入選名單共三名：陳彥宇、奉季光、鄭惟中

甄選結果說明：

2009年第一梯次赴美人員招生經過初選後共計12名候選人進入複選面試，入選人員並於3月25日進行第二階段複選面試

經4位國內評審委員與2位國外評委組成之評審委員會進行複選面試後，選出本梯次赴美受訓人員共3名，名單如下：陳彥宇、奉季光、鄭惟中

High-level R&D milestones
Milestones: key events corresponding to retirement of risks.

1. Proof-of-concept: scientific & technical feasibility
2. First effective bench model prototype
3. First effective  tissue testing prototype
4. First effective prototype in acute animal models
5. First effective & safe prototype in chronic animal models
6. First effective & safe prototype in humans
7. Pre-production device in manufacturing feasibility
8. Production device in scalable manufacturing

Anticipate and prioritize technical challenges
- Functional blocks of the device
- Break down of different disciplines
- Critical questions of all the functional blocks
- Which challenges have not been solved?
- Which is most difficult to address?
- Involve individuals from all the engineering fields
- Look-out for unexpected problem

Initial R&D Plan
R&D Personnel
Types, skill sets and number of engineers: time, cost & difficulties of challenges
Hiring engineers/consultants on a contract basis:
(1) Gaining access to expensive, specialized expertise
(2) Responding to temporary or short-term peaks in workload
(3) Bringing a fresh perspective to the resolution of challenging problems
(4) Without having to hire and then lay off dedicated resources
Cautious
(1) Work differently from in-house staff and require different incentives
(2) May not exercise the same urgency as dedicated, full-time employees
(3) Confidentiality and IP issues
(4) Incomplete knowledge transfer and documentation
Engineering resources
- Investments in facilities, equipments and other resources
- Acquisition matches the availability of R&D personnel. Both are fully and efficiently utilized
- In-house or outsource decisions affect the level of funding required
- Lead time & lab space requirements of the milestones
Test methods
- Iteratively assess various designs in order to create a effective and safe solution
- Validate & verify the solution meets key user requirement and technical specification as part of quality system
- Testing and development methods influence the company’s R&D culture and strategy
- Nonclinical: idea communication, bench testing, simulated use testing, tissue testing
- Preclinical: acute animal testing, human cadaver testing, chronic animal testing
- Clinical: live human testing
Overall timeline
- Time: a driver of both value and risk given its connection to consumption of capital and resources
- Key inputs: personnel required, engineering resources employed, testing to prove effectiveness and safety, documentation of user requirements, technical designs, experimental reports, verification and validation testing.
- Length of R&D: simple disposable < complex disposable < passive implantable < active implantable < combination product < biologic < standard pharmaceutical < biopharmaceutical

Fundametals of Strategic Focus
Taking Inventory
-Identify mission, strengths and weakness
- Define project acceptance criteria

Mission: A broad, directional aispiration that defines what an individual or group wants to accomplish.
- Academia: an exceptional long-term research project that might have a dramatic impact to the world.
- Entrepreneur/Startup: Identification of a solution that is readily achievable and profitable in the near term.
- Large coportation: Driving incremental improvement or longer-term investment to stay ahead of competitors.

Strengths and Weakness
- Evaluate what individual/group does well and how to capitalize it.
- Consider where less experienced, competent, or confident and how to compensate for these.
- Collaborating with others offering different, complimentary skill sets.

Acceptance Criterias
Common criteria to evaluate and determine an area of strategic focus as opportunities
- Fit with individual/group’s capabilities
- Effect / outcomes / impact
- Time required to achieve the target
- The resource requirement
- The customers who need to be cultivated
- The revenue tarkets required
- The anticipated growth of the market
- Dynamics of the market / number and type of competitors
Example Acceptance Criteria for a Medtch Startup
- Has a potential market of U$1B of more
- Attractive enought to getting funding from investors
- Significant impact on quality of life of patients
- A platform technology that can rapidly leveraged to implement in other practice area
- Not a patient segment where head-to-head competition with entrenched companies

Aticulating Strategic Focus
- Explore different practice areas till one that meets the acceptance criteria will emerge
- Define the project’s scope (breadth of opportunity) and focus (point of purpose)
- Examples of scope: “Well-defined market” vs. “Sleepier areas”
- Personal interest or passion is certainly a valid reason for defining the scope.
- Regardless of passion, practive areas should be considered against the acceptance criteria, including team’s strengths and weaknesses, as well as business opportunity.

