans
New Product Development(NPD)
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Figure: Technology development for line of products

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• Early identification of product lines to stay alive in market(very important for
SME’s)
• Two Methods:
• Failure Mode Effect Analysis(FMEA)
• Severity levels, Occurrence of failure levels, current controls
• Risk priority number(RPN)
• Stage – Gate Approach
Killing of Project
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Figure: Stage-Gate approach of Biomedical Wearable device

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• Biomedical Implantable devices
concept to design 12 months
preclinical testing 24 – 36 months
clinical testing up to 36 months (>$10m)
approval time 1 2 - 24 months
concept to design 12 months
Average market arrival time 8years
Product development process
design of Johnson & Johnson hip Implants
went wrong and nearly 40% of ASR hip
Implants are estimated to fail within 5 years of
time prematurely as the hip Implant life cycle
was estimated to be 15 years[6]
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Figure: Biomedical Implant development process

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Biomedical Wearable devices
• Average market arrival time 3-8years
• Considerations
• battery life
• accuracy
• sensitivity
• computing algorithms
• data security
• Integration with healthcare units software system
Product development process
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Indication and End points
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Figure: end points for breast Implants and Wearable ECG device

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• Classification of device: class I, class II, class III
• Medical implant : class II, class III
• Wearable device known as Medical device data system(MDDS),
class I
• PMA, 510(k), de novo 510(k)
• quality Requirements part 820 quality system regulation
• minimum of two scheduled meetings
• require FDA marking for marketing
Regulatory Compliance - FDA
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Regulatory Compliance – FDA(Combinational Products)
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Figure: Product intended to market as Drug
Figure: Product intended to market as Medical device

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• Classification of device: class I, class IIa, class IIb, class III
• Medical implant : class IIa(dental implants, wearable devices), class IIb, class III
• manufacturer should hire NB(72 NB under EU, VTT in Finland)
• quality Requirements ISO 13485 (Medical devices – QMS- requirements for
regulatory purpose)
• classification defines the conformity assessment through annex’s
• EC Type Examination Certificate (issued during the design phase)
• EC Design Examination Certificate (issued covering design and production phase)
• EC Certificate Full Quality Assurance System
• EC Certificate Production Quality Assurance
• EC Certificate Product Quality Assurance
• Certificate of Conformity (after product has been verified)
• combinational devices NB EMEA NB Approval
• require CE marking to market in EU
Regulatory Compliance – EU MDD
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• Project Management
• Gnatt chart
• Critical Path Method(CPM)
• Outsourcing Product Development
• Pre-clinical and clinical trials
• Manufacturing process
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Figure: outsource decision making matrix

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• technology transfer from labo-
ratory to production
• GMP, SOP’s, records, DHR
• marketing
• communication with third parties
• Suppliers and contractors: in
accordance to regulatory compliance
Manufacturing
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Figure: manufacturing scale-up of Biomedical Implants and Wearable Devices

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• “Addictive manufacturing”
• ability to design complex designs
rather than standard designs
• minimisation of carpentry work
• minimizing inventory which in turn
reduces obsolete devices
• design of computing algorithms
based on specifications
Demand-based manufacturing
CAGR for orthopaedic Implants
grows at 13.5% between the periods
2012 to 2017 and the market value for
such products shall raise to $3.5
billion in 2017[7]
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Figure: outline of demand-based manufacturing

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• Healthcare system is complex
• Insurance companies (treatment should cover in the catalogues)
• International classification of disease (ICD-9)
• HCPCS(Healthcare Common Procedure Coding System) in USA
• Manufactures have to establish strategies at the time of clinical trial
stages
• National bodies such as Valvira in Finland, and NHS in UK can
promote if shown efficacy and safety of the treatment
Reimbursement, Sales, & Distribution
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• traceability of the device
• to identify the device for
distribution and use
• reducing medical errors
• to capture the statistics
Unique Device Identification(UDI)
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Figure: Outline of UDI approach

Quality Requirements
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• Design history file(DHF)
• Device master record(DMR)
• Device specifications(DS)
• Manufacturing process specifications(MP)
• Quality assurance procedures(QA)
• Packaging and Labelling(PL)
• Installation, Maintenance, and servicing
• Device history record(DHR)
• Manufacturing date
• No. of units manufactured
• No. of units released
• Acceptance record as per DMR
• Traceability
• Labelling and sterilisation
Design Control
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Figure: design control and quality systems outline

