Clinical Evaluation Systematic Literature Review - Apec-ahc.org

Clinical Evaluation
Systematic Literature Review
Kathy Harris
November 15, 2010
Agenda
• Clinical Evidence Harmonization Effort
• Clinical Evaluation: A Guide for Manufacturers and
Notified Bodies, MEDDEV 2.7.1 Rev. 3
• Examples of Clinical Evaluation Systematic Literature
Review using MEDDEV 2.7.1 Rev. 3
1

Rationale
• Medical device regulatory systems are primarily
intended to help protect and promote the public health
and safety. Public trust and confidence in these
systems depends upon the safety and performance of
medical devices throughout their life-cycles.
Global Harmonization Task Force Medical Device Regulation Model 2 July 2009
Risks
Clinical Evidence – Key Definitions and
Concepts
• Promote the convergence of the regulatory
requirements for the generation and presentation of
evidence of the clinical safety and performance of
medical devices
Benefits
• Presentation of data that are acceptable in principle to
relevant authorities as the basis for meeting regulatory
requirements for both pre and post market
• Reduce burden to manufacturer, regulators, physicians
and patients
Clinical Evidence – Key Definitions and Concepts
Study Group 5 Final Document SG5/N1R8, page 4
2

Clinical Evidence – Key Definitions and
Concepts
• Convergence of requirements for clinical evidence,
including common data submissions, will lead to:
• Better understanding of medical device safety and
performance by all stakeholders
• More efficient use of resources of the clinical community,
medical device regulators and industry
• Increased transparency and confidence in the global
regulatory model.
• Ultimately, there should be more efficient, predictable and
timely access to safe and effective medical technology by
patients and society worldwide
Clinical Evidence – Key Definitions and Concepts
Study Group 5 Final Document SG5/N1R8, page 4
Clinical Evidence – Key Definitions and
Concepts
• Controlled clinical trials are only one type of valid
scientific evidence
• Level of risk and not device classification determine
type of valid scientific evidence required
• New or “unproven” technologies require support
generated by clinical investigations (trials) while
existing technologies may not
• Good Clinical Practice standards must always be
applied
Clinical Evidence – Key Definitions and Concepts
Study Group 5 Final Document SG5/N1R8, page 6
3

GHTF SG5/N1R8
When is Clinical Evaluation Undertaken?
• Clinical evaluation is an ongoing process
• First performed during the conformity assessment
process leading to the marketing of a medical device
• Repeated periodically as new clinical safety and
performance information about the device is obtained
during its use.
• This information is fed into the ongoing risk analysis
and may result in changes to the Instructions for Use
Clinical Evidence – Key Definitions and Concepts
Study Group 5 Final Document SG5/N1R8, page 6
Clinical Trial Requirements Should be
Risk-Based
• Under GHTF guidelines, the requirement for a clinical
trial should be based on an evaluation of the specific
risks and issues presented by a medical device
• Clinical trials should be reserved for technology that
cannot be verified by preclinical testing or clinical data
evaluation
• Even a high-risk category device may not need a
clinical trial if the issues it raises in comparison with a
previous generation can be adequately assessed by
bench testing
Clinical Evaluation Study Group 5 Final Document SG5/N2R8, page 13
4

Effects of Unnecessary Clinical Trials on
Patient
• Patients may need to travel to the study site more
frequently and be subjected to additional examinations,
testing, treatments and hospitalizations than are
normally necessary
• Delays potential benefits of new products due to
increased registration time to conduct clinical trials
Effects of Unnecessary Clinical Trials on
Physicians
• Most physicians agree to conduct clinical trials to:
• Further scientific knowledge for their own practice
• To publish information to advance scientific knowledge of
other physicians
• Clinical data generated only for registration purposes
may be of limited interest to physicians
• Limited opportunity for physicians to publish clinical
trial data generated only for registration purposes
5

Effects of Unnecessary Clinical Trials on
Physicians (cont.)
• Occupy physicians’ time planning, conducting, performing
additional tests and evaluations and writing reports for
devices with established safety and efficacy profiles and
where clinical data is used only for registration purposes
• May limits physicians’ time to perform more advanced
studies
• Delays potential benefits of new products due to increased
registration time to conduct clinical trials
• Will reduce the amount of new technology available
Effects of Unnecessary Clinical Trials on
Manufacturers
• Difficult to get physicians to agree to do trials for
products already in use in other parts of the world
• Multiple companies will be competing for limited
physician resources
• Will make clinical trials necessary for evaluating safety
and efficacy of new technology more difficult to schedule
and execute
• Costs and registration delays
6

Effects of Unnecessary Clinical Trials
(Summary)
• Delays introduction of new products that could benefit
patients and physicians
• Burdens patients, physicians and Health Care
Systems
Harmonization
• WW Health Authorities recognize that preclinical and
clinical data other than prospective clinical trials may
be used for registration of higher class devices with
established safety profiles
7

US FDA Clinical Trail/Evidence Requirements
• Premarket Approvals (PMAs) are required for most
Class III products
• PMAs typically require clinical data
• FDA follows a “least burdensome” approach
concerning clinical data
US FDA
• The majority of devices are Class I or Class II and are
exempt or enter the market through the premarket
notification (510(k)) process without clinical trial data
• Approvals/Clearances
• October 2009 through September 2010
• 19 PMAs and Panel track supplements
• 2764 510(k)s
8

FDA Submissions Requiring Clinical Trial
10/1/2009 to 9/30/2010 FDA website
Acceptability of Foreign Clinical Data 21 CFR 814.15
• The data are scientifically valid and that the rights, safety, and welfare of human
subjects have not been violated.
• A PMA based solely on foreign clinical data and otherwise meeting the criteria
for approval under this part may be approved if:
• (1) The foreign data are applicable to the U.S. population and U.S. medical
practice;
• (2) The studies have been performed by clinical investigators of recognized
competence; and
• (3) The data may be considered valid without the need for an on-site
inspection by FDA or, if FDA considers such an inspection to be necessary, FDA
can validate the data through an on-site inspection or other appropriate means.
9

US FDA Paper PMA
• A “Paper PMA” is one that is based on bench testing
and/or information derived from peer-reviewed
scientific literature.
• “Objective performance criteria” are performance
criteria based on broad sets of data from historical
databases (e.g., literature or registries) that are
generally recognized as acceptable values. These
criteria may be used for surrogate or clinical
endpoints in demonstrating the safety or
effectiveness of a device
Summary
• Clinical trials should be required based on a risk
assessment of the individual device, not based on
the classification of the devices
• In most cases, clinical data collected through a
variety of means is sufficient for proving safety and
efficacy of medical devices as there is no scientific
rationale for requiring a local or regional clinical
trials
10

MEDDEV. 2.7.1 Rev 3
• Clinical Evaluation: A Guide for Manufacturers and
Notified Bodies
• Format used for clinical evaluation in the following
case studies
Clinical Evaluation Process
• To conduct a clinical evaluation, a manufacturer needs to:
• identify the Essential Requirements that require support from relevant
clinical data;
• identify available clinical data relevant to the device and its intended
use;
• evaluate data in terms of its suitability for establishing the safety and
performance of the device;
• generate any clinical data needed to address outstanding issues;
• bring all the clinical data together to reach conclusions about the
clinical safety and performance of the device.
• The results of this process are documented in a clinical evaluation
report.
MEDDEV. 2.7.1 Rev.3, page 4
11

What is the Scope of a Clinical
Evaluation?
• (a) whether there are any design features of the device
or target treatment populations that require specific
attention
• (b) whether data from equivalent devices can be used
to support the safety and/or performance of the device
in question
• (c) the data source(s) and type(s) of data to be used in
the clinical evaluation
Figure 1: Stages of clinical evaluation
Stage 1*
Identify clinical data from
· Literature searching &/or
· Clinical experience &/or
· Clinical investigation
Generate new or additional clinical
data
No
Is clinical evidence
sufficient to be
able to declare
conformity with
relevant ERs?
Yes
Produce clinical evaluation report
*Conformity to harmonized performance standards may be sufficient to demonstrate
compliance to relevant Essential Requirements (ERs)
6. Sources of data/documentation used in a clinical evaluation (Stage 1)
MEDDEV. 2.7.1 Rev.3, page 8
Stage 2
Appraisal of individual data sets
· Suitability
· Contribution of results to
demonstration of performance
and safety
Stage 3
Analysis of relevant data
· Strength of overall evidence
· Conclusions about performance
and safety
MEDDEV. 2.7.1 Rev.3, page 10
Data relevant to the clinical evaluation may be held by the manufacturer (e.g. manufacturer sponsored pre and post market investigation reports and adverse event
reports for the device in question) or in the scientific literature (e.g. published articles of clinical investigations and adverse event reports for the device in question or for
equivalent devices).
page 10 of 46
12

Data Generated Through Literature Search
• The literature search protocol should include:
• the sources of data that will be used and a justification for their
choice;
• the extent of any searches of scientific literature databases (the
database search strategy);
• the selection/criteria to be applied to published literature and
justification for their choice; and
• strategies for addressing the potential for duplication of data
across multiple publications
MEDDEV. 2.7.1 Rev.3, page 11
Five Literature Evaluation Categories
• Level I Randomized Controlled Trial
• Level II or II-1 Prospective Comparative Study
Excluding Registries
• Level III Case-control Studies
• Level IV Prospective and Retrospective Cohort or
Case Series Studies
• Level V Review papers and Expert Opinions
13

APPENDIX B:
A POSSIBLE METHODOLOGY FOR DOCUMENTING THE SCREENING AND SELECTION OF
LITERATURE WITHIN A LITERATURE SEARCH REPORT 6
Potentially relevant literature identified
through the search
(copy of all citations)
Literature retrieved for more detailed
assessment
Literature with relevant useable data
included in the clinical evaluation, by
outcome:
• Device performance*
• Device safety*
• Device comparability
(if applicable)
*some literature will address issue of both performance and safety
___________________________________
Literature excluded, with reasons
Literature excluded from clinical
evaluation, with reasons
6 Adapted from Moher D, Cook DJ, Eastwood S, Olkin I, Rennie, D & Stroup DF. Improving the quality of reports and meta-analyses of randomised controlled trials: the QUORUM
statement. Quality of Reporting of Meta-analyses. Lancet 1999; 354:1896-1900
page 27 of 46
MEDDEV. 2.7.1 Rev.3, page 27
Data generated Through Clinical Experience
• Manufacturer-generated post market surveillance
reports
• Registries or cohort studies
• Adverse events databases
• Compassionate usage programs
• Clinically relevant field corrective actions
MEDDEV. 2.7.1 Rev.3, page 12
14

Data from Clinical Investigations
• Carried out by or on behalf of the manufacturer for
purposes of conformity assessment in accordance with
applicable regulations
• Meet applicable regulations
MEDDEV. 2.7.1 Rev.3, page 13
Example Clinical Evaluation
Systematic Literature Reviews
15

Total Knee Implant
Knee Implant
Subject of Clinical Evaluation
• Information in this presentation was extracted from a
Clinical Evaluation Systematic Literature Review to
demonstrate the Clinical Evaluation Systematic
Literature Review Process
• Product is US Class II and cleared by 510(k)--clinical
trial not required and product marketed
•Knee
• May possibly be US Class IIb in the future
• CE Marked as Class III Device
• Some data and details were changed
16

Qualifications of Evaluators
• As a general principle, evaluators should possess
knowledge of the following:
• The device technology and its application;
• Research methodology (clinical investigation design and
biostatistics); and
• Diagnosis and management of the conditions intended
to be treated or diagnosed by the device
MEDDEV 2.7.1 Rev. 3, page 9
Qualifications of Evaluators in Knee
Implant Example
• Personnel:
• Orthopedic Surgeon with significant Clinical and Surgical
experience
• Clinical Managers and Biostatisticians and Associates
• Clinical Technical writers
• Expertise in:
• The subject device technology and its application
• Clinical investigation design and biostatistics
• Diagnosis and management of the conditions intended to be
treated or diagnosed by the device
17

Clinical Evaluation Systematic Literature
Review
• Aims and objectives of the literature review:
• The critical review follows the recommended
methodology for literature reviews and uses an
evidence-based approach to the search for
relevant studies, the selection of relevant studies,
the extraction of key data, with the critical
evaluation of the quality and validity of the clinical
evidence in a transparent, reproducible, and
objective manner.
Clinical Evaluation Systematic Literature Review
Partial Contents
• Introduction
• Description of underlying health problem
• Current treatment options and interventions
• Description of currently used medical devices and maturity of
technology
• Description of medical device under assessment
• Intended function
• Technology, critical performance criteria and design
• Method of use and instrumentation
• Indications
• Contra-indications
• Intended clinical setting, user profile and training requirements
18

Risk Analysis Requirements
• Notified Bodies are to ensure that the manufacturer has
adequately:
• Performed an appropriate risk analysis and estimated the
undesirable side effects
• Involved appropriate clinical expertise in the compilation of the risk
analysis to ensure risks and benefits associated with real clinical use
are adequately defined
• Justified the chosen route(s) of clinical data; ...identified, appraised,
analyzed and assessed the clinical data...and demonstrated the
relevance and any limitations of the clinical data identified in
demonstrating compliance with particular requirements of the
Directive or cited in particular aspects of the risk analysis
MEDDEV 2.7.1 Rev. 3, page 19
Summary of Risk Analysis Performed
• Risk analysis for the intervention for which the total knee implant
is intended was performed including:
• Early postoperative
• Late postoperative
• Warnings and Precautions
• Adverse Events
• Other
• Risk analysis for the particular technical solution adopted
• Risk analysis specific to the design and use of the subject device
19

Risk Analysis For The Intervention For
Which The Subject Device Is Intended
• Risks or complications associated with total knee replacement include,
but are not limited to:
• Early or late infection possibly necessitating the removal of the knee implant
• Damage to nerves and blood vessels
• Fracture of the bone surrounding the implant
• Decrease in range of motion and/or mobility of the joint
• Dislocation, fracture or loosening of the implant
• Development of phlebitis, thrombosis, and/or pulmonary embolism
• Possible revision surgery employing and alternative prosthesis or arthrodesis
• Other complications like pain, deformity, decreased function of knee joint and
need for transfusions or prolonged illness
Clinical Evaluation Stage 1
MEDDEV 2.7.1 Rev. 3, page 10
20

Methodology for Systematic Review
• Search strategy and bibliographic databases used
• Databases and search engines used
• Search strategies developed based on terminology and indexing
terms found in articles retrieved in scoping searches
• National Joint Registries
• Language requirements
Clinical Evaluation Stage 2
MEDDEV 2.7.1 Rev. 3, page 10
21

APPENDIX B:
A POSSIBLE METHODOLOGY FOR DOCUMENTING THE SCREENING AND SELECTION OF
LITERATURE WITHIN A LITERATURE SEARCH REPORT 6
Potentially relevant literature identified
through the search
(copy of all citations)
Literature retrieved for more detailed
assessment
Literature with relevant useable data
included in the clinical evaluation, by
outcome:
• Device performance*
• Device safety*
• Device comparability
(if applicable)
*some literature will address issue of both performance and safety
___________________________________
Literature excluded, with reasons
Literature excluded from clinical
evaluation, with reasons
6 Adapted from Moher D, Cook DJ, Eastwood S, Olkin I, Rennie, D & Stroup DF. Improving the quality of reports and meta-analyses of randomised controlled trials: the QUORUM
statement. Quality of Reporting of Meta-analyses. Lancet 1999; 354:1896-1900
page 27 of 46
MEDDEV 2.7.1 Rev. 3, page 27
Methodology for Systematic Review
• Inclusion criteria for studies
• Population
• Adults of either gender
• Intervention
• Total Knee Replacement only
• Outcome measures
• Clinical
• Radiographic
• Patient-related effectiveness and safety outcomes
• Others
22

Methodology for Systematic Review
• Comparator
• Not deemed necessary in this example
• Study methodology
• All studies designs considered
• Length of study
• All length studies considered
• Exclusion criteria for studies
• Abstracts containing insufficient data
• Biomechanical studies (not safety and efficacy)
• Studies on other products
• Studies on unicompartmental knee
Methodology for Systematic Review
• Identification of unpublished studies
• Internal company clinical studies archive
• Internet searches
• Searching conference abstracts
• Other
• Data generated through Clinical Experience
• Data generated through Clinical Investigations
23

Clinical Evaluation Stage 2 Result Table
Level Trial Type Included Studies
I Randomized Controlled
Trial
1
II or II-1 Prospective Comparative
Study Excluding Registries
12
III Case-control Studies 2
IV Prospective and
Retrospective Cohort or
Case Series Studies
10
V Review papers and Expert
Opinions
0
Total 25 studies/ 4347 patients
Note significant number of patients
Methodology for Systematic Review
• Data Extraction Strategy
• Extracted directly to tables
• Double checked to reduce errors
• Quality Assessment Strategy
• Whether the cohort was consecutive or not
• Whether the intention to treat principle was used
• Number of cases lost to follow-up
• Other, in-depth evaluation
• Methods of Data Analysis and Synthesis
• Key study characteristics and clinical performance data presented
24

Ref
No
Evaluation of Type I Study
• All studies analyzed as below
• Not all parameters included
Ref
Study
Name Level of
Evidence
1 XX Randomized
Clinical Trial
Re
f
No
Inclusion/Exclusion
Specified?
Generation of
Allocation
Sequence
adequate
(Random)?
Allocation
Concealment
adequate?
Selection
Criteria
Clear?
Groups Lost
To Follow-
Up
Comparable
at baseline?
Blinded
Outcome
assessors?
Blinded
patients?
Consecutive
cases?
Numbers of
withdrawals
and follow
up same in
each group?
Intention
to Treat
Analysis?
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 2
Evaluation of Type II Study
• All studies analyzed as below
• Not all parameters included
Ref
Stud
y
Name Level
of
Evidence
2 XX Prospectiv
e
Comparati
ve Study
Study
Design
Selection
Criteria
Clear?
Groups
comparabl
e at
baseline?
Adequate
controls for
potential
confounders
?
Groups
Lost To
follow up
comparabl
e at
baseline?
Blinded
Outcome
assessors
?
Follow Up
Adequate
?
Consecutiv
e cases?
Any
exclusion
s from
the
analysis?
Number of
withdrawal
s and
follow up
the same in
each
group?
Yes Yes Yes Yes No Yes No No Yes 0
Lost to
Follow
up
Lost
to
Follo
w up
25

Evaluation of Type III Study
Ref No
Design
• All studies analyzed as below
• Not all parameters included
. Ref
Study
Name Level
of
Evidence
10 XX Retrospective
Comparative
study
Study
Design
Selection
Criteria
Clear?
Subjects
with
similar
state of
disease?
Were
controls
Randomly
selected
from
population?
Groups
Comparable
at baseline?
Adequate
controls for
potential
confounders?
Blinded
outcome
Assessors?
Yes Yes Yes Yes NA No Yes
Evaluation of Type IV Study
Ref No
Design
• All studies analyzed as below
• Not all parameters included
. Ref
Study
Name Level
of
Evidence
10 XX Retrospective
Comparative
study
Study
Design
Selection
Criteria
Clear?
Subjects
with
similar
state of
disease?
Were
controls
Randomly
selected
from
population?
Groups
Comparable
at baseline?
Adequate
controls for
potential
confounders?
Blinded
outcome
Assessors?
Yes Yes Yes Yes NA No Yes
Matching
Appropriate?
Matching
Appropriate?
26

Clinical Evaluation Stage 2 Example
8 studies identified
from XXX
Database
3 studies identified
from XXX search
1 study identified
from secondary
search
109 studied identified from the XXX
search engine
13 potential studies identified from
searches, analyzed and included in
review
25 studies included
8 National Knee
arthroplasty
registers included
100 studies excluded:
No clinical outcomes were reported
studies on kinematics
studies not on knee product
Methodological Quality of Included
Studies
• Non-randomized prospective comparative studies (Level II) were the
largest group of cases (48%) obtained from the searches
• The second largest group obtained from the searches were either
retrospective or prospective case series Level IV (40%).
• Follow-up of the clinical outcomes
• No control groups or randomization of cases.
• Two Level III, case-control studies were included
• One Level I randomized control trial (RCT)
27

Ref
No
Data from Each Study Evaluated
• Partial sample data exaction evaluation
• Data extracted from each study
. Ref
Stud
y
Study
Design
1 XX Randomi
zed
Clinical
Trial
2 XX Prospecti
ve
Compara
tive
Study
Patient
Number
s
Patient
joints
Age
Mea
n
Age
Rang
e
134 134 71.5 56 to
78
62 62 73 50 to
89
Sex
Mal
e
Sex
Femal
e
Weigh
t
Mean
Weigh
t
Range
57 77 63 40 to
85
22 40 111 89 to
163
Heigh
t
Mean
Heigh
t
Range
153 140
to
171
160 147
to
182
Summary Narrative Review and
Evaluation of Included Studies
• Small portion of Narrative Review:
Diagnosis
Most
Common
Osteoarthr
itis 33
Rheumato
id arthritis
1
Osteoarthr
itis 21
Rheumato
id arthritis
4
Follow
Up
Mean
(years)
Follo
w Up
Range
(years
)
5.5 2 to 10
6.75 5 to 8
• The knee system literature search identified a total 25 studies. One
was a randomized controlled trial (RCT), 12 were prospective
comparative studies, 2 retrospective comparative studies, and 10
were prospective/retrospective case series. The 25 studies included
a total population of 4347 with 5439 knees. Of the total population,
60.6% were females and 39.4% were males. The mean age of the
patients was 69.1 years (range 28 to 91 years). The follow up varied
from 3 months to 11 years.
28

Evidence of Clinical Performance
• Knee Society Clinical scores
• Range of Motion
• Knee Society functional scores
• Radiographic changes
• Others
Partial Example of Clinical Performance
• All studies evaluated
Ref Ref Name Clinical
Outcome
Pre-Op
2 XXX 56
Clinical
KSCS
Clinical
Outcomes Post-
Op
96 Clinical
KSCS
Patient
Outcomes Pre-
Op
50 Functional
KSCS
Patient
Outcomes Post-
Op
96 Functional
KSCS
Radiographic
Outcomes
Mild patellar tilt
was seen in 1
knee
Survivorship Other
Outcomes RSA-
DEXA
Using rerevision
as an
end-point five
year
survival was
95% and
eight year
survival was
94%
No subluxations,
dislocations or
infection.
• Some fields removed and some Safety Performance
included in this example
Comments
Preoperative
ROM 97°
(82°-112°)
and changed to
109°
(91° -127°).
29

Evidence of Clinical Safety
• Complications
• Revision Rate and Reasons for Revision
• Survivorship – overall
• Others
Clinical Safety
• All studies evaluated
Ref Ref Name Intraoperative
Adverse Events
Death Reoperations Revisions
Some fields removed for this example
Components
Revised
Reason for
Revision
Other
Comments on
Safety
1 XXX None None None None None NA No
complications
were reported
related in the
patients with
standard
surgical
procedure.
30

Survivorship – Overall
• Survivorship data for knee system was available from
10 studies
• Example: The survivorship reported by XXX et al. was
95% 5 years and by YYY et al. was 96.6% at 9 years
using re-revision as the endpoint.
• Survivorship summarized and documented from each
study
Clinical Evaluation Stage 3
MEDDEV 2.7.1 Rev. 3, page 10
31

Portion of Conclusion Section
• Thorough clinical evaluation of the safety and efficacy
of the knee implant can be made through the
systematic evaluation and analysis of Clinical
Literature ,the Risk Analysis and Post Market
Surveillance and other data indicating that the device
functions as intended
• Additional clinical trials are not necessary to establish
the safety and effectiveness of the device
Total Hip Replacement
Subject of Clinical Evaluation
•Stem
32

Qualifications of Evaluators in Example
• Personnel:
• Orthopedic Surgeon with significant Clinical and Surgical
experience
• Clinical Managers and Biostatisticians and Associates
• Clinical Technical writers
• Expertise in:
• The subject device technology and its application;
• Research methodology (clinical investigation design and
biostatistics); and
• Diagnosis and management of the conditions intended to be
treated or diagnosed by the device
Clinical Evaluation Systematic Literature Review
• Aims and objectives of the literature review:
• The critical review follows the recommended
methodology for literature reviews and uses an
evidence-based approach to the search for
relevant studies, the selection of relevant studies,
the extraction of key data, with the critical
evaluation of the quality and validity of the clinical
evidence in a transparent, reproducible, and
objective manner.
33

Clinical Evaluation Systematic Literature Review
Partial Contents
• Introduction
• Description of underlying health problem
• Current treatment options and interventions
• Description of currently used medical devices and maturity of technology
• Description of medical device under assessment
• Intended function
• Technology, critical performance criteria and design
• Method of use and instrumentation
• Indications
• Contra-indications
• Intended clinical setting, user profile and training requirements
Summary of Risk Analysis Performed
• Risk analysis for the intervention for which the total knee implant
is intended was performed including:
• Early postoperative
• Late postoperative
• Warnings and Precautions
• Adverse Events
• Other
• Risk analysis for the particular technical solution adopted
• Risk analysis specific to the design and use of the subject device
and total hip replacement
34

Risk Analysis For The Intervention For
Which The Subject Device Is Intended
• Risks or complications associated with total knee replacement include,
but are not limited to:
• Early or late infection possibly necessitating the removal of the hip implant
• Damage to nerves and blood vessels
• Fracture of the bone surrounding the implant
• Decrease in range of motion and/or mobility of the joint
• Dislocation, fracture or loosening of the implant
• Development of phlebitis, thrombosis, and/or pulmonary embolism
• Possible revision surgery employing and alternative prosthesis or arthrodesis
• Other complications like pain, deformity, decreased function of hip joint and
need for transfusions or prolonged illness
Clinical Evaluation Stage 1
MEDDEV 2.7.1 Rev. 3, page 10
35

Methodology for Systematic Review
• Search strategy and bibliographic databases used
• Four databases and search engines used
• Search strategies developed based on terminology and indexing
terms found in articles retrieved in scoping searches
• National Joint Registries
• Language requirements
Clinical Evidence Example Search
Stem WWW Database XXX Database YYY Database ZZZ Database
Stem 3 46 0 65
Stem and hip 4 29 0 42
Stem and hip and safety 0 0 0 6
Stem and hip and efficacy 0 0 1 10
Stem and hip and
outcomes
3 3 1 30
Stem and hip and
Company
11 11 0 22
Stem and hip and revision 20 19 0 51
Total
Total 377
41 108 2 226
36

Clinical Evaluation Stage 2
MEDDEV 2.7.1 Rev. 3, page 10
APPENDIX B:
A POSSIBLE METHODOLOGY FOR DOCUMENTING THE SCREENING AND SELECTION OF
LITERATURE WITHIN A LITERATURE SEARCH REPORT 6
Potentially relevant literature identified
through the search
(copy of all citations)
Literature retrieved for more detailed
assessment
Literature with relevant useable data
included in the clinical evaluation, by
outcome:
• Device performance*
• Device safety*
• Device comparability
(if applicable)
*some literature will address issue of both performance and safety
___________________________________
Literature excluded, with reasons
Literature excluded from clinical
evaluation, with reasons
6 Adapted from Moher D, Cook DJ, Eastwood S, Olkin I, Rennie, D & Stroup DF. Improving the quality of reports and meta-analyses of randomised controlled trials: the QUORUM
statement. Quality of Reporting of Meta-analyses. Lancet 1999; 354:1896-1900
page 27 of 46
MEDDEV 2.7.1 Rev. 3, page 27
37

Methodology for Systematic Review
• Inclusion criteria for studies
• Population
• Adults of either gender
• Intervention
• Subject femoral stem
• Total Hip Replacement only
• Outcome measures
• Clinical
• Radiographic
• Patient-related effectiveness and safety outcomes
• Others
Methodology for Systematic Review
• Comparator
• Not deemed necessary in this example
• Study methodology
• All studies designs considered
• Length of study
• All length studies considered
• Exclusion criteria for studies
• Abstracts containing insufficient data
• Biomechanical studies (not safety and efficacy)
• Studies on other products
38

Methodology for Systematic Review
• Identification of unpublished studies
• Internal company clinical studies archive
• Internet searches
• Searching conference abstracts
• Other
• Data generated through Clinical Experience
• Data generated through Clinical Investigations
Clinical Literature Review Results
Level Trial Type Included Studies
I Randomized Controlled
Trial
0
II or II-1 Prospective Comparative
Study Excluding Registries
15
III Case-control Studies 7
IV Prospective and
Retrospective Cohort or
Case Series Studies
8
V Review papers and Expert
Opinions
0
Total 30 studies/ 2149 patients
• Note large patient numbers
39

Methodology for Systematic Review
• Data Extraction Strategy
• Extracted directly to tables
• Double checked to reduce errors
• Quality Assessment Strategy
• Whether the cohort was consecutive or not
• Whether the intention to treat principle was used
• Number of cases lost to follow-up
• Other, in-depth evaluation
• Methods of Data Analysis and Synthesis
• Key study characteristics and clinical performance data presented
Evaluation of Type II Study
• All studies analyzed as below
• Not all parameters included
Re
f
No
Ref
Stud
y
Name Level
of
Evidence
1 XX Prospectiv
e
Comparati
ve Study
2 YYY Prospectiv
e
Comparati
ve Study
Study
Design
Selection
Criteria
Clear?
Groups
comparabl
e at
baseline?
Adequate
controls for
potential
confounders
?
Groups
Lost To
follow up
comparabl
e at
baseline?
Blinded
Outcome
assessors
?
Follow Up
Adequate
?
Consecutiv
e cases?
Any
exclusion
s from
the
analysis?
Number of
withdrawal
s and
follow up
the same in
each
group?
Yes Yes Yes Yes No Yes No No Yes 2
• Evaluation of other study types omitted for brevity
Lost
to
Follo
w up
Yes Yes Yes Yes Yes Yes No No Yes 4 in
each
cohor
t
40

Clinical Evaluation Stage 2 Example
Methodological Quality of Included
Studies
• Non-randomized prospective comparative studies (Level II) were the
largest group of cases (50%) obtained from the searches
• The second largest group obtained from the searches were either
retrospective or prospective case series Level IV (26%).
• Follow-up of the clinical outcomes
• No control groups or randomization of cases.
• Two Level III, case-control studies were included (23%)
41

Data from Each Study Evaluated
• Partial sample data exaction evaluation
• Data extracted from each study
Ref Study
Design
1
5
Case Series
(Level IV)
Prognostic
Study
(Level II-
1)
Patients
Initial
Numbers Age Sex Weight Height Indications Diagnosis
Implants
Initial
Mean Range Men Women Mean Range Mean Range
45/33 55/40 57 30-73 23 22 77 49-
126
52/42
53/43
70 34-
86
Portion of Sample Narrative
170 145-
187
NR
Osteoarthritis
40
Congenital hip
dysplasia 5
24 18 NR NR NR NR NR Osteoarthritis
50
Avascular
necrosis 2
• XX, YY and ZZ (Ref 1, published XXX) in a retrospective Level-IV
case series, reported on the use of 50 stems in 43 patients (mean
age 58 years) during primary and revision procedures. The mean
follow-up was 12.5 years. The outcomes were encouraging with a
mean Harris hip score of 87 points reported during the most
recent follow-up and 25 patients (75%) showing mild or no pain.
There was 1 revision post-op. They concluded that the femoral
component provided excellent long-term results at 10 to 14 years.
42

Evidence of Clinical Performance
• Pain
• Limp
• Range of Motion
• Harris Hip functional scores
• Activity levels and lifestyle
• Radiographic changes
• Others
Evidence of Clinical Safety
• Complications
• Dislocations
• Infections
• Loosening that does not require revision
• Revision Rate and Reasons for Revision
• Survivorship – overall
• Others
43

Outcomes Data
• Data from all 30 studies extracted—2 examples below
• Not all fields included
Ref Clinical Outcomes Patient Outcomes Radiographic
Outcomes
PreOp Post Op PreOp Post Op
1 NR HHS (avg)
87
5
HHS (avg)
41±16
HHS
(avg)
86±21
NR Pain patients
25 mild or no
thigh pain + 1
moderate
pain
Radiolucency
Absent in 24
NR NR Bone ingrowth 39
Radiolucency
Proximal in 8
Osteolysis Severe
in none
Survivorship Failures Revisions Comments
>90% at 13.3
years (Kaplan–
Meier)
95% at 3.9
years (avg)
with revision
as the endpoint
Registry Data Available
• Clinical Experience
3 [1 revision + 1
dislocation + 1
infection (Primary
set)]
4 (2 revisions +
2 dislocations)
Primary set None
Revision 1 (pain)
2 (1 loosening
with subsidence
+ 1 thigh pain)
• Australian Orthopaedic Association Registry
• Norwegian Arthroplasty Registry
• Swedish National Hip Registry
• England and Wales National Joint Registry
• Canadian Registry.
“This study shows excellent longterm
results of the prosthesis at 10 to
14 years”
“We found that use of a stem
with either a porous-coated or
a HA coated proximal
surface can yield excellent
results in patients…..”
44

Survival Data
• Data from all 30 studies extracted—2 examples below
• Not all fields included
Ref Product type & count Mean Follow-up (Years) Survivorship Revisions post-op Comments*
1 Stem 12.25 >90% at 13.3 years
(Kaplan–Meier)
2 Stem 10 100% at 10 years mean
follow-up
Clinical Evaluation Stage 3
Primary set None Revision 1
(pain)
“This study shows excellent
long-term results of the stem
prosthesis at 10 to 14 years”
0 “At a mean of 10 years
follow-up, the stem femoral
component implanted for an
anatomically difficult
primary THR has excellent
clinical and radiological
results”
MEDDEV 2.7.1 Rev. 3, page 10
45

Portion of Conclusion Section
• Thorough clinical evaluation of the safety and efficacy
of the Femoral Stem can be made through the
systematic evaluation and analysis of Clinical
Literature, the Risk Analysis and Post Market
Surveillance and other data indicating that the device
functions as intended
• Additional clinical trials are not necessary to establish
the safety and effectiveness of the device
Questions?
46