Conflicts of Interest
Balance bewtween the interesets of investors and the needs of the target patients.

Ethical Principles
Truthfulness – Being clear and honest
Fairness – Dealing in a just and even manner
Beneficence – Maximizing benefits while minimizing potential harm
Respect – Recognizing autonomy, freedom of choice, right to act or refuse
Confidentiality – Understanding and protecting rigorously the priviledged information

Purpose
- Regulatory Approval: 510(k) Clinical Data / PMA
- Reimbursement
- Marketing / Adoption

Study Rationale
- Study Hypothesis
- Study Endpoints (Primary & Secondary)
- Study Population (Type & Number)
- Study Enrollment/Consent
- Study Comparison Arm (Standard or Care?)
- Study Blinded (Sham)
- Randomized?
- Follow-up intervals (Efficacy vs. Safety)
- Safety Monitoring

Clinical Development Program
- Non Clinical: in-vitro / ex-vivo
- Pre-Clinical: Non GLP / GLP
- Clinical: FIH / Pilot / Pivotal / Post-marketing

Models
Bench
- Require building anatomic or physiological model
- Simplest method for testing concept
- May be used to ask fundamental question
Ex-vivo
- Allows for near-real anatomy/physiology testing
- Minimizes assumptions
- Useful for understanding fundamental problems
In-vivo
- Real anatomy/physiology
- May assume no pathologic disease present
- Large animal ideal for assessing feasibility & risk

Good Laboratory Practice (GLP)
- Guidelines for conducting and reporting non-clinical or pre-clinical studies to ensure quality and integrity of data
- FDA encourages but does not require

Good Clinical Practice (GCP)
- Guidelines for conducting and reporting an IDE clinical trials for investigators, sponsors, and IRB
- Absolutely FDA required!

Investigational Device Exemption (IDE)
- Required for clinical studies supporting a regulatory device submission
- Allows a pre-market device to be tested in humans such that the necessary safety and effectiveness data can be collected
- All PMA studies and 510(k) which requiring clinical data data must have an IDE prior to starting the trial

Off-Label Usage
- Device approval for specific indication but used by physician for any purpose deemed clinically appropriate
- Method to discover new applications for existing technologies
- Company cannot promote “off label” usage
- When “off-label” usage significant, companies often initiate trials using IDE to add additional indication

IDE Exemptions
Legally marketed device
- “on-label” use: 510(k) device not requiring clinical data
Diagnostic Devices
- Non-invasive
- Low risk sampling procedure
- Does not introduce energy into body
- Is not used as sole diagnostic tool
Consumer Preference Testing
- Combining features of approved devices

Patient Recruitment
- Inclusion Criteria: Characteristics or indications that a subject must have in order to participate in the trial
- Exclusion Criteria: Characteristics or contraindications that eliminate subjects from participate in a study

Human Subject Informed Consent
- Standard governing the protection of human subjects in clinical research
- History of abuse (Nazi Germany, Tuskegee)
- No investigator may involve human beings as a subject in research unless informed consent has been obtained: Informed & Consent
- Risk vs. Benefit Analysis

Institutional Review Board (IRB)
- Any board, committee, or other group formally designated by an institute to review and approve the initiation of biomedical research involving human subjects
- Primary purpose of review is to ensure the protection of the tights and welfare of human subjects
- Conduct ongoing reviews during the study

Cost
- Device (IDE and Standard)
- Performing the Procedure
- Evaluating the Clinical Result (Follow-up)
- Core Labs (Centralized Analysis): Unbiased 2nd Opinions
- Investigator/Institutional Fee
- Conduction the Trial (Training/Monitoring): CRO
- Patient Recruitment (Advertising, Compensation)
- In-house Management
- Institutional Review Board (IRB)
- Data Safety Monitoring Board (DSMB)
- Advisory Boards (Planning)

[Source: lecture by Todd Brinton]

Frame the question for the new health technology
- Alternative therapy? (better than?)
- Adjunctive?
- Specific population?
- Reduced length of stay (LOS), less invasive?

