This document discusses clinical investigations and strategies from a management perspective. It outlines BioMedical Strategy's mission to coordinate scientific endeavors with regulations to benefit clients. The key topics covered include the importance of regulatory approvals and clinical data for market success, strategies for intended use claims and clinical trials, and considerations for clinical study design such as objectives, populations, and team roles.

1. Clinical
Investigations:
The Management Perspective
Orna Oz, PhD
BioMedical Strategy (2004) Ltd
March 15th 2007

2. BioMedical Strategy (2004) Ltd
Clinical & Regulatory Affairs Group
Founded by: Gal Ehrlich, Ami Eyal & Orna Oz
The Team: Skilled scientists (PhDs in the
fields of Physics Chemistry &
Biology – TAU & the Weizmann
Inst.)
Trained in Clinical & Regulatory
Affairs
March 15th 2007

3. BioMedical Strategy (2004) Ltd
Clinical & Regulatory Affairs Group
Our Mission: To coordinate scientific
endeavor with regulation
for the benefit of our clients’
business milestones
Main Field of Expertise: Medical Devices
March 15th 2007

4. The Key to Market Penetration
A breakthrough technology is great but does not
ensure market success
Regulatory approvals are meaningful milestones
•In creating value for strategic agreements
and funding
•In entrance to the market
Clinical data IS the Leading Force in
successful market penetration and
positioning
March 15th 2007

5. The Key to Market Penetration
A breakthrough technology is great but does not
ensure market success
Regulatory approvals are meaningful milestones
e
orts th agreements
ta for p and
•In creating value supstrategic
andlin ical da beling
C funding or la
•In entrancefto theemarket
claim
mar k ting
Clinical data IS the Leading Force in
successful market penetration and
positioning
March 15th 2007

6. Claims are the driving force
behind clinical trials
Labeling
Bench,
Animal
CLINICAL Intended
& + TRIALS
= CLAIMS
Use
Literature
data
Promotion
March 15th 2007

7. Intended Use Claim
Level of Specificity
1. Identification of function Tool Claim
2. Identification of tissue
type an organ system or
Identification of a specific Higher clinical
organ evidence
3. Identification of a
particular disease or
target population
4. Identification of an effect
on clinical outcome Clinical Claim
March 15th 2007

8. General Vs. Specific Claims
Examples
•Skin resurfacing vs. Wrinkle removal
•Evaluation of soft tissue vs. Aid in differentiation
of benign from malignant breast lesions
•Cut/coagulate soft tissue vs. Photorefractive
keratectomy (PRK) for myopia
March 15th 2007

9. Tool Vs. Clinical Claims
Cardiac Pacing device
Tool:
The Frontier Biventricular Cardiac Pacing System is
indicated for maintaining synchrony of the left and
right ventricles in patients who…….
Clinical:
The InSync model 8040 pulse generator is indicated
for the reduction of the symptoms of moderate to
severe heart failure (NYHA Functional III or IV) in
those patients who…….
March 15th 2007

10. Adjunctive Tool - Given Imaging
The Given® Diagnostic System is intended for visualization
of the small bowel mucosa. It may be used as an
adjunctive tool in the detection of abnormalities of the
small bowel.
Meta- analysis of
clinical data from:
> 600 cases
in
> 30 studies
The Given® Diagnostic System is intended for visualization
of the small bowel mucosa. It may be used as a tool in the
detection of abnormalities of the small bowel in adults and
children of 10 years of age and up.
March 15th 2007

11. Claim
Intended Use & Indications For Use
Design Specifications Test Plan to Verify
Regulatory & Clinical and Validate Claim
strategies (including
target markets)
1. Bench Testing
2. Animal Testing
3. Clinical Data
March 15th 2007

12. Product Life Cycle
A Multi-task Project
March 15th 2007

13. Clinical Study Distribution
Almost half of the studies were used to
support 510(k)s, PMAs or CE Marks
Ref: Clinical Device Group Inc, 2003
March 15th 2007

14. Clinical Strategy: Main Aspects
Do I need premarket clinical data?
• Yes - for a PMA route
• No and Yes – for a 510(k) route
No – all aspects of safety and efficacy are
covered by rationale of similarity to marketed
products (SE) and pre clinical performance tests
Yes – There are still safety and efficacy aspects
not proven by SE and pre clinical tests OR
Demonstration of clinical usability is important
March 15th 2007