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Biomedical Implants
• manufacture/authorized person details, control number
• intended use of the device(indication)
• information for the identification of the device
• sterilisation method used(also sterilisation method to be used in case packaging is
broken)
• warning and precautions, risks (also in regards to external interferences)
• any medicinal products
• storage and handling conditions
• indication of single use
• indication for risks associated with indications for handling of the implant
• safe disposal of the implant
Labelling
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Wearable devices
• procedure for installation
• operation principles
• performance indications
• instructions for operation of the device and calibration procedures
• manual to change any external components
• hazards and risks related to device
• service and maintenance information
• clinical evaluations for clinicians
Investigational Device Exemption(IDE)
• Clinical protocol document
• “CAUTION: Investigational Device. Limited by Federal (or United States) law
to investigational use”
• "CAUTION - Device for investigational use in laboratory animals or other tests
that do not involve human subjects”
Labelling
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• ISO 11607-1 “Requirements for materials, sterile barrier systems and
packaging systems”
• ISO 11607-2 “Validation requirements”
• justification of the method
• physical and chemical properties do not change beyond the threshold limits
• Packaging considerations: temperature range, cleanliness, bio-burden,
electrostatic conductivity, pressure range, humidity range, and exposure to
sunlight
• Packaging materials: non-leaching, odourless, and impermeable to
microorganisms
• Sterilisation requirements: no harm to physical and chemical properties, shelf-
life limitations, toxicity levels, biocompatibility nature
Packaging and Sterilisation
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• ISO 10993-1(Evaluation and testing in the risk management process) and ISO
10993-6 (Tests for local effects after implantation)
Preclinical Studies
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Figure: outline of preclinical trials quality requirements

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• Material characterisation in regards to tissue response
• chronic toxicity, carcinogenicity, biodegradation, toxicokinetics,
immunotoxicity, reproductive/developmental toxicity or other
organ-specific toxicities
Preclinical Studies
Evaluation Test
(A-limited( 24h),B-prolonged(>24h to 30days), C-
permanent(>30days))
Tissue/Bone medical
implants
Contact duration
Blood related
medical
implants
Contact
duration
Cytotoxicity
Sanitization
Irritation or
intracutaneous reactivity
Systemic toxicity(acute)
Sub-chronic toxicity(subacute toxicity)
Genotoxicity
Implantation
Haemocompatibility
A
x
x
x
B
x
x
x
x
x
x
C
x
x
x
x
x
x
A
x
x
x
x
x
x
x
B
x
x
x
x
x
x
x
x
C
x
x
x
x
x
x
x
x
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Table: biological evaluation chart for Biomedical Implants

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• short-term assessment for non-degradable/non-resorbable is between 1week to
4weeks, and long-term assessment it is over 12 weeks
• degradable/resorbable Implants the estimated time period for assessment
depends on degradation time of the Implant
• The evaluation of degradation should be done at various time points:
• when there is no or minimal degradation(1week to 12 weeks after
implantation)
• during the occurrence of degradation
• during the tissue restoration or degradation ending point
• Macroscopic and Microscopic assessment
Preclinical Studies
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• objective of the clinical investigation
• end points to assess the objective of the clinical investigation
• stages of clinical trials
• follow up time period and adverse events reporting
• mode of recruitment of the subjects, identification of the subjects for
clinical trials
• anticipated risk analysis during clinical trials(ISO 14971)
• residual risks after placing the Biomedical Implant in the patient
• control groups to be tested
• inclusion and exclusion criteria of the subjects
• measurement variables, statistical methods, pass/fail criteria of the tests
• subject identification procedures
Clinical Studies: Clinical Investigation Plan(CIP)
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• should be carried on unknown risks
• safety and rights of human subjects are protected
• human subjects can withdraw at any period of time
• Clinical investigation design should be done according to intended
purpose of the device in question, considering subject population,
dosage levels(in case of medicinal use in implants), clinical end points,
analysis methods for clinical evaluation, and statistical approach
Clinical Studies: Clinical Investigation
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• Clinical evaluation can be done using:
• data obtained through literature search
• data obtained from previous clinical investigation studies
• date obtained through clinical investigation of the Implant
• data obtained through identical Implant using same material or technology
• Once clinical data is appraised and relevant clinical evaluation
should show:
• that the Implant is working as intended by the manufacturer and claims made
about the safety and efficacy of the Implant
• that the clinical data gathered from sources is relevant for the safety of the
device for human use
• that the benefits are outnumbered compared to the risks associated with the
implant
Clinical Studies: Clinical Evaluation
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• subject inclusion or exclusion criteria
• justification of study design and use of control groups
• appoint of investigators and study sites
• endpoints and statistical methods
• time period of follow-up
• justification for termination of clinical trials
• quality measures undertaken
• Adverse event reporting
Clinical Studies: Post-market clinical follow up(PMCF)
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Post-market Surveillance
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Figure: reporting of post-market surveillance

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• to reduce the risk of physical features
• effects of foreseeable effects of external environment such as magnetic fields,
electrical fields, temperature changes, pressure changes etc.
• to avoid risks of explosion or fire
• the display , measurements, or monitoring scales/indicators should follow
ergonomic principles
• to show accuracy and stability of the measurements, and the values as per the
country competent authorities
• to design instruments emitting radiation's as not to have any effects on users, or
controlling or adjustment of radiation should be adopted
• to show repeatability, reliability, and intended performance for the software
used in the device
Wearable Devices
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Risk Management
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Figure: risk management process of a Medical devices

Validation of Standalone Software
• active devices
• measuring vital physiological data
• designing software
• software algorithms
• telemedicine software for monitoring of patients
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Good Practices(GxP)
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• Organisation and Personnel
• Quality Assurance Unit(QAU)
• Facilities
• Equipment
• Test and Control Articles
• Protocol
• Records and Reports
Good Laboratory Practices(GLP)
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• Duties of IRB/IEC
• Investigator
• Sponsor
• Protocol and Amendments
• Investigator’s Brochure(IB)
Good Clinical Practices(GCP)
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• Validation
• Design controls
• Purchasing controls
• Identification and traceability
• Production and process control
• Acceptance activities
• Corrective and prevention action
• Labelling and Packaging control
• Handling, Storage, Distribution, and Installation
• Record and servicing
Good Manufacturing Practices(GMP)
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Discussions
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USA vs. EU Regulatory System
• PMA approval period by FDA has been increased by 135%, 12.5 months in
2000 to 29.3 months in 2010[8]
• 200 small and medium medical devices companies indicated that
• 85%EU- 22%FDA(predictability), 91%EU -25%FDA(reasonable), 85%EU-
27%FDA(transparent), 75%EU-16%FDA(excellent experience)[9]
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EU FDA
Approval Standard Safety of the device, technical
performance, no clinical
evidence required
Safety, and clinical evidence
required
Evidence required literature studies, data from
laboratory studies, and small
clinical trials
valid clinical trials
Approval authority Notified bodies(NB) and
national competent authorities
FDA(centralized authority)
post market and adverse
reporting transparency
adverse events, and recalls
must be reported to NB and
displayed for public
adverse events, and recalls
must be reported to FDA, and
is displayed for public[10]

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• harmonise the standards
• follow minimum regional regulatory requirement's
• increase global SCM
• Global traceability of the products(UID)
International Medical Device Regulatory
Forum(IMDRF)
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Complex medical devices
Biomedical Implants
Biomedical Wearable devices
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Conclusion
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• High demand
• Consideration of Risk
• Global regulatory system
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Thank you for your Patience
Question hour ?
Commercialization and Quality Requirements in Biomedical
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57Commercialization and Quality Requirements in Biomedical
02.05.1013
References
[1]. MarketsandMarkets: Global Biomaterials Market worth US$58.1 Billion by 2014. 2013. MarketandMarkets. [accessed on: 24 April 2013].
Available at: http://www.marketsandmarkets.com/PressReleases/global-biomaterials-market-worth-US58.1-Billion-by-2014.asp
[2]. Gilbert Acherman. 2012. How will dentistry look in 2020?. 17 pp. [accessed on: 23 April 2013]. Available at: https://www.tut.fi/pop/study-
info/international-office/Thesis_Writing_Guide_TUT_020201%20_4_.pdf
[3]. Sudden cardiac arrest key facts. 2013. Health Rhythm Foundation. [accessed on: 23 April 2013]. Available at:
http://www.heartrhythmfoundation.org/facts/scd.asp
[4]. Febrile Seizures Fact Sheet. 2013. National Institute of Neurological Disorder and Strokes. [accessed on: 23 April 2013]. Available at
:http://www.ninds.nih.gov/disorders/febrile_seizures/detail_febrile_seizures.htm
[5]. The U.S. Healthcare Industry. 2013. Selectusa, Department of Health and Human Services, The Health and Medical Technology Industry
in the United States. [accessed on: 15 February 2013]. Available at: http://selectusa.commerce.gov/industry-snapshots/health-and-medical-
technology-industry-united-states
[6]. Marry Meier. 2013. The New York Times, Maker Aware of 40% Failure in Hip Implant. [accessed on: 25 April 2013]. Available at:
http://www.nytimes.com/2013/01/23/business/jj-study-suggested-hip-device-could-fail-in-thousands-more.html?_r=0
[7]. The Future of Additive Manufacturing in Orthopaedic Implants. 2013. BONEZONE. [accessed on: 07 February 2013]. Available at:
http://www.bonezonepub.com/component/content/article/689-48-bonezone-march-2013-research-a-development-thefuture-of-additive-
manufacturing-in-orthopaedic-implants?limitstart=0
[8]. A comparison of the FDA and EU Approval Processes and their Impact on Patients and Industry. 2012. Regulation and Access to
Innovative Medical Technologies, BCG. [accessed on: 05 April 2013]. Available at:
http://www.eucomed.org/uploads/ModuleXtender/Newsroom/97/2012_bcg_report_regulation_and_access_to_innovative_medical_technologi
es.pdf
[9]. Josh makower, Aabed meer, lyn Denend. 2010. FDA IMPACT ON U.S. MEDICAL TECHNOLOGY INNOVATION. [accessed on: 22
February 2013]. Available at:
http://eucomed.org/uploads/Press%20Releases/FDA%20impact%20on%20U.S.%20Medical%20Technology%20Innovation.pdf
[10]. Unsafe and Ineffective Devices Approved in the EU that were Not Approved in the US. 2012. FDA. [accessed on: 19 April 2013].
Available at: http://www.elsevierbi.com/~/media/Supporting%20Documents/The%20Gray%20Sheet/38/20/FDA_EU_Devices_Report.pdf

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