Process: Potential Elements
1. Identify topics
2. Formulate the assessment problem
3. Retrieve available evidence
4. Collect primary data (as appropriate)
5. Interpret evidence
6. Synthesize and consolidate evidence
7. Formulate findings
8. Report and disseminate findings
9. Monitor impact

Blue Cross Blue Shield Technology Evaluation Center (TEC)
Five Criteria:
1. The technology must have final approval from the appropriate government regulatory bodies
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes
3. The technology must improve the net health outcomes
4. The technology must be as beneficial as any established alternatives
5. The improvement must be attainable outside the investigational setting

Who Dose T/A?
Public Sector
- The Medicare, Medicaid and SCHIP Agency (CMS)
- Agency for Healthcare Research and Quality (AHRQ)
- Food and Drug Administration (FDA)
- The U.S. Government Accountability Office (GAO)
- National Institutes of Health / Medical Executive Committee (NIH / MEC)
Private Sector Payers
- Managed care organizations
- Other payers
- Medical professional societies
- Hospitals
- Academic medical centers
- Technology industry
Vendors
ECRI Institute
Blue Cross Blue Shield Association Technology Evaluation Center (TEC)
Hayes Inc.
MetaWorks Inc. / United BioSource Corporation
University Healthsystems Consortium (UHC)
International Agencies
The Cochrane Collaboration
National Institute for Clinical Excellence (NICE)
International Network of Agencies for Health Technology Assessment (INAHTA)
European Collaboration for Health Technology Assessment (EUnetHTA)

Different Perspectives
FDA (Regulator)
- Safety
- Efficacy: Benefit of using a technology for a particular health problem in ideal conditions
- Substantially equivalent or comparison to placebo
- Intermediate, short-term outcomes
Medicare (Payer)
- Experience relevant to members (65+)
- Effectiveness: Benefit of using a technology for a particular health problem in general or routine conditions
- Comparisons to standard of care
- Longer-term, health outcomes
- Operational impact (cost!)

Current Issues
- Gainsharing: Aligning physician and hospital incentives
- Pay for Performance: Rewarding quality, cost-effective performance with a financial incentive
- Stricter National Coverage Decisions (e.g. Carotid Stenting)
- Coverage with Evidence (conditional coverage)
- Willingness to ration health care (especially outside US)

[Source: lecture by Mitch Sugarman]

Reimbursement Planning Model

Concept Assessment Phase
- Will it be in-patient or out-patient?
— If in, will current DRG cover it? If not, what ICD-9 changes need to take place?
— If out, will a C-code be needed? Will threshold be met?
- Will data be adequate to support coding and coverage needs? Will data timing work?
- What is publication schedule?
- Who will cover (Who pays?) this and why? What are current coverage policies?
- Who will do technology assessment (T/A)?
- Cost Effectiveness Analysis (CEA): will it work with clinical data being collected?

Pre-Market Phase
- Planning: What are anticipated health policy or reimbursement policy changes that may be required to successfully launch this procedure?
- Research: What guidelines and/or technology assessments exist for similar technology?
- Input to Clinical Study: What outcomes data will assist in advocating for coverage and payment with the payers?

Intro to Market
- FDA device categorization (for Medicare)
— Category A (experimental / investigational): No coverage
— Category B (non-experimental / investigational): May be covered
- Pre-launch reimbursement materials
— Provide reimbursement guide to assist physicians and hospitals with coding, coverage and payment under the clinical
- Payment/coverage strategy test
— Educate physicians and hospitals in coverage request process
— Adjust launch strategy as appropriate based on payer responses

Market Release
Implement launch strategies
- Coordinates tools for gaining coverage & payment
— Peer-reviewed journal articles (at least two)
— Demonstrate cost-saving
— Provider acceptance
— Provider assistance in coverage process
- Seek coverage
— case-by-case
— Payer-by-payer
— National vs local coverage for Medicare

Market Adoption
- Update launch materials
- Monitor health policy for changes that impact your product
- Adjust to market

Final Thoughts for Reimbursement
- Establish the function
- Start early
- Budget adequately
- Understand the process and risks
- Manage expectations
— Establish realistic time lines
— Establish realistic goals
— Reassess and remain flexible

[Source: lecture by Mitch Sugarman]

