Post on 25-Mar-2018
A Comprehensive Analysis of the FDA 510(k) Process
Industry Practice and the Implications for Reform
John H. Linehan, Ph.D. Northwestern University
Jan B. Pietzsch, Ph.D. Wing Tech Inc.; Stanford University
National Press Club, Washington, D.C.May 24, 2011
Outline
• The Medical Device Industry and Device Development
• Introduction to the Research Study• Objectives and Methodology
• Respondent Characteristics
• Key Findings• Predictability and Interaction with FDA
• Different Impact on Large and Small Companies
• International Comparison
• Observations: Opportunities for Improvement
• Concluding Remarks
2
The Medical Device Industry and Medical Device Development
Medical Device Companies by Size
4Source: US Dept Commerce
Small companies
Medium companies
Large companies
5
Device Development Is an Iterative Process
• Medical device development is a highly iterative process
• Need to improve product continuously through frequent, positive iterations, while avoiding unnecessary iterations
• Efficient planning and execution requires predictable process
Design device / Iterate design
Prototype device
Obtain clinician feedback
Medical Device Development Functions
6
Cross-Functional Management
Marketing
Research and Development
Legal
Regulatory
Reimbursement
Manufacturing & Operations
Quality
Clinical
Sales
Impacts of Regulation on Device Development
Gate1
Pro
ject
Def
initi
on A
ccep
tanc
e/ C
once
pt C
harte
r
Gate2
Initi
al D
esig
n Ac
cept
ance
/ D
evel
opm
ent A
gree
men
t
Gate3
Fina
l Des
ign
Acce
ptan
ce/
Ram
p U
p R
eadi
ness
Gate4
Pro
duct
Lau
nch
Acce
ptan
ce/ L
aunc
h R
eadi
ness
Formulation/
Concept and Feasibility
Phase
Initiation/ Opportunity
and Risk Analysis
Design and Development/
Verification & Validation
Phase
Final Validation/
Product Launch Preparation
Phase
Product Launch and Post-Launch
Assessment
Market Analysis
Competitive Assessment
Financial Review
Legal/ IP Analysis and Filings
Early Risk Assessment
Regulatory and Clinical Path
Initial evaluation of possible
development of commercial product
Definition of design input based on customer needs and technical requirements
XDevelopment of product design and of manufacturing process; verification and
validation
XXFinal validation of manufacturing process;
preparation of product introduction
XXMarket introduction of product; continuous
improvement
D E V E L O P M E N T
Project Core Team Selection
Early Concept Selection
Customer Input / VOC
Initial Design Risk Analysis (dFMEA)
Initiate & Maintain Design History File (DHF)
Product Design Development
Clinical Validation Plan
Supplier Collaboration
Detailed Producibility Analysis
Initial Regulatory Strategy
Regulatory Strategy Update
Reimbursement Strategy Update
Initial Process FMEA (pFMEA)
Clinical Validation
Final Patent Review with R&D
Mfg/ Ops Scale Up
Full Process Qualification
DHF Completion
Obtain Regulatory Approval/ Clearance
dFMEA Update & Review
Market Launch Plan/ Forecast
Update design control docs as needed
Value Proposition Viable &
Sustainable
Technical Feasibility Proven
and Optimized
Product Risks Acceptable
Manufacturing and Value Chain Conf idence
Commercialization Readiness
Design Output meets Targets
Risk Mitigation Conf irmed
Regulatory Submission
Testing Complete
Sales Launch Final Validation
Stable Manufacturing
Process
Business Launch Plan Adjust
Cross-functional
Mgmt
Functional Groups
Marketing
Research & Development
Legal
Regulatory
Reimbursement
Manufacturing & Operations
Quality
Clinical
Gate 1 Decisions
General Project Plan & Timeline
Prototype Analysis
IP Landscape Review & Review of Filings
Initial Reimbursement Strategy
Initiate DFM (Tooling, Fixturing)
Maintain DHF & Project Timeline
Design Verification and Validation
Design Risk Analysis (dFMEA)
Customer Prototype Eval.
Regulatory Submission
Product Branding
Finalize Reimburse-ment Strategy
Begin Process IQ/OQ/PQ/PPQ
Finalize Process IQ/OQ/PQ/PPQ Quality Audits
Process improvmts. as needed
Post-market Surveillance/ MDR
Product improvmts. as needed
Physician training & contd. sales efforts
Update reimbursmt. as needed
Design FreezeGate 2 Decisions Gate 3 Decisions Gate 4 Decisions
Phases
Continued Clinical Validation
Reimbursement Path
Market Opportunity
Basis for Competition
Tech, Regulatory, IP Approach
Feasible
Manageable Risk and Executional
Gaps
Gate 1 Decisions
Customer Prototype Eval
SalesSales Training Reps Attend
Surgical Cases
Phase I Phase II Phase III Phase IV Phase V
Design Outputs = Design Inputs
Patent Review
7
Introduction to the Research Study
8
Study Objective and Methodology
9
• Elicit from those engaged in medical device development, what seems to work well and how the 510(k) regulatory process could be further strengthened.
• Collect comprehensive data set to provide the basis for constructive input to strengthening the process:– Timelines
– Interactions with the agency
– Issues and challenges in current implementation
– Comparison among international regulatory programs
Approach and Study Methodology
Topic Identification
Interviews with 80+ medical device experts (industry and FDA)
Survey design
Two rounds of expert review and prioritization
Data gathering
Online surveyDec. 22–Feb. 22
Analysis and Results
Analysis and results presentation
8/2010 5/2011
10
• Target respondents: – Individuals closely involved with the 510(k) process
– Broad outreach through professional societies, industry groups, and trade media
• Survey Structure:– General part and Device-specific part
– 86 questions total
• Responses:– N=356 respondents total
– Number of respondents varied per question, as not all questions were answered by every respondent
– N per question stated for each question in graphs and appendix
11
Approach and Study Methodology
Years of 510(k)-Related Experience
12
0%
5%
10%
15%
20%
25%
30%
20 or more
15-19 10-14 5-9 2-4 Less than 2
Resp
onde
nts
Years of 510(k)-Related Experience N= 354
26%
14%
21% 21%
10%
7%
Representativeness: Breakdown by Device Type
Type of Device Actual % of FDA Applications
Survey Respondents %
Surgical, Orthopedic, and Restorative Devices 28% 37%
Cardiovascular Devices 13% 23%
Anesthesiology, General Hospital, Infection Control,and Dental Devices 23% 13%
Reproductive, Abdominal, and Radiological Devices 17% 7%
Ophthalmic, Neurological, and ENT Devices 6% 5%
Chemistry and Toxicology Devices 5% 3%
Immunology and Hematology Devices 3% 2%
Microbiology Devices 2% 1%
Other 3% 9%
Actual % FDA applications: Based on all applications to FDA in 2008-2010 (from FDA database); Survey Respondents %: Based on respondent’s statement about device field with most extensive 510(k) experience. 13
FDA’s Internal Assessment compared to Survey Responses
SE
Source: - FDA CDRH, 510(k) Working Group - Preliminary Report and Recommendations, Vol. 1, August 2010.- MDUFA Meeting Report, 2011.
NSE 8%
18%
14* Includes the following responses: De-Novo, Converted to PMA, Other
N= 240
73%
12%Other*
80%
2010
8%
SURVEY
FDA’s Internal Assessment compared to Survey Responses
116
15
N= 224
* SE and NSE only. Avg. duration for SE: 204 days (N=179); NSE: 279 days (N=18); Withdrawn: 330 days (N=13), with long tail.
225 211 days*
FY 2010
SURVEY
148
77
Source: - FDA CDRH, 510(k) Working Group - Preliminary Report and Recommendations, Vol. 1, August 2010.- MDUFA Meeting Report, 2011.
FDA’s Internal Assessment compared to Survey Responses
2.2 Cycles
16N= 211; SE: 2.1 cycles (N=191); NSE: 2.8 cycles (N=20)
Withdrawals (not included in computation): 2.9 cycles (N=14)
2009 2010
2.1
SURVEYN= 211
2.0
Source: - FDA CDRH, 510(k) Working Group - Preliminary Report and Recommendations, Vol. 1, August 2010.- MDUFA Meeting Report, 2011.
Key Findings Predictability and Interaction with FDA
17
0%
10%
20%
30%
40%
50%
60%
Top of the list One of top 3 factors
Important Not important
Resp
onde
nts
How important are regulatory requirements to your business decision to a major investment in a new product?
Importance of Regulatory Requirements in Decision to Invest in a New Product
18
21%
N= 351
58%
19%
2%
0%
10%
20%
30%
40%
50%
60%
70%
Critically important Important Not of major importance
Resp
onde
nts
For the technologies you have worked on, how important is predictability of the regulatory process in deciding first country for market launch?
Importance of Regulatory Process Predictability for Decision about First Country for Market Launch
19N= 351
68%
20%
12%
Respondents Perceiving Substantive Changes in FDA Review Process
20
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Yes No
Resp
onde
nts
From your experience in the last 3 years, have you perceived any substantive changes in the FDA review process and/or clearance decision of a 510(k) submission?
85%
15%
N= 349
Perceived Changes in FDA’s Requirements
21
0%
10%
20%
30%
40%
50%
60%
Clinical: endpoints, duration,
sample size, post-hoc statistical analyses
Preclinical work Regulation: appropiateness
of 510(k)
"Least burdensome"
Animal studies Labeling Other
Resp
onde
nts
In the last 3 years, in what specific areas have you perceived changes in the FDA's requirements?
N= 337
58% 57% 53%49%
34%
2%
13%
Note: More than one choice possible per respondent.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Yes No Other
Resp
onde
nts
81%
12%7%
Have Guidance Documents been Critical to your Company in Preparing Successful Submissions?
22
Availability of Guidance Document has an Impact on the Ultimate Decision
11%
89%
19%
81%
0%10%20%30%40%50%60%70%80%90%
100%
Total NSE + Withdrawn SE
Device Specific: Guidance Document Existing for Technology
Device Specific: Guidance Document NOT Existing for Technology
23
(N=93)
Total: N=222
(N=129)
Clarity of Preparation Requirements for a 510(k) Submission
24
0%
10%
20%
30%
40%
50%
60%
Very clear/certain Somewhat unclear/uncertain
Very unclear/uncertain
Resp
onde
nts
Based on your understanding, what is the current level of clarity of the requirements for preparation and submission of a 510(k)?N= 354
24%
57%
19%
Respondents Perceiving Differences Between Guidance Document and FDA Review
25
0%
10%
20%
30%
40%
50%
60%
70%
Yes No
Resp
onde
nts
If an appropriate guidance existed and was used by your company during submission of a 510(k), did you perceive any difference between the guidance document and the way the FDA reviewed your submission?
N= 300
72%
28%
Reason for Perceived Difference between Guidance Document and FDA Review
26
87%
6%2%
5%
FDA asked for information beyond that required by the
guidance
FDA indicated that unnecessary information had been provided by the sponsor
Other
FDA indicated that all necessary information had been provided by the sponsor, but the way the information was presented was
deemed inadequate N= 216
9%3%
6%
15%
2%4%
61%
Proportion of Time FDA Followed Through on Matters Discussed/Directed
Never Followed Through
Did not Follow Through in 76-99% of cases
Did not Follow Through in 51-75% of cases
Did not Follow Through in 26-50% of cases
Did not Follow Through in 11-25% of cases
Unspecified
Did Follow Through
27(N=211)
Perceived Difference between Pre-Submission Meeting Discussion and FDA Review
FDA did “generally
follow-through”
Interaction: Questions/Requests for Information
28
38%
4%
2%
43%
13%
Perceived as not adding to
safety and effectiveness
Other
Perceived as “scientifically
justified”
Perceived as not adding to
safety
Perceived as not adding to effectiveness
Percent of Requests for Information Obtained During Days 75-90 of FDA’s 90-day Review Period
29
0%
10%
20%
30%
40%
50%
60%
70%
80%
Received during days 75-90 Other times during review process
75%
25%
Resp
onde
nts
N= 293
Interaction: Respondent’s Perspective
30
39%
Yes No
61%
26%
74%
41%
59%
Shouldhave
Already answered
N= 282
N= 275
27%
73%
Not fully clear
N= 216
N= 260
Key Findings Different Impact on Large and Small Companies
31
Key Differences between Large and Small companies
32
Small Companies
Large Companies
New product (vs. line extension) [%] 72% 35%
SE Decision [%] 61% 88%
NSE Decision [%] 13% 1%
Interaction with FDA during development process
earlier later
Pre-submission meeting with FDA sought 39% 17%
Duration of pre-IDE process [months] 10.8 7.4
Change in lead reviewer [%] 19% 10%
Total avg. review time [days] 330 177
33
Respondents perceive:Small
CompaniesLarge
Companies
Major difference with FDA’s risk assessment [%]
48% 23%
% of FDA requests already answered in original submission
53% 33%
% of FDA requests “scientifically justified” 30% 42%
FDA requests having major effect on time[%]
45% 36%
FDA requests having major or medium effect on financial resources [%]
76% 64%
Key Differences between Large and Small companies
Key Findings International Comparison
34
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 1-2 3-5 6-9 10-19 20-29 30 or more
Com
plet
ed R
evie
ws
Review Time [Months]
US, n=121
Australia, n=48
Canada, n=75
EU=115
Japan, n=27
Comparison of International Review Time from Submission to Clearance/Registration
US
JP
CANEUAUS
Length of review process in months (based on data points for “1-2”, “3-5”, “6-9”, “10-19”, “20-29”, “30+ months” for the various regulatory systems. N per country: see above. Graph shows ultimately cleared/registered devices only. 35
Major Reason to Bring a Device OUS First
36
49%22%
9%5%
Within the last 3 years, if your company chose to first bring to market a specific device OUS, what was the major reason?
N = 201
Unpredictable 510(k)
requirements
Cost of clinical trials
Quicker process
Easier process
International Comparison between EU and US
37
EU US
Considered “most predictable regulatory system” [%]
64% 8%
First regulator/”body” approached to discuss and plan submission [%]
80% 4%
Review time (submission to decision) for products not requiring clinical data [months]
2.7 5.9
Review time (submission to decision) for products requiring clinical data [months]
4.8 13.2
Moving Forward to Foster Innovation and Timely Patient Access to Safe & Effective Technologies
38
Enhance predictability
• Increase number of guidance documents
• Timely update of guidance documents
• Clear and timely communication of new FDA expectations before publication in guidance
Increase process consistency
• Increase training (particularly implementation of current regulations)
• Reduce perceived differences in agency follow-through (by enhanced communication)
• Reduce reviewer turnover39
Opportunities
Ensure efficient review process
• Preparation of clear and complete submissions
• Eliminate repeat requests of information already provided
• Timely access to meetings
• Increased use of interactive review concept
Close gap with international systems
• Continued harmonization efforts (GHTF)
• Sharing best practices (particularly on process side), while acknowledging differences in regulatory requirements
40
Opportunities
Increase attention to specific needs of small companies (while maintaining a level playing field)
• Improve opportunities for interaction
• Provide training support in areas where small companies tend to face particular challenges
Monitor effect of process changes
• Evaluate impact of any process changes through appropriate performance metrics
• Work with industry to monitor process performance over time
41
Opportunities
Respondent-Suggested Metrics to Evaluate Future Changes in the 510(k) Process
42Assuming that the FDA will make changes to the 510(k) clearance process, what primary metrics should be used to evaluate the overall performance of the revised 510(k) process?
0%
10%
20%
30%
40%
50%
60%
Predictability Appropiate alignment of
device risk and review
intensity
Review time Number of device-related
recalls
Other
N=356
Resp
onde
nts
58% 57%51%
22%
9%
Note: More than one choice possible per respondent.
Concluding Remarks
43
Funding Source
44
Outreach Partners
45
Research Team
Investigators:
John H. Linehan, Ph.D.
Jan B. Pietzsch, Ph.D.
Research Team:
Marta G. Zanchi, Ph.D.
Abigail Garner, M.S.
Remy Durand, M.S.
Brett Kuekan, M.S.
46
Study website @ www.510k.net
47
Resource Center @ www.510k.net
• 510(k) Basics
• FDA, Government and Medical DevicesCDRH, ODE and OIVD documents, Medical Device User Fee and Modernization Act (MDUFMA) and US House of Representatives: Committee on Energy and Commerce
• FDA Guidance Documents relating to 510(k) regulatory process
• Workshops & Conferences - Webinars, TownHall and Public mtgs
• Literature - published articles pertaining to 510(k) process
• FDA Training and Continuing Education Courses
• Institute of Medicine of the National Academies (IOM)Links to agendas, webcast, presentations and reports from Meetings 1, 2 and 3 relating to 510(k)
• International Regulations 48
Appendix:Background and Additional Data
49
Previous study forming Basis for current Work:“Medical Device Development Models”
50
Journal Articles:
• Review of the U.S. Medical Device Regulation
J. Med. Devices, 283 – 292, 2007
• Stage-Gate Process for the Development of Medical Devices
J. Med. Devices, 021004-1 to 021004-152009
Pietzsch, J. B., Pate-Cornell, M. E., Yock, P. G., Aquino, L. M., Linehan, J. H.
Respondent Characteristics
51
0%
5%
10%
15%
20%
25%
30%
5 or less 6-9 10-19 20-29 30 or more
Resp
onde
nts
Number of 510(k)s during career
510(k) Submissions Involved - During Career
52
17% 17%
27%
12%
27%
How many 510(k) submissions have you been involved with over the course of your career? N= 353
510(k) Submissions -- Last 3 years
53
0%
5%
10%
15%
20%
25%
30%
35%
1-2 3-5 6-9 11-19 20 or more
Resp
onde
nts
Number of 510(k)s submitted over last 3 years
3%
16%
22%
36%
23%
N= 349
Employment Status
54
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Device manufacturer:
Large (500+ employees)
Device manufacturer:
Small (<100 employees)
Device manufacturer: Medium (100-
499 employees)
Regulatory consultant
Other
Resp
onde
nts
46%
26%
12%8% 9%
N= 351
Timelines and Performance Metrics
55
Development Process Time
• The results show that the average length of the product development process is slightly less than two years (21.7 months). (N=216) (Definition of product development process:: From initiation of formal design controls to submission of the 510(k) application; for line extensions and changes: from begin of R&D work for changes to submission of the 510(k))
• For devices that ultimately received clearance, the development process length is stated as 18.5 months (N=168), compared to almost double the time (34.6 months (N=31)) in devices that ultimately received a NSE decision or were withdrawn by the sponsor (a statistically significant difference).
56
Differences in Review Time between ODE, OIVD
• Survey results do not suggest statistically significant differences between review times among ODE divisions, and between ODE and OIVD
57
Predictability and Interaction
58
Importance of Regulatory Requirements for Business Decisions
• 98% of respondents state that regulatory requirements are either important or very important to their business decision to a major investment in a new product. 21% state it is the top of the list in their investment decision making, and 58% state it is one of the top 3 factors for their decision-making. (N=265)
• Respondents of small firms and those with longer industry experience rank the importance generally higher than their peers. (Basis: N=73 for small companies; N=121 for large companies)
59
Perceived Changes and Response
• 85% of the respondents have perceived substantive changes in the FDA review process over the course of the last 3 years. (N=349)
• 64% of respondents state that the product development R&D process at their company has changed because of 510(k) requirements. (N=260)
60
Respondents Indicating “Internal Guidelines” Cited as Justification
61
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Yes No
Resp
onde
nts
In working with a reviewer, has the reviewer cited "internal guidelines" to justify a request for information?
Clarity of Guidance Documents Related to Modification/Design Changes
62
0%
10%
20%
30%
40%
50%
60%
Yes No
Resp
onde
nts
Regarding modification and design changes: Do current guidance documents ("Deciding when to submit...") provide reasonable clarity about when to file a new 510(k) application vs. add a 'letter-to-file'?
Respondents Indicating Changes in R&D Process Due to 510(k) Requirements
63
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Yes No
Resp
onde
nts
Over the last 3 years, has the product development R&D process at your company changed because of 510(k) requirements?
Predictability & Guidance Documents
• Only 41% of respondents stated that guidance existed for their device. (N=239)
• 81% of respondents felt that specific requests from the FDA were unexpected. (N=351)
• Respondents who felt that requirements were very unclear/uncertain, were substantially more likely to receive a NSE decision or to withdraw their application (30%) compared to those who felt requirements were very clear/certain (9.1%). (Basis: N=40 for unclear; N=55 for very certain/clear)
• Of those who ultimately received a NSE decision or decided to withdraw their application, 71% said that there was not a guidance document for their device. (N=34)
64
Predictability & Guidance Documents
• For modification and design changes: 41% of respondents state that current guidance documents do not provide reasonable clarity about when to file a new 510(k) compared to "letter-to-file". (N=352)
• 31% of respondents do not feel confident (7% not confident at all, 24% not very confident) about correctly deciding when to use a special 510(k) vs. a traditional 510(k). (N=352)
65
Predictability
• More than half of the respondents (57%) felt that their own risk assessment differed from that of the FDA (32% state a major difference; 25% a minor difference). (N=230)
• Where major differences were perceived, 33% of the applications ultimately resulted in a NSE decision or withdrawal (Basis: N=73), compared to 4.0% in cases where no difference in risk assessment was perceived (Basis: N=99).
• Of those who received requests for additional information from the FDA, respondents felt that the requests were "scientifically justified" in only 38% of cases. (N=248)
66
Interaction: Pre-Submission Meetings
• 31% of respondents sought interaction with the FDA prior to submitting their application. Respondents with less 510(k) experience (<5 yrs.) sought interactions only half as often as respondents with long-term experience (>15 years), a statistically significant difference. (N=242)
• Respondents who sought a pre-submission meeting with the FDA state they were able to obtain a meeting in a reasonable time frame in 43% of cases. In 57% of the cases, it was perceived as difficult to obtain a meeting. (N=221)
• Of those who ultimately received a NSE decision or withdrew their application, 47% had interacted with the FDA prior to submission. (N=225)
67
• 61% of respondents feel that FDA did generally follow-through on matters discussed and directed at pre-submission meetings (N=211)
– Large companies evaluated the FDA more positively in this regard (74% vs. 54%, statistically significant)
– Less experienced responders (<5 yrs. 510(k) experience) evaluated FDA more positively in this regard than more experienced responders (>15 yrs. experience) (63% vs. 51%)
– For respondents who state that the FDA did generally not follow through, differences exist in the assessment of the degree to which FDA does not follow through. Large companies state that FDA did not follow through in 54% of cases, small companies in 72%. (N=82)
Interaction: Pre-Submission Meetings
68
Interaction: Pre-IDE Process
• 48% of respondents whose device required clinical data reported interaction with the FDA in a pre-IDE process. (N=73)
• On average, the pre-IDE interaction period with FDA was 8.6 months long. (N=35)
• Respondents from large companies tend to experience shorter duration of the pre-IDE process (7.4 months) than respondents from small companies (10.8 months). (N=23)
69
Interaction: Meetings during Review
• Respondents who reported difficulty in obtaining a meeting in a reasonable timeframe during the 510(k) review also reported statistically significantly higher NSE/withdrawal rates (23%) compared to those able to obtain meeting in reasonable time frame (11%). (N=222)
70
Interaction: Change in Lead Reviewer
• Respondents experienced changes in the lead reviewer in approx. 14% of their submissions in the last three years. (N=346)
• There is a statistically significant difference between small and large companies, where small companies experience double the turnover that large companies do (19.3% vs. 9.7%). (Basis: N=155 large comp.; N=91 small comp.)
• 62% of the respondents who did experience a change in the lead reviewer feel that it had a somewhat negative or very negative impact on their review process. (N=194)
71
Interaction: Questions/Requests for Information
• Of those who received requests for additional information from FDA, respondents felt that the requests were "scientifically justified" in only 38% of cases. (N=248)
• Of those requests that were deemed "not scientifically justified" by respondents: – 10% were qualified as such because the data had already been
provided
– 72% because respondents were of the opinion that the data did not add information regarding safety or effectiveness
• 7% not to safety
• 3% not to effectiveness
• 62% to neither
• A significant difference exists between large company and small company perception (42% vs. 30% scientifically justified). (Basis: N=118 large comp.; N=60 small comp.)
72
Interaction: Requests for Information
• 75% of the total FDA questions during the review were received by sponsors during days 75-90 of the 90-day review cycle; results show that there is a statistically significant correlation between this percentage and the ultimate decision (83% for NSE/Withdrawal vs. 73% for SE). (N=293)
• Respondents state that 27% of the FDA questions they received in the last 3 years were not fully clear to them. (N=282)
• Respondents state that, of the last 10 requests they received by the FDA, 4 of the 10 were already addressed in the original submission. (N=275)
– Small companies report that 53% of requests were already answered, whereas large companies report only 33%, a statistically significant difference. 73
Effect of Requests for Information on Time and Resources
• 41% of respondents state that FDA requests for information had a major effect on time, 32% state a medium effect, and 22% a minor effect. 6% of respondents state no effect on time. (N=195)
• Respondents from small companies feel that requests have a larger effect on time compared to respondents in large companies (45% vs. 36% state major effect). (Basis: N=49 small comp.; N=92 small comp.)
• More than 2/3 of respondents state that FDA requests had a major effect (36%) or medium effect (33%) on financial resources. (N=195)
• As can be expected, this figure is higher for respondents from small companies (76%) compared to respondents from large companies (64%). (Basis: N=49 small comp.; N=92 small comp.) 74
Clinical Data Requirements
75
Clinical Data Requirements
• 34% of respondents state that their most recent 510(k) required clinical data. (N=233)
• 41% of those requiring clinical data state that the predicate technology did not require clinical data. In this cohort, 50% ultimately received a NSE decision or withdrew their application, as compared to 25% in those whose predicate did also require clinical data. (N=76)
• The average number of patients ("n") enrolled in clinical trials was 292 (192 for small comp.; 595 for large comp.) (N=59)
• 74% of the trials were controlled (randomized, historical controls, etc.) (68% in small, 82% in large companies) (N=59)
• The average length of follow-up in these studies was 7.9 months (10.4 mths. in small, 7.3 mths. in large comp.) (N=55) 76
Differences between small and large companies
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• The survey responses suggest statistically significant differences between product innovation in small companies and large companies:
• Small companies tend to be involved with completely new products twice as often as large companies. Large companies have a significantly higher percentage of line extensions compared to completely new products. (N=241)
• This difference is consistent with a statistically significantly higher number of successful applications of large companies compared to small companies (89% vs. 75%). (N=163)
• The development process in small companies (26.6 months) is significantly longer than the process in large companies (17.7 months). (Basis: N=57 small comp.; N=103 large comp.)
Key Differences observed between large and small companies
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Key Differences observed between large and small companies
• Responses suggest small companies generally tend to interact with the agency earlier in the development process than large companies. (Basis: N=29 small comp.; N=23 large comp.)
• Respondents from small companies tend to seek pre-submission meetings with the FDA more often than large companies (38.9% vs. 17.3%). (Basis: N=88 small comp.; N=146 large comp.)
• Respondents from large companies tend to experience shorter duration of the pre-IDE process (7.4 months) than respondents from small companies (10.8 months). (Basis: N=15 small comp.; N=8 large comp.)
• Respondents from large companies report total review times that are statistically significantly shorter (approx. 177 days)) than respondents from small companies (approx. 330 days)). (Basis: N=110 large comp.; N=55 small comp.)
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Key Differences observed between large and small companies
• Small company respondents report major differences in risk assessment with the FDA at a rate more than double that of large company respondents (48% vs. 23%), a statistically significant difference. (Basis: N=58 small comp.; N=110 large comp.)
• Respondents from large companies report a statistically significantly higher rate of own predicates compared to respondents from small companies. Higher rates of using other company's predicates as opposed to own predicates is correlated with statistically significantly higher NSE/ withdrawal rate. (Basis: N=52 small comp.; N=106 large comp.)
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International Comparison
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International Comparison
• 68% of respondents felt that predictability of the regulatory process was critically important in deciding in which country to launch first. (N=351)
• 64% of respondents felt that the EU's CE-marking process is the most predictable regulatory system, compared to 8% for US FDA's process. (N=351)
• 80% of respondents state that the first regulator/”body” they approached to discuss and plan their submission was one of the EU notified bodies; only 4% approached the FDA as the first regulator (Cardiovascular and IVD companies selected US FDA at higher rates of 8% and 16%). (N=167)
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International Comparison
• A statistically significant difference exists between respondents from small companies (89% EU first) and large companies (72% EU first). (Basis: N=46 small comp.; N=79 large comp.)
• 65% of the devices in the device-specific part of the survey were CE-marked first. (N=192)
• Of the devices that required clinical data, 90% were CE-marked (Europe) first, compared to only 51% of devices not requiring clinical data (statistically significant). (N=62)
• When comparing process length of the CE registration process with the US FDA's clearance process, the data suggest that current process times in the US are more than twice as long as the comparable time in the EU (13.2 vs. 4.8 months for products requiring clinical data; 5.9 vs. 2.7 months for products not requiring clinical data). (Basis: N=115 EU; N=120 US) 83
International Comparison
• Respondents in the device-specific part of the survey report a mean length of 3.3 months for the CE-marking process (from submission to registration/CE-mark). (N=115)
• A statistically significant difference exists between respondents from large companies who report substantially shorter process length (2.1 month) compared to respondents from small companies (5.0 months). (Basis: N=33 small comp.; N=46 large comp.)
• Respondents who, within the last 3 years, chose to bring to market a specific device OUS first, state in 49% of cases unpredictable 510(k) requirements as the major reason , followed by cost of clinical trials (22%), quicker process OUS (9%), and easier process (5%). (N=201)
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Industry Improvement Opportunities
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Industry Improvement Opportunities
• Respondents state that in 39% of the applications they submitted in the last 3 years, their company could have improved the initial submission. This response is consistent across company sizes; respondents with less experience (<5 yrs.) respond higher rates (46% compared with those with more experience (5-14 yrs.: 36%; >15 yrs. 39%). (N=260)
• Respondents, on average, state that 26% of the FDA reviewers' questions should have been anticipated by the company. There is a statistically significant difference between respondents with longer 510(k) experience (> 15 yrs.) who state that only 21% of questions should have been anticipated, compared to 30% stated by respondents with less experience. (N=216)
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Industry Improvement Opportunities
• Respondents state that, of the last 10 requests they received by the FDA, 4 of the 10 were already addressed in the original submission. This suggests improvement potential for both FDA and industry. (N=275)
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FDA Improvement Opportunities
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Reviewer Experience & Training
• 53% of the respondents opined that a correlation between tenure/training of the reviewer and the number of requests for additional info exists. (N=294)
• Those who state a correlation have a statistically significantly higher rate of NSE decision/withdrawal (70% vs. 50% in SE). (N=153)
• Of those that noted a correlation between tenure/training, 92% felt that lower tenure led to more questions. (N=153)
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