Category: Technologies

10 Best Startup Accelerators

Y Combinator

Y Combinator is a pioneer in the startup accelerator space. Each year the accelerator funds a group of new startups with $120k. A number that was lowered to reduce friction between founders. So far, the companies it has been involved with have a combined valuation of over $100B. Some of the most notable include: Airbnb, Dropbox, Stripe, Reddit, Twitch, Coinbase, and Weebly.

500 Startups

500 Startups is a seed and early stage venture capital fund, consisting of 4 major funds and 13 micro funds which have invested in startups in at least 60 countries. Funded startups include Udemy and Credit Karma. Exits have included sales to Google and Rakuten. 500 Startups recently took in equity from Abu Dhabi Financial Group, giving the firm one of its only two board seats.

TechStars Boulder
Techstars funds, mentors and accelerates startups. Its accelerator program has produced over 1,000 companies valued at over $8B. Techstars is the name behind Startup Week and Startup Weekend, which spur entrepreneurs to kick procrastination to the curb and launch new ventures in a matter of hours.

Plug and Play

Plug and Play Ventures has put 51% of its investments into pre-seed ventures, achieved 8 exits in 2017, invested in 262 new startups last year and holds networking events every day. The accelerator’s in-house VC is reportedly willing to write checks from $25,000 to $500,000. It’s portfolio companies have raised a combined $7B.

Mass Challenge

Although based in Boston, MassChallenge has accelerator programs around the world, with locations in Israel, the UK, Mexico and Switzerland. In the past 8 years the accelerator says its startups have created 80,000 jobs. The program appears to be heavy in Biotech and Fintech.


SOSV closed its own third round of funding for $150M in January 2017. The ‘accelerator VC’ started by Sean O’ Sullivan prides itself on creating real products, not just digital ones. With access to real labs and makerspaces it appears to be popular with food-tech and biotech startups.

Startup BootCamp

Startupbootcamp runs IOT, Fintech, Insurtech and Foodtech programs around the world from Singapore to London, Mexico City, Mumbai, Dublin, Dubai and Amsterdam. To date Startupbootcamp has accelerated startups with an average funding amount of 1.168M Euros.

Internet Initiatives Development Fund

The accelerator specializes in startups in Cybersecurity, Retail, Adtech, Edutech, Big Data and IOT. Over 4,500 startups participate in the basic online program every year, with 20,000 attending events and hackathons.


Wayra began in Latin America, then expanded to Spain before launching in the UK. The accelerator is financially backed by one of the biggest telecommunications companies in the world, Telefonica. Wayra invests up to $50k in startups and boasts that 45% of its ventures have female founders.

Start-Up Chile

Startup-Chile appears to be one of the most active, unique and fastest growing accelerator programs in the world. It was launched by the Chilean government to spur investment and attract entrepreneurs. Accepted entrepreneurs can receive up to $80k in equity free funding and $100k in perks. Start-Up Chile also offers a pre-acceleration program just for startups led by female founders called The S Factory.

Excelerator Labs


LaunchBox Digital

TechStars Boston


Techstars Seattle

Tech Wildcatter

DreamIt Ventures

The Brandery

Capital Factory

NYC SeedStart




10 Best
based on the Number of Exits

1) Y Combinator
Number of investments: 1,834
Number of exits: 192
Location: Mountain View, California, USA

2) 500 Startups 
Number of investments: 1,694
Number of exits: 162
Location: Mountain View, California, USA

3) Techstars
Number of investments: 1,557
Number of exits: 134
Location: Boulder, Colorado, USA

4) Plug and Play
Number of investments: 731
Number of exits: 60
Location: Sunnyvale, California, USA

5) MassChallenge
Number of investments: 1,387
Number of exits: 39
Location: Boston, Massachusetts, USA

Number of investments: 1,152
Number of exits: 23
Location: Princeton, New Jersey, USA

7) Startupbootcamp
Number of investments: 424
Number of exits: 21
Location: London, UK

8) Internet Initiatives Development Fund (IIDF)
Number of investments: 335
Number of exits: 21
Location: Moscow, Russia

9) Wayra
Number of investments: 960
Number of exits: 18
Location: Slough, Buckinghamshire, UK

10) Start-Up Chile
Number of investments: 837
Number of exits: 16
Location: Santiago, Chile

Success Based on
Aggregate Amount of Dollars

  1. Y Combinator – $5B
  2. Techstars – $1B
  3. AngelPad – $493M
  4. DreamIT Ventures – $397M
  5. fbFund – $359M
  6. LaunchpadLA – $185M
  7. SeedCamp – $137M
  8. NYC SeedStart – $130M
  9. Amplify.LA – $57M
  10. Wayra – $44M



Top U.S. Startup Accelerators.

Here’s the list of the top startup accelerator programs in the United States.

TechStars Boulder narrowly edged out Y Combinator for the top spot. and these two programs are very different when it comes to their approaches.

TechStars takes a very hands-on approach giving founders a lot of guidance and mentorship, while according to some participants.

Y Combinator has a more loose structure offering startup founders access to their strong Silicon Valley mentorship network and full-time advisors.

Coming in very close in third and fourth place in the rankings respectively were Excelerate Labs in Chicago only in it’s second year of operation and LaunchBox Digital in Raleigh-Durham, North Carolina (formerly based in Washington, D.C.).

Taking a solid fifth place was another TechStars program, this time in Boston where there has been a resurgence of tech startup activity.

Taking the sixth, seventh and eighth spots in the rankings were KickLabs in San Francisco, TechStars Seattle and Tech Wildcatters based in Dallas, Texas.

Dreamit Ventures and The Brandery rounded out the top ten.

Ranked 11 through 15 were Capital Factory, NYC SeedStart, BetaSpring, BoomStartup and AlphaLab in that order.

Considered but not ranked: I/O Ventures, LaunchHouse, JumpStart Foundry, Momentum, Shotput Ventures, NextStart, Extreme Venture Partners University.