Define the Role of Reimbursement in a Medtech Company
- Health Economics Policy & Payment
- Research Reimbursement: Coding / Coverage / Payment
- Training & Education
- Submission: New codes / Payment
- Cost / Cost-Effectiveness

Who are the customers?
- External: physicians, professional societies, hospitals, hospital associations, payers (Medicare, private insurer, self-pay…)
- Internal: marketing, clinical, regulatory, research & development, business development, sales
The Players
Industry: Payers think industry is greedy and interestedd in selling products that don’t necessarily benefit the patient and are not cost-effective
Payers: Industry think payers are greedy and use evidence-based medicine (EBM) and technology assessment (T/A) to withhold care
Doctors: Industry wants to make their partners but know they are not “loyal”. Payers think they just want to use the newest gadget.
Hospitals: Feel trapped between low reimbursement rates and want to do everything

HOW can make a difference?
Strategic
- Advise on Business Development Investments
- Participate in Clinical Trial Design
- Develop Cost-Effectiveness Analysis
Tactical
- Provide device specific physician and hospital Medicare coding, coverage and payment
- Develop coding tools to assist customers

Why is This Important?
- Economics can be a barrier to adoption of a technology – if no coverage, coding or payment
- Creates a foundation for device therapy growth and profitability: growing the market
- Regulatory approval (FDA, Shonin, CE Mark) and launching the product is one step along the way. Reimbursement is the end game.
- The reimbursement function starts at product conception. Make sure to get paid after launching the product.

What are the Components of Reimbursement?
1. Coding: The language of reimbursement (What & why was it done)
CPT Process (How long does it take to get a code?)
- Lengthy process requiring support of the specialty societies
- Critical to gamer the support of key opinion leaders within the specialty society
- Can take up to 3 years to establish new or revised code if it meets criteria

2. Coverage: The decision to pay or not to pay, for an item or service
- National Coverage Decision: CMS
- Local Medical Review Policy: Local Fiscal Intermediary (Part A) / Local Carriers (Part B)
- Different payers have different coverage: Medicare / Medicaid / Aetna / BCBS/ Cigna
- If a device isn’t covered, nothing else matters
- Coverage: Reasonable & Necessary, not only Safety & Effective

3. Payment: Methodologies used to determine how, and how much, a product is reimbursed
Hospital Inpatient Prospective Payment System (HIPPS)
Diagnosis Related Groups (DRGs)
Principal Diagnosis / Patient Sex, Age / Discharge Status / Procedure Code / Complications and Comorbidities – Assign to higher paying DRG
Core Elements: DRG Relative Weight (RW) x Hospital Base Rate
Hospital Outpatient Prospective Payment System (HOPPS)
Ambulatory Payment  Classification (APC)
Status Indicators:
- “S” not discounted for multiple procedures
- “T” is discounted for multiple procedures (50%)
- “N” costs folded to APC amount
Transitional Pass Through Payments
- “C” Codes – device pass through payment, e.g. C1884 Embolic Protection System


Coding and Payment: Timeline
Earliest approval date for application submitted on Oct 2006
- CPT – Jan 2008 or 2009 (15 or 27 months)
- HCPCS C Code – April 2007 (7 months)
- ICD-9-CM – Oct 2007 (12 months)
- Payment become effective next Jan or Oct for Hospitals

[Source: lecture by Mitch Sugarman]

Third Party Payer System
Step 1: Patient seeks treatment
Step 2: Provider provides treatment
Step 3: Provider submits bill to patient’s insurer
Step 4: Insurer reimburses providers
What is needed for reimbursement?
- Codes for bill submitted to the insurer
- Positive coverage decision by insurer

Reimbursement Codes

ICD-9-CM: International Classification of Disease, 9th Rev., Clinical Modification
CPT: Current Procedural Terminology
HCPCS: Health Care Financing Administration’s Common Procedure Coding System
DRG: Diagnosis Related Group
APC: Ambulatory Payment Classification

Reimbursement Analysis
Step 1: Search for Coverage Decisions
Search medical policies of private insurers and Medicare
1) Blue Cross / Blue Shield Regence Group
2) Wellmark lue Cross / Blue Shield
3) Medicare Coverage Devisions
Summary:
- Is there direct evidence for positive coverage?
- Identify a CPT code as reasonable proxy

Step 2: Find physician reimbursement
Lookup Medicare’s Physician Fee Schedule

Step 3: Identify APC Code
Lock APC code at Medicare’s Web Site

Step 4: Data on Cost of Procedures
Look cost and procedure data from Medicare

Step 5: Data on Number of Procedures
Use the Medicare Part B Physician/Supplier File

Deliverables from Reimbursement Analysis
- Relevant codes and reimbursement levels
- Number of procedures and possibly cost of procedures for Medicare
- Relevant coverage decisions
- Strategic overview: applicability of existing codes, reimbursement levels and coverage decisions to your device

[Source: lecture by Stefanos Zenios]

Before the Financial Model

1. Research competitors and potential customers
2. Develop an “elevator pitch”
3. Determine your Sustainable Competitive Advantage
   Patented Technology / Unpatented Designs / Cycle Time /
   Marketing and Advertising / Salesforce / Low-Cost Manufacturing
4. Develop a Financial Model & Business Plan to leverage that Sustainable Competitive Advantage

Typical Business Phases

1. Proof of Concept, Market Research
2. Product Development
3. Manufacturing Feasibility
4. Clinicals & FDA submission 510K or PMA
5. Build Scalable Manufacturing
6. Develop Marketing & Sales

Significant Risks
1. People   2. Technical   3. Development   4. Clinical   5. Government   6. Manufacturing   7. Competitive   8. Market   9. Sales

How much Money do I need?

People Drive Cash Needs (= Most Important Asset)
1. How Many?   2. What Skill Sets?   3. Hire or Outsource?   4. When?

Typical People Cost (in USA)
Research & Development
- Scientists & Engineers $120K each
- Technicians & Lab Workers $ 50K each
Management
- Vice Presidents $225K each
- Directors $100K each
Sales & Marketing Sales Reps $100K each
Administration Administrative $40K each
Manufacturing Assemblers $30K each

The “Real Cost” of an Employee
Total Costs = 2X Salary
Benefits / Employer Taxes / Travel & Entertainment / Supplies / Computers & Equipment (Depreciation) / Facilities / Yearly Salary Increases / Stock Options

Outside Costs
- Consultant $1-2K a day (may take stock)
- Attorneys: IP / Securities Law / Contracts
- Recruiters / Accountants / Auditors

Projecting Revenue & Manufacturing Costs

Estimate Sales Growth
Who will buy it?
How much will they buy?
Does it have recurring Revenue?
At what Price?

How Many People Will Buy It?
Total Market Size X 0.001 = First Year Sales Estimate
What will be the sales ramp?

How Will You Sell It?
What Sales Channel?
Direct vs.
- Distributors: 30% margins
- Partnering: 50-70% margins
- Direct more $$$$: more focused & controlled
Europe & Japan
- Special employment benefits: cars, vacations, severance
- Additional regulatory approval
- Tariffs

Financial Statements
Operating Statement (P&L: Profit & Loss)
Cash Flow: How much is needed? Raise 12-24 months of cash needed
Balance Sheet: Value of assets vs. versus liability

Determine Likely Profit Model (Minimal Goal 15-20% Pretax)
Sales 100% Gross Margin 50% Mkt & Sales, Admin 25% R&D 10% Pre-tax 15%

Capital Spending
- Develop Separate Budget
- Cost of efficiency: model return on investment
- Facility Improvements
- Everyone wants computers & toys
- Phone & Information Technology (IT)
- Make vs. Buy Decisions
- Depreciation over Useful Life: Non-cash item

When do I need the Money?
When will you Break Even?

Cash is King
- Don’t raise too little
- Spend it wisely
- Review it weekly

Company Ownership
How much I owe?

The Ownership Model
Having determined how much money we need & the ~ timing
- Early VCs want 50-60% in 1st Round: Milestone or Event Driven
- Early Stage dilutes you further
- Carefully select your VCs: Long term relationship / ups & downs

Stocks Options: the most important part of Compensation
Stock Options = 20% of shares
- CEO 5-8%
- VPs 1-2 %
- Relationship between salary & options
- Usually 1 year cliff & 4 year vesting, monthly or quarterly

[Sources: speech of Larry Tannenbaum]