15. Clinical Strategy:
Premarket Phase
Pilot Pivotal OR Single study
•Safety
•Performance
•Efficacy
•Usability
March 15th 2007

16. Clinical Strategy:
Premarket Phase
Pilot Pivotal OR Single study
•Safety nd Good
tions a
Regula tice (GCP)
Follow al Prac
•Performance
Clinic
•Efficacy
•Usability
March 15th 2007

17. Good Clinical Practice
(GCP)
A standard for the design, conduct, performance,
monitoring, auditing, recording, analyses, and
reporting of clinical trials that provides
assurance that the data and reported results are
credible and accurate, and that the rights,
integrity, and confidentiality of trial subjects are
protected.
March 15th 2007

18. Clinical Strategy:
Postmarket Phase
Do I need valid postmarket clinical data? Yes!
• First In Man (FIM) in 510(k)
• Postmarket surveillance (PMA) and long-term
observations
• Market penetration
• Scientific publications
• Reimbursement – cost effectiveness
March 15th 2007

19. Clinical Strategy:
Postmarket Phase
Do I need valid postmarket clinical data? Yes!
• First In Man (FIM) in 510(k)
• Postmarket surveillance (PMA) l dalong-term ld
ica and ta shou
n
market cli
Pre and Post
observations -analysis
build-up your meta
• Market penetration
• Scientific publications
• Reimbursement – cost effectiveness
March 15th 2007

20. Clinical Strategy
Post-market
.
.
.
Study # 3
Study #2
FIM
Investigational/pre-market
March 15th 2007

21. The Global Clinical Shell
Clinical strategy (pre and post market)
Design of clinical study/ies and preparation of
clinical package
Meeting with prospective investigators – Road
show
Regulatory approvals (IRB/EC, FDA/CA) &
Signing of agreements
Study management (budget, investigators & sites,
study manager and monitors, data management,
etc.)
March 15th 2007

22. Clinical Design:
The Team
• A Multidisciplinary team:
Management
Clinical – Project Manager
Medical practitioners (SAB)
Regulatory
Bio Statistician
Marketing and Reimbursement
R&D
March 15th 2007

23. Clinical Design:
The Team
• A Multidisciplinary team:
Management
Clinical – Project Manager
Process!
Medicalsider it as a (SAB)
Con practitioners
Regulatory
Bio Statistician
Marketing and Reimbursement
R&D
March 15th 2007

24. Clinical Study Design:
Critical Elements
Based on the claim for intended use of the tested product
• Study objectives and endpoints:
Safety, Performance and/or Efficacy
Usability, Quality of Life, Cost Effectiveness
• Study population – Eligibility criteria
• Type of study
Single arm or randomized (to untreated or “Gold
Standard” or predicate)
Equivalency (as good as) or Superiority (better
than)
March 15th 2007

25. Study Design:
Study Objectives
1. Feasibility/Pilot – safety, performance, refine
product design, refine clinical design for Pivotal
2. Technological characteristics – sensitivity, Pre
accuracy, specificity, precision, etc market
3. Pivotal – safety, efficacy, and/or performance
4. Usability - Consumer preference test
5. New claim substantiation
6. Market positioning Post market
7. Marketing support
8. Reimbursement – cost effectiveness
9. Post market surveillance
March 15th 2007

26. Eligibility Criteria
Sponsor Risk limitation,
speed, and
success
Investigators fast scientific
publications, RECRUITMENT
and success RATE
Statisticians Study
Homogeneity
IRB Risk limitation
March 15th 2007

27. Eligibility Criteria
Sponsor Risk limitation,
speed, and
success
Investigators fast scientific criteria
B e eligibility
alancpublications, RECRUITMENT
and success RATE
Statisticians Study
Homogeneity
IRB Risk limitation
March 15th 2007

28. March 15th 2007

29. Critical Decisions in Study
Management
March 15th 2007

30. Investigator Selection
Opinion Leader Availability
March 15th 2007

31. Clinical Sites - EU and/or US?
• Objective dependent – US Regulatory requirements
• Field experts (prospective investigators) -
geographical location
If you have the choice:
1. Usually shorter time to study initiation in some
European countries
2. Study costs may be lower in the EU
3. European physicians may be more open to new
technologies
4. Investigators tend to act more independently in
Europe
5. EU investigational sites are less respective of
regulatory aspects of GCP – may require more
monitoring
March 15th 2007

32. Site Selection
IP
Laws of
Country
Costs
Scientific
Publications
Location /
Market
Availability
Personnel &
Facilities Regulatory
Expected subjects- eligibility
March 15th 2007

33. Financial Aspects
Costs of clinical study are mainly based on:
1. Sample size
2. The procedure
3. Requested clinical assessments (imaging, lab.
tests, etc.) & medications
4. Number of follow-up visits
5. Required site participating personnel
6. Monitoring
7. Requested presence of sponsor personnel
(technical, clinical)
8. Costs for ethical committee
9. Hospital overhead
March 15th 2007

34. Financial Aspects
Costs of clinical study are mainly based on:
1. Sample size
2. The procedure
3. Requested clinical assessments (imaging, lab.
d
tests, etc.) & medications s not reimburse
i
al center
m follow-up visits al investigatio
4. Number of edic
e
n
rmally, th in a clinic
Fo Required nrollparticipating personnel
5. subject e site ed
fo6. aMonitoring
r
7. Requested presence of sponsor personnel
(technical, clinical)
8. Costs for ethical committee
9. Hospital overhead
March 15th 2007

35. Reimbursement for US Clinical Study
FDA will place all IDEs it approves in one of two
categories (A or B) on the IDE approval letter to the
sponsor and also forwards this information to payer
• Category A – Experimental
• Category B - Investigational; Non-experimental
FDA does not determine whether there will be a
reimbursement for the device and/or study costs
There are other Medicare policies for reimbursement
of clinical trial related costs for category A devices
March 15th 2007

36. Reimbursement for US Clinical Study
FDA will place all IDEs it approves in one of two
categories (A or B) on the IDE approval letter to the
sponsor and also forwards this information to payer
• Category A – Experimental
xpert
• Category B - Investigational; Non-experimental
ursement e
lt your reimb
Consu
FDA does not determine whether there will be a
reimbursement for the device and/or study costs
There are other Medicare policies for reimbursement
of clinical trial related costs for category A devices
March 15th 2007

37. Commercial Agreement
With Investigational Site
1. Confidentiality
2. Intellectual Property
3. Publications
4. Financial conflicts of interest
5. Financial arrangements on a per-subject
basis to investigator or institution (tied to
milestone), for study procedures or cost of
device etc…
6. Termination of Trial
7. Replacement of Principal investigator
8. Competitive Devices Trials
9. Allocation of Risk
March 15th 2007

38. Investigator Agreement
Investigator agrees to:
1. Obtaining informed consent
2. Obtain IRB and comply
3. Follow study protocol explicitly
4. Notify sponsor on adverse events
5. Attest that members of the staff are trained and
qualified.
6. Allow sponsor or its agent to audit the site
7. Complete CRFs and other records promptly
8. Observe applicable regulatory requirements
9. Provide financial information required (if FDA
trial)
March 15th 2007

39. Some Common Pitfalls
• Bad study design
• Inappropriate selection of sites and/or investigators
• Incomplete and/or inappropriate study management
tools (procedures, logs CRFs…)
• Using under-qualified clinical research personnel
(sponsor and/or site)
• Poor compliance with GCP– not only necessary for
regulatory reasons but also to reduce the company’s
risk from potential adverse publicity and lawsuits
March 15th 2007

40. Study Management -Monitoring
Inadequate monitoring continues to be the top
deficiency cited in FDA inspections of sponsors
Ref: Building Quality into Device Trails, Part 2 – Marcarelli M. Etal, 2006
March 15th 2007

41. Study Management -
Investigator Compliance
The regulations require sponsors to bring
noncompliant investigators into compliance
Ref: Building Quality into Device Trails, Part 2 – Marcarelli M. Etal, 2006
March 15th 2007

42. Some Important Tips
• Maintain ongoing relationships with
participating site personnel
• Be responsive to their needs and difficulties
• Continuously and closely Manage & Monitor the
study (compliance of site personnel,
recruitment, compliance to protocol and
regulation)
March 15th 2007

43. In Conclusion
Valid Clinical Data is a Composite Result of:
(1) Team Work
(2) Pre Planned Global Clinical Strategy
(3) Well Designed Study/ies
(4) Closely controlled implementation
March 15th 2007