TechStars Boulder

Y Combinator

Excelerator Labs


LaunchBox Digital

TechStars Boston


Techstars Seattle

Tech Wildcatter

DreamIt Ventures

The Brandery

Capital Factory

NYC SeedStart




Protected: Biotech Valuation

The Top 100 VCs in US biotechs

Where the money is: The top 100(+) VCs investing in U.S. biotechs

Warning: Read this before looking at the sortable list below.
(No, I mean it. Stop.)


2015 proved to be the biggest year on record for venture investing in U.S. biotechs. A total of $7.7 billion flowed into a range of startups, some clustered in Boston/Cambridge and San Francisco, but with quite a large amount finding its way to drug developers off the beaten biotech path.

This year the money has continued to flow at the same torrid pace, even though the IPO window for drug developers has dropped down to an uncomfortable squeeze space for the hottest, or most desperate, companies to aim at.

But how do the VCs rank in terms of deals and dollars? I asked Thomson Reuters, which does the numbers for the MoneyTree Report from PricewaterhouseCoopers LLP and the National Venture Capital Association, and they came back with the list below. (No, wait for it.)

Thomson Reuters’ analyst gleans information for these numbers out of press releases, SEC filings, and wherever else they can be found. Deal numbers are fairly easy to track, as the VCs and companies enjoy putting out the numbers on their progress. Specific dollar amounts invested, which typically aren’t announced, are much harder to follow.

To come up with a dollar amount for the total invested by each VC, they took the total round reported and, in the absence of hard numbers, broke it down by averages. If 5 VCs bet $50 million on a company, that would count for $10 million each – even if the hard numbers don’t stack up that way. If there’s only one VC doing the round, that’s easier to keep track of.

David Mott, NEA

David Mott, NEA

What you get is an approximation of the total, which is why New Enterprise Associates—a VC group with a $3 billion global megafund that likes to go in big—ranks at the top of the list. If you base the list on the number of deals alone, a busy Polaris comes out on top.Many of the most prominent VCs do much, much more than just offer money. Third Rock has launched a wave of new companies on both coasts, always dispatching a partner to play interim helmsman. David Mott at NEA didn’t just back Mersana and its ADC tech, he grabbed the chairman’s spot on the board and has a hands-on role in management with CEO Anna Protopapas. When Amy Schulman left Pfizer’s consumer healthcare division and later took up residence at Polaris, she swiftly settled into playing a key role at 7 companies: CEO of Arsia, co-founder Lyndra and a board member of 5 more companies.

Amy Schulman, Polaris

Amy Schulman, Polaris

There’s also an interesting angle to watch in terms of the geography of money. Four of the top 5 VCs on this list are based in Boston/Cambridge. But California is home for 9 of the top 20. Throw in a couple from New York, close to the markets, and GSK’s S.R. One, with offices in Cambridge, MA and San Francisco as well as the pharma giant’s U.S. base in Pennsylvania, and you can see how the money at the top VCs stays close to the companies they invest in — or vice versa.

That’s an important distinction, as many of these venture investors don’t like to travel far for a board meeting. If a partner has 7 companies to watch, they’re likely not going to want to go globetrotting constantly. And that’s one reason why London and New York continue to be shortchanged on startup cash.

Fix that, and you’ll fix your hub development issues in up-and-coming territories. But trends are difficult things to fight, which is why San Francisco and Boston/Cambridge will continue to attract the lion’s share of the cash for some time to come.

I expect I’ll get quite a few calls on this one. And I’ll be happy to update the numbers if firms want to open up.

(You’re good to go.) — John Carroll


Top 100 VC firms investing in U.S. biotech companies
Based on 2015 deals

Click on row header to sort ->
Firm # Cos # Deals Avg Deal Avg Co. Approx $(M) State
1 New Enterprise Associates, Inc. 23 28 7.41 9.02 207.36 California
2 F-Prime Capital Partners 16 17 11.03 11.72 187.59 Massachusetts
3 Third Rock Ventures LLC 13 16 8.47 10.42 135.52 Massachusetts
4 Sanofi-Genzyme BioVentures 7 7 18.42 18.42 128.95 Massachusetts
5 RA Capital Management LLC 18 19 6.78 7.15 128.75 Massachusetts
6 OrbiMed Advisors LLC 20 23 5.45 6.27 125.35 New York
7 Polaris Partners 29 40 3.12 4.30 124.84 Massachusetts
8 Flagship Ventures 10 11 10.17 11.19 111.87 Massachusetts
9 Deerfield Management Company LP 14 16 6.77 7.74 108.34 New York
10 Venrock Inc 12 13 8.18 8.86 106.32 California
11 Sofinnova Ventures Inc 13 16 6.33 7.79 101.22 California
12 Norwest Venture Partners 3 4 23.87 31.83 95.50 California
13 Kleiner Perkins Caufield & Byers LLC 13 17 5.28 6.91 89.82 California
14 MPM Capital LLC 16 24 3.66 5.49 87.83 Massachusetts
15 Canaan Partners 23 27 3.19 3.74 86.06 California
16 Versant Venture Management, LLC 16 20 4.29 5.36 85.83 California
17 New Leaf Venture Partners LLC 13 13 6.53 6.53 84.84 New York
18 Tpg Growth LLC 3 3 27.13 27.13 81.39 California
19 Foresite Capital Management LLC 11 11 6.85 6.85 75.38 California
20 S.R. One, Limited 10 12 6.03 7.24 72.35 Pennsylvania
21 Arch Venture Partners LLC 14 14 4.92 4.92 68.94 Illinois
22 Novartis Venture Funds 12 14 4.53 5.28 63.40 Non-US
23 Column Group 7 7 8.94 8.94 62.60 California
24 5AM Ventures LLC 12 14 4.38 5.11 61.37 California
25 Frazier Management LLC 13 18 3.32 4.59 59.70 Washington
26 Atlas Venture Advisors Inc 18 22 2.57 3.15 56.64 Massachusetts
27 InterWest Partners LLC 11 12 4.48 4.89 53.81 California
28 Longitude Capital Management Co LLC 10 11 4.83 5.32 53.16 California
29 Wellington Management Company LLP 8 8 6.54 6.54 52.30 Massachusetts
30 EcoR1 Capital LLC 8 8 6.42 6.42 51.32 California
31 Ally Bridge Group Capital Partners II LP 9 11 4.67 5.70 51.32 Non-US
32 Arboretum Ventures 6 8 5.40 7.21 43.23 Michigan
33 Domain Associates LLC 12 14 2.96 3.46 41.50 New Jersey
34 Sandbox Industries LLC 4 5 8.23 10.29 41.15 Illinois
35 Novo A/S 17 19 2.07 2.31 39.35 Non-US
36 Hatteras Venture Partners 10 12 3.21 3.85 38.53 North Carolina
37 ProQuest Investments 2 2 19.03 19.03 38.06 Florida
38 F Hoffmann La Roche AG 6 7 5.30 6.18 37.07 Non-US
39 CHL Medical Partners LP 3 3 12.29 12.29 36.86 Connecticut
40 Khosla Ventures LLC 5 5 7.34 7.34 36.72 California
41 Rock Springs Capital Management LP 8 8 4.59 4.59 36.69 Maryland
42 Venture Investors LLC 12 14 2.56 2.98 35.80 Wisconsin
43 Lumira Capital Corp. 7 7 5.04 5.04 35.25 Non-US
44 Chicago Pacific Founders Fund LP 1 1 35.00 35.00 35.00 Illinois
45 HIG Capital LLC 4 4 8.70 8.70 34.79 Florida
46 Sequoia Capital 4 4 8.59 8.59 34.38 California
47 Aisling Capital LLC 4 4 8.40 8.40 33.60 New York
48 Vatera Healthcare Partners LLC 1 1 33.50 33.50 33.50 New York
49 Hope Investments Management Co Ltd 1 1 33.33 33.33 33.33 Non-US
50 Warburg Pincus LLC 2 4 8.33 16.66 33.32 New York
51 Alexandria Real Estate Equities, LLC 3 3 11.00 11.00 33.01 California
52 Windham Venture Partners 5 5 6.32 6.32 31.58 New York
53 Lightstone Ventures LP 7 7 4.39 4.39 30.76 California
54 Takeda Ventures Inc 2 2 15.23 15.23 30.45 California
55 Sailing Capital Management Co Ltd 2 2 15.14 15.14 30.27 Non-US
56 Sanderling Ventures 6 7 4.31 5.02 30.15 California
57 Oak Investment Partners 2 2 15.00 15.00 30.00 Connecticut
58 Mohr Davidow Ventures 4 5 5.94 7.42 29.70 California
59 Mission Bay Capital LLC 6 8 3.70 4.93 29.61 California
60 HBM Healthcare Investments AG 5 5 5.63 5.63 28.17 Non-US
61 Tiger Management Corp 2 2 13.90 13.90 27.79 New York
62 Venbio Partners LLC 5 5 5.44 5.44 27.19 California
63 Morgenthaler Ventures 10 14 1.94 2.72 27.17 California
64 Edmond de Rothschild Investment Partners SAS 4 5 5.38 6.73 26.91 Non-US
65 Pfizer Venture Investments 6 6 4.41 4.41 26.44 New York
66 Sutter Hill Ventures 2 2 13.19 13.19 26.38 California
67 Puretech Ventures 2 3 8.67 13.01 26.02 Massachusetts
68 Omega Fund Management LLC 5 5 5.15 5.15 25.73 Massachusetts
69 Morningside Technologies 4 4 6.39 6.39 25.54 Non-US
70 Sectoral Asset Management Inc 4 4 6.33 6.33 25.31 Non-US
71 Avalon Ventures, LLC 6 6 4.21 4.21 25.25 California
72 Bezos Expeditions 1 1 25.00 25.00 25.00 Washington
73 Osage Partners 7 7 3.54 3.54 24.81 Pennsylvania
74 Partners Innovation Fund LLC 6 6 4.09 4.09 24.55 Massachusetts
75 Aperture Venture Partners LLC 7 7 3.49 3.49 24.41 New York
76 Keiretsu Forum 20 23 1.05 1.21 24.19 California
77 Sante Ventures 7 7 3.32 3.32 23.23 Texas
78 Pappas Ventures 6 6 3.81 3.81 22.83 North Carolina
79 Advanced Technology Ventures 4 6 3.57 5.36 21.44 California
80 Abingworth Management Ltd 5 6 3.57 4.28 21.41 Non-US
81 Baxter Ventures 5 5 3.99 3.99 19.96 Illinois
82 RiverVest Venture Partners LLC 6 7 2.74 3.20 19.21 Missouri
83 Tekla Healthcare Investors 4 5 3.83 4.78 19.13 Massachusetts
84 Correlation Ventures LP 8 8 2.35 2.35 18.81 California
85 Google Ventures 6 6 3.10 3.10 18.57 California
86 Remeditex Ventures LLC 4 5 3.30 4.12 16.49 Texas
87 HealthQuest Capital 4 6 2.63 3.94 15.78 California
88 Mountain Group Capital LLC 7 8 1.93 2.20 15.43 Tennessee
89 Advantage Capital Partners 4 7 2.06 3.61 14.45 Louisiana
90 U.S. Venture Partners 5 8 1.81 2.89 14.44 California
91 Lilly Ventures 3 5 2.87 4.78 14.34 Indiana
92 Radius Ventures LLC 2 5 2.79 6.98 13.95 New York
93 Intersouth Partners 5 6 2.24 2.68 13.41 North Carolina
94 Ascension Ventures 4 5 2.32 2.91 11.62 Missouri
95 Johnson & Johnson Innovation-JJDC Inc 5 6 1.84 2.21 11.04 New Jersey
96 Prolog Ventures 5 5 2.08 2.08 10.39 Missouri
97 InCube Ventures LLC 3 5 1.99 3.31 9.94 California
98 Partisan Management Group, Inc. 5 6 1.45 1.74 8.71 Colorado
99 Healthcare Ventures, LLC 5 5 1.57 1.57 7.84 Massachusetts
100 Tullis Health Investors 4 7 1.01 1.76 7.05 Connecticut
101 MB Venture Partners LLC 11 14 0.44 0.56 6.21 Tennessee
102 Connecticut Innovations Inc 10 14 0.39 0.55 5.47 Connecticut
103 Mercury Partners Management LLC 6 7 0.75 0.87 5.23 Texas
104 BioGenerator 10 11 0.46 0.50 5.01 Missouri
105 Sv Life Sciences Advisers Llp 6 6 0.76 0.76 4.54 Massachusetts
106 Tech Coast Angels 4 5 0.69 0.86 3.44 California
107 Innova Memphis Inc 11 13 0.19 0.23 2.49 Tennessee
108 Ben Franklin Technology Partners Southeastern PA 9 9 0.17 0.17 1.53 Pennsylvania
109 Innovation Works Inc 6 6 0.04 0.04 0.26 Pennsylvania

Protected: Biotech Valuation

U.S. med tech venture investment wanes

U.S. med tech venture investment wanes–even as venture-backed M&A holds strong

Venture capital investment in the U.S. jumped to $59 billion last year–almost twice what it was a scant 5 years ago, according to the latest annual healthcare report from Silicon Valley Bank. But medical devices are capturing an ever-shrinking portion of all that largesse for innovation–down to a mere 4% of that VC total for last year or $2.4 billion, which is roughly right where it was in 2014.

Medical devices and diagnostics are in a precarious but potentially promising spot; because while strategic interest in these segments is growing as activity holds strong, venture investment–particularly in early stage companies–is suffering.

In addition, earlier stage acquisitions for companies with just a CE mark or no regulatory approval in hand at all heated up last year. That’s notable since device acquisitions typically happen at a much later stage than in the biopharma industry. This shift suggests that strategic acquirers are becoming more interested in and confident of early stage device innovation. If that trend continues, it could ultimately spark a deeper commitment to med tech by VCs.

Jonathan Norris, managing partner, Silicon Valley Bank





“The not-approved and CE mark deals outnumbered any commercial deals. That hasn’t happened since 2009. That’s good news–and they got snapped up for good dollar amounts,” noted Silicon Valley Bank’s Healthcare Practice Managing Director Jonathan Norris in an interview with FierceMedicalDevices.

“The Series A investment was off substantially, but look at the M&A happening in the sector. The number of Series A rounds equals the number of M&A deals. That seems like a great time for venture investors–they can get pick of the litter and don’t have to have a lot of me-too companies. It seems like that would be a great time for Series A activity, so we’re hoping that it will pick up,” he added.

SVB found that there were only 22 Series A medical device financings worth a total of just $96 million in 2015; that’s down from 39 in 2014 worth a whopping sum of $327 million. And the majority of medical device Series A rounds were for less than $5 million, keeping those startups on a very tight leash.

New diagnostics and tools startups were similarly starved, down to 17 financings last year worth only $165 million–that’s down sharply from 45 Series A financings worth $354 million in 2014.

The nitty gritty on VC

NEA again was the most active medical device investor in 2015 with 8 deals for a total of $136 million, followed closely by Life Sciences Partners and Windham Venture Partners that each made 7 investments. OrbiMed Advisors, Lightstone Ventures and Novo each also did 5 or 6 med tech venture financings last year.

Boston Scientific ($BSX) was the most active corporate investor in medical devices last year with 7 investments totaling $75 million. Johnson & Johnson’s ($JNJ) JJDC also weighed in with 4 deals worth $60 million in total. Cleveland Clinic Innovations was also busy with four very early deals totaling only $4 million.

Like the oncology-oriented biotech sector, medical device investors largely stick to familiar specialties with a history of being more lucrative. Over the last two years, first-time venture investments have clustered largely in cardiovascular (20 deals worth $368 million); orthopedics (12 deals worth $159 million); vascular (10 deals worth $225 million) and surgical (9 deals worth $225 million). Cardio was obviously boosted by the bandwagon that is mitral valve replacement, which attracted a number of major acquirers and partners throughout the year.

Orthopedics and vascular pushed neurology and ophthalmology out of the second and third spots on that list that they previously held. Drug delivery made its appearance on this top 10 list for the first time–surging on with 6 deals worth $60 million. 5AM Ventures has been particularly active in drug delivery venture investment.

“Drug delivery is on the list for the first time,” noted SVB’s Norris. “I think that trend will continue–finding ways of delivering noninvasive or minimally therapies. We’re seeing a lot of investment in minimally invasive devices to take market share from drugs or unique tech for drug delivery.”

Life science crossovers have gained some traction in medical devices over the last few years, with 6 investments from Deerfield Management, four from RA Capital and three from Foresite Capital. Crossovers are public company investors that sometimes invest in private companies that typically have a relatively short path to the public markets.

Diagnostics and tools companies also attracted their share of crossover attention in that timeframe with 6 investments by Casdin Capital as well as two each from RA Capital, Rock Springs Capital and Woodford Investment. Norris expects Dx companies will continue to gain traction with rising interest in next generation sequencing tech and synthetic biology. OrbiMed and Khosla Ventures were the most active investors in new diagnostics companies in the last few years with five each.

Making more from M&A

There were 11 medical device IPOs last year; that’s comparable to 2014 when there were 10. On the diagnostics side, there were 5 IPOs in 2015 with 7 of them in the year prior. There were 5 venture-backed M&A deals in diagnostics last year, down from 10 in 2014.

But with recent weakness in biotech IPOs, overall market choppiness and a dearth of filings it could be tough to see many med tech IPOs this year. Part of the caution in the sector by VCs is because, many still retain device and diagnostic portfolio companies for which they need an exit.

On the venture-backed M&A front, there were 17 in medical devices last year–largely on par with the 18 in 2014 but with a median valuation that’s 20% higher than. Time-to-exit for these fell to a four-year low last year of 5.5 years.

Six of the medical device acquisitions were by sector giant Medtronic ($MDT), which didn’t slow its appetite at all as it digested the Covidien deal. Covidien was the second-most prolific medical device acquirer prior to the acquisition, but its absence was scarcely felt as other entrants took up the slack.

The wild card last year was Google, which was far more aggressive than anyone expected last year forming med tech Verily as its first company under new parent company Alphabet ($GOOG) and starting robotics and medical device focused Verb Surgical as a joint venture with Johnson & Johnson ($JNJ).

SVB’s Norris expects to see more tech players pile into med tech in 2016, but cautions that technology companies have had a tough time breaking into the life sciences given some lack of understanding around market uptake and reimbursement. He would like to see other tech entrants follow Google’s example of hiring industry vets and structuring its med tech efforts with some autonomy and accountability.

“There’s going to be at least one or two big tech players that will create a group within their company or a new company to focus on the life sciences,” predicted Norris for 2016. “It wouldn’t surprise me to see someone like Apple become more focused themselves.”

– here is the report

For more:
Medical device, diagnostic venture investment at $2.7B, highest since 2008
Med tech exits pick up in 2014, momentum to continue into 2015
Medtronic to buy Twelve for $408M+, joining Abbott and Edwards on the transcatheter mitral valve bandwagon
Abbott moves more into mitral valve med tech, to buy startup for $250M and options another
Abbott creates electrophysiology biz by moving in on a trio of NEA startups

Protected: Biotech Valuation

The Most Active VCs In Medical Devices

The Most Active VCs In Medical Devices and Their Investments In One Infographic


NEA, Versant Ventures, and High-Tech Grunderfonds are the three most active investors in medical device startups.

Funding to medical device startups is on track to pick back up this year, following a 13% year-over-year drop in 2015.

Since 2012, venture capital dollars have been distributed across the category into a variety of startups focused on advancing medical diagnostics, imaging, surgery, and genomics, among other specialties.

Six of the VCs listed below invest exclusively in the life sciences. These include Versant Ventures, Johnson & Johnson Innovation, OrbiMed Advisors, SV Life Sciences, Domain Associates, and De Novo Ventures. NEA, Morgenthaler Ventures, and Interwest Partners focus on both IT and healthcare while High-Tech Gruenderfonds supports-early stage technology companies across sectors.

Other than High-Tech Gruenderfonds, which backed 15 seed or Series A deals since 2012, Versant Ventures was the only investor with more than 1 deal to an early-stage medical device company.

Which firms are most active? We used CB Insights data to rank VCs by their unique medical device investments over the past 4 years.


Modern Medicine: Trends In Medical Devices
 Join us for a webinar as we take you through private market trends, major investors, and pioneering medical device startups.
NEA and Versant Ventures top the list as the two most active investors in medical device startups. (However, neither make the top five among the most active early-stage investors overall in the category during 2012-2016.) Some other takeaways from our infographic:
  • In the past year, NEA has invested in an array of medical device businesses including EarLens, CVRx, and Spine Wave. EarLens develops a light-based hearing aid, CVRx developed an implantable device that uses the body’s baroreceptor reflex to lower blood pressure, and Spine Wave produces devices intended for use in spinal surgeries such as vertebral compression fracture repair.
  • The healthcare focused Versant Ventures came in second as the most active medical device investor since 2012. They have recently taken part in two Series F rounds to Minerva Surgical, which developed an FDA-approved endometrial ablation system to treat heavy menstrual bleeding, and Benvenue Medical, which develops spinal implants and devices geared towards spinal surgery.
  • The third- and fourth-most active VCs investing in medical devices were Germany based High-Tech Gruenderfonds and NYC based OrbiMed Advisors, High-Tech Gruenderfonds, which tops the list of early-stage investors, recently contributed to SeNostic’s seed round and provided early capital to Abviris.
  • Other firms listed include the venture arm of Johnson & Johnson, Johnson & Johnson Innovation, as well as Morgenthaler Ventures, SV Life Sciences, InterWest Partners, Domain Associates, and De Novo Ventures. The most common co-investment among these VCs is Benvenue Medical, which is backed by four of the investors listed below — Versant Ventures, InterWest Partners, Domain Associates, and De Novo Ventures.

See the rest below. Click image to enlarge.

Newest graphic

The FDA Approval Process for Medical Devices

An Inherently Flawed System or a Valuable Pathway for Innovation?

Kyle M Fargen; Donald Frei; David Fiorella; Cameron G McDougall; Philip M Myers; Joshua A Hirsch; J Mocco

J NeuroIntervent Surg. 2013;5(4):269-275.


Medical devices, developed through physician and industry partnerships, have helped to revolutionize the treatment of disease spanning most medical disciplines. This includes such entities as deep brain stimulation implants for Parkinson’s disease, knee replacements for osteoarthritis, coil embolization technologies for intracranial aneurysms and implantable cardiac defibrillators for life-threatening arrhythmias. These remarkable products have undeniably led to increased patient longevity and improved quality of life. Such marvels of modern medicine, however, do not come without cost, to either the consumer or the manufacturer. Recent estimates suggest that the annual expenditures on medical devices in the USA approximates $95–150 billion, which represents almost one-half to three-quarters of the $200 billion spent on such devices across the world and about 6% of our total national health expenditures.[1, 2]

Development of new technologies requires considerable investment from companies in terms of research and development costs, manufacturing and marketing, as well as a rigorous approval process through the Food and Drug Administration (FDA). All-in-all, the price of innovation is monumental for those invested in advancing medicine through cutting edge technologies. Recently, there has been a push among lobbyists representing device manufacturers to streamline the lengthy FDA approval process,[3] arguing that the USA will lose its ability to compete globally due to the excessive costs and delays in obtaining FDA approval.

However, in direct contrast to any effort to ‘streamline’ the approval process, the oversight of device innovation and the approval process has been criticized recently due to several notable device ‘failures’ that have been linked to patient harm. These devices were approved for use through FDA humanitarian device exemption (HDE) or 510(k) processes, which do not require randomized controlled trial evidence demonstrating safety and effectiveness prior to approval.

Unfortunately, such failures are certainly not new. Between 2005 and 2009 nearly 700 voluntary recalls of devices occurred per year, and the vast majority of these were class II recalls, defined as technologies that could result in ‘temporary or medically reversible adverse health consequences’.[4] The failure of these processes to detect potentially harmful devices before their release onto the US market has led to a strong backlash, by both physicians and the public at large,[5]against the current regulatory processes in place through which such technologies are approved for use.

The specialty of neurointerventional surgery (also known as interventional neuroradiology or endovascular neurosurgery) is heavily leveraged to medical device development. In this article we will review some recent devices that have generated controversy, review the current FDA approval processes, discuss current issues being debated regarding these processes for new devices and offer further insight into the effect of experience in outcomes for new devices. Finally, we will review possible alternative pathways towards improving the safety and effectiveness of new devices through regulation that both encourages innovation among clinicians and industry and closely monitors new devices after their release.

Recent Device Failures

Adoption of new technologies is not without risk. While initial experience may demonstrate benefit, further experience or longitudinal measures may detect concept, design or manufacturing flaws that were not immediately evident. The most prominent of such devices is the ASR XL Acetabular System (DePuy, Johnson & Johnson, Warsaw, Indiana, USA), which was approved for use by the FDA through 510(k) clearance (described below) and introduced into the US market in 2005. This device has gained considerable negative media attention[6, 7]with numerous websites recruiting clients for plaintiff attorneys and over one million unique web pages produced after a Google search using the keywords ‘Depuy ASR hip recall’. The ASR featured a metal-on-metal acetabular cup design that was borrowed from a second device, the ASR Hip Resurfacing System, and fitted onto a predicate hip implant. Depuy applied for 510(k) clearance and the new device was deemed substantially equivalent to the prior hip implant without rigorous safety and effectiveness testing. Between 2005 and 2010, approximately 100 000 ASR Acetabular systems were implanted. By 2008 the FDA had received about 300 complaints regarding the device, most arising from patients who had had to undergo early revision surgery.[6]Recent studies have demonstrated an increased rate of implant dysfunction with need for revision surgery that far exceeds that of other hip replacement devices.[8, 9] In fact, results presented at the British Hip Society meeting in 2011 indicated a failure rate nearing 50% at 6 years, which is three times the rate of other devices (approximately 15% at 5 years).[8] Furthermore, elevated levels of blood chromium and cobalt were identified as a side effect of dysfunctional joints. Based on these data, a voluntary recall of the ASR devices was enacted in August 2010 after an estimated 100 000 ASR devices had been implanted (one-third in the USA) and 6 months after the company warned physicians of a high early failure rate.[6, 7] Examination of the dysfunctional implants after removal identified flaws inherent to the design.[10] It is possible that more rigorous safety testing prior to market release, or close post-market clinical follow-up, would have detected irregularities and prevented (or halted) the implantation of ASR devices.

A more familiar neurointerventional device recently drawing considerable negative attention is the Wingspan Stent System (Stryker, Kalamazoo, Michigan, USA), a stent designed for use with the Gateway PTA Balloon Catheter in the treatment of intracranial atherosclerotic disease. The stent was approved under a FDA HDE in 2005, based on a safety study conducted in 45 patients at 12 sites in Asia and Europe, for the treatment of intracranial atherosclerotic disease refractory to medical therapy in intracranial vessels with stenosis of ≥50%. Early retrospective analyses of outcomes performed by independent centers indicated both safety and efficacy with the Wingspan,[11] and many clinicians involved in stroke care were optimistic about how the system would fare in a randomized controlled trial of stroke prevention. The Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial (SAMMPRIS), the first randomized trial comparing best medical therapies to angioplasty and stenting, began enrolling its first patients in October 2008. However, enrollment for SAMMPRIS was halted prematurely in a report in September 2011 owing to a 30-day stroke rate of 14.7% in the angioplasty and stenting arm compared with 5.8% in the medical management arm.[12]These results have led a consumer advocacy group to seek the repeal of the Wingspan HDE and to criticize the FDA for the original approval.[13–15]However, these efforts are not without controversy as the patient population evaluated in SAMMPRIS was in some respects different from the population indicated on the patient HDE (who would only comprise a subset of the patients evaluated in SAMMPRIS), and the 1-year stroke rate of 20.2% was still perceived as a dramatic improvement over the 24.9% stroke rate demonstrated in the WASID[16] study for the HDE-approved population. Thus, while portrayed as ‘dangerous’ by groups such as Public Citizen, outcomes with Wingspan in SAMMPRIS were no different from those observed in the same patient cohort treated with conventional medical therapy. The true advance in the SAMMPRIS trial was an observation that was independent of the actual device in that aggressive medical management resulted in a primary event rate that was half the rate (12.2% over 1 year) expected on the basis of the WASID study (24.9%). So while no one debates that aggressive medical management is superior to angioplasty and stenting in the SAMMPRIS study population, this unexpected finding in no way indicates a breakdown of the regulatory process but merely reflects a tremendous advance in the medical management of the disease process.

A final example of a neurointerventional device not performing as anticipated is the Cerecyte coil (Micrus Endovascular, San Jose, California, USA), a specific type of detachable bioactive coil designed for the endovascular embolization of intracranial aneurysms. The Cerecyte coil contains a polyglycolic acid element within the wind of the coil, in contrast to traditional coils which are composed of bare platinum. The Cerecyte coil was approved for use in the USA via the 510(k) process in 2004. Early non-randomized studies suggested better results than bare platinum coils,[17–21]leading the device manufacturer to charge a premium for these coils as they were deemed superior to traditional coils. However, the Cerecyte Coil Trial, a company-sponsored randomized controlled trial comparing Cerecyte coils with bare platinum coils, demonstrated no benefit for Cerecyte over traditional coils.[22–24] Although it is unlikely that patients were physically harmed due to the use of this technology, the amount of money spent on premiums for what was eventually determined to be an equivalent product is substantial. This problem is not isolated to the Cerecyte coil; other devices such as the Matrix coil (Stryker)[25] were similarly charged at a premium for years, only to reveal no difference in primary outcomes in later definitive trials. This scenario represents an additional point of contention: unvalidated increases in financial expenditures following a market release without rigorous testing and post-market follow-up.


When considering device pathways to FDA approval, it may be helpful to first review the pathway to FDA approval for drugs. It is estimated that the average length of time from concept to market for investigational new drugs is about 12 years, which has increased significantly from just under 8 years in the 1960s, with an estimated total cost per drug of $800 million.[26]

The process can be divided into several stages: a research and development phase with preclinical testing (average 1–3 years), a clinical research and development period including phase I, II and III testing (average 5–10 years), and a new drug application FDA review with post-marketing surveillance (average 2 years). During this time period, drugs are tested in a sequential manner that incrementally increases patient risk while targeting a specific therapeutic goal.

Phase I studies are usually conducted in healthy volunteers to determine the side effect profile and relative safety of the medication as well as the route of metabolism. If phase I studies demonstrate an acceptable safety profile, phase II studies are undertaken that evaluate medication effectiveness. This phase aims to obtain preliminary data on whether the drug is effective against a target condition, usually through randomization of patients with the diagnosis of interest to varying drug doses, including a placebo group. Safety continues to be evaluate, and short-term side effects are studied. Patients’ responses to each dose are monitored and optimal dosing, based upon a risk-benefit ratio, is identified.

At the conclusion of phase II the FDA and drug development company meet to plan phase III studies. Phase III studies evaluate the new medication head-to-head with other standard treatments, with the goal of comparing the intrinsic effectiveness and safety of the new medication against alternative or standard-of care therapies. Phase III studies are frequently randomized controlled trials that compare the new medication with alternative therapies that are already accepted treatments for the given condition. Drugs that successfully navigate these three phases with satisfactory effectiveness and safety profiles are reviewed and approved for use. Following approval, post-marketing requirements and commitment studies (phase IV) are mandated in which the medication is monitored for safety, efficacy and alternative uses even after release onto the market.

In contrast, the regulatory process for medical devices is much shorter and, generally, less stringent and costly. It has been estimated that the time from concept to market for medical devices is 3–7 years, although no concrete data could be identified in the literature regarding time or cost. The Medical Device Amendments of 1976 to the Federal Food Drug and Cosmetic Act established the current FDA policies regarding medical device approval. Within this framework, many new regulated devices are catalogued as Class III, which is defined as a device that ‘supports or sustains human life or is of substantial importance in preventing impairment of human health or presents a potential, unreasonable risk of illness or injury’. Manufacturers may petition to have their device downgraded to Class I (low risk) or II (moderate risk) should the device harbor only minor differences from devices previously approved. All such devices placed into Class III are subject to premarket approval (PMA) requirements, while those that are classified as Class I or II are subject to less stringent requirements. Therefore, unlike the drug development pathway that mandates successful results in all three clinical phases to obtain new drug approval, the medical device pathway has separate fast-track routes of obtaining approval. These pathways are discussed in the sections that follow. Further information regarding medical device approval is available on the FDA website at

Premarket Approval

Premarket approval (PMA) is the most stringent type of device marketing application required by the FDA and is required for new devices for which there is no existing equivalent or predicate (Class III devices). PMA approval is granted only if the FDA determines that the new device has sufficient scientific evidence demonstrating that the device is safe and effective for its intended use. Usually, Class I or Class II evidence (prospective data compared with historical controls or randomized clinical trials) are necessary to obtain PMA. In effect, a PMA acts as a license granted to the applicant for the sale and use of their product in the USA. PMA may be considered the ‘gold standard’ regulatory process through which devices are approved because these devices must have valid prospective scientific evidence supporting their benefit and safety. However, it should be emphasized that PMA approval can be achieved with Class II data (such as the Pipeline Embolization Device; ev3, Irvine, California, USA) without an active comparator. Evidence-based medicine specialists will point out that this raises significant potential limitations to the quality of the data regarding some PMA-approved devices. Additionally, there is no requirement for post-marketing surveillance studies to validate the pre-marketing experience.

Premarketing Notification

A Premarketing Notification (510(k)) is a fast-track process wherein applicants must demonstrate that the device to be marketed (moderate risk or Class II) is ‘substantially equivalent’ to a pre-existing legally-marketed device (predicate) in terms of safety and effectiveness. The predicate must have been approved either via PMA or 510(k); devices currently under review are not acceptable predicates. The 510(k) application to the FDA is required at least 90 days before marketing.

This process is usually used when manufacturers develop small iterations upon a previously approved device that are thought to improve effectiveness without compromising safety, allowing for expedited approval without costly and lengthy scientific studies confirming safety and effectiveness. Although this process allows for quick turnover of cutting edge technology from bench to bedside, it also introduces an element of risk should the equivalence assumption be invalid (eg, the Depuy ASR). Furthermore, as devices may be approved based on equivalence to devices now on the market that had 510(k) approval, it is possible that a device could be found equivalent to one approved years ago and that the prior device was deemed equivalent to one three decades ago, and so on, without any recent scientific evidence supporting the technology’s use.

The ‘de novo’ 510(k) process was initiated as part of the 1997 FDA Modernization Act and may be used when no predicate exists but there are substantial data to suggest the device does not carry high-risk (Class III) status. Most devices without a predicate are automatically classified as Class III. This process involves the submission of a 510(k) application, even though a predicate does not exist, resulting in a letter of non-substantial equivalence from the FDA. The manufacturer may then petition the FDA (‘de novo’ petition) to have the device reclassified to Class I or II by providing ample evidence that Class III status is not necessary.

Humanitarian Device Exemption (HDE)

The third means of approval is via a HDE application. It is important to note that neurointerventional surgery, as a specialty, features a relatively high number of HDE-approved devices. A Humanitarian Use Device (HUD) is a medical device designed to treat or diagnose a condition that affects <4000 individuals in the USA annually. In addition, the use of a HUD requires local institutional review board (IRB) approval and supervision. The HDE application is similar to the PMA application; however, the HDE is exempt from the PMA requirement of valid prospective scientific evidence arguing its effectiveness.

The HDE carries this exemption because it could potentially take years just to enroll enough patients with a rare disease to obtain a power sufficient to demonstrate statistical effectiveness. However, data to support the HDE must demonstrate that there is a probable benefit to health from the use of the device and that the probable benefit outweighs the risk of injury or illness from the use of the device. Therefore, to allow for continued technological advancement and treatment of diseases of low prevalence, the HDE only requires demonstration of device safety with the assumption of device effectiveness. To keep manufacturers from profiting from devices that lack evidence supporting their effectiveness but allow for patients with rare disorders to receive continued treatment, the HDE mandates that manufacturers charge a price that covers manufacturing fees, research and development and other associated expenditures only.

If this value is more than $250, the HDE holder must provide the FDA with an independent certified accountant report or representative attestation indicating the reasons for the higher cost. An exception to this rule is an HUD designed to be used in pediatric populations and some devices used to treat both children and adults. Similar to the 510(k) process, this process helps to expedite approval for medical devices aimed at benefiting uncommon diseases, but also introduces an element of risk should the effectiveness assumption be invalid or become outdated with advancing alternative treatments.

Investigational Device Exemption (IDE)

An investigational device exemption (IDE) is required prior to evaluating investigational devices in a clinical study. Unlike other device pathways, an IDE requires local IRB approval, informed consent from all treated patients, labeling of the device for investigational use only and rigorous monitoring of the study. Investigational devices are dichotomized into two groups based on the potential for serious risk to health of subjects: significant risk devices and non-significant risk devices. Significant risk devices, given their inherent risk to patients, require both FDA and IRB approval before initiation of a clinical study, while non-significant risk devices require only IRB approval. The IDE process provides manufacturers of new devices a means to evaluate for device safety and effectiveness to support a PMA or 510(k) application.

Postmarket Device Reporting

All devices approved for market have mandatory manufacturer and facility reporting requirements. Most notably, manufacturers and the facility must report all device-related deaths, serious injuries and adverse events secondary to device failure or adverse events in which the device may have contributed. These include 30-day reports in which manufacturers have 30 days from time of event to report device-related deaths, serious injuries or malfunctions to the FDA (available at; 5-day reports which require manufacturers to report serious public health concerns stemming from device use to the FDA within 5 days of becoming aware of the concern; baseline reports which are for first-time adverse events; supplemental reports; and annual certifications. However, substantial criticism exists with this reporting process as no formal system is in place to ensure capture of all events. For the most part, the reporting process is dependent upon physicians reporting any events back to the company. It is probably fair to say that, currently, such reporting is sporadic at best.

The FDA may order manufacturers of certain Class II and Class III devices to establish tracking systems in which each individual device may be tracked to the patient in which it was used. This provision allows the FDA and manufacturer to locate and expeditiously remove those devices from the market that have been identified in postmarket reporting as potentially dangerous or defective (facilitating device recalls) or to notify treated patients of a potential health concern associated with device use. Generally, devices subject to such tracking provisions are those that are intended for implantation in the body for >1 year, those that may cause significant harm or death should the device malfunction, or those that are intended for use outside the treatment facility and are life-saving or life-sustaining.

The FDA may also order holders of a PMA or HDE to perform a 522 postmarket surveillance (522PMS) study to help assure continued safety and effectiveness after the device has been released on the market for a period of up to 36 months. The FDA has authority to require a 522PMS on any Class II or Class III device that meets one of the three tracking criteria (listed above) and/or is expected to have significant use in a pediatric population. The 522PMS is highly specific to the given device and may range from animal studies to randomized controlled trials. Frequently, a required 522PMS will involve active or enhanced surveillance studies where the incidence, distribution and trends of adverse events are actively or passively recorded and reported.

Growing Concerns About the Current FDA Approval Processes

There is a growing discussion in both the medical literature and in public commentary regarding potential faults in the FDA approval process for medical devices.

Most notably, the 510(k) and HDE processes have sparked considerable controversy due to the Depuy ASR and Wingspan System, as well as other devices, which were approved through ‘fast track’ routes lacking scientific evidence confirming device safety and effectiveness.

Safety concerns have been raised over the FDA’s 510(k) clearance process whereby devices demonstrated to be ‘substantially equivalent’ to previously approved devices, and therefore thought to share similar safety and benefit profiles, are approved for marketing without clinical trials. These concerns led the Institute of Medicine (IOM) to recommend eliminating the 510(k) process altogether in their July 2011 FDA-commissioned report.[27]

Within this report the IOM argues that the 35-year-old 510(k) process cannot ensure device safety or effectiveness because it lacks any means to do so; it can merely determine equivalence to a predicate device. The IOM therefore argues that the 510(k) process should be disbanded and a new forward-thinking process developed. Furthermore, the report argues for enhanced post-marketing surveillance monitoring of devices, a feature that 510(k) approval currently lacks. Unfortunately, the report does not deliver new blueprints for overhauling the system; it merely identifies that the 35-year-old 510(k) process is antiquated and no longer appropriate. The report does list a number of attributes that would be ideal for any new FDA approval system for Class II devices including evidence-based, fair, clear, self-improving, risk-based, and others.[28]This report has been met with praise[29] but also criticism, particularly from the medical device industry which argued that changes to regulation would slow technological innovation, cost jobs and harm patients.[30, 31]

An additional concern of this process revolves around the financial incentive for manufacturers to develop new devices via the 510(k) clearance process with only minor improvements. As stated by Curfman and Redberg in a commentary published in the New England Journal of Medicine: “Since regulatory approval hinges on claims of similarity to previously approved devices, the process may encourage the development of devices that provide only small improvements at higher cost than their predecessors. The trade-offs between incremental improvement and the additional costs and technical complexity of the required procedure are poorly understood and seldom investigated rigorously.”[29] As seen with the Cerecyte coils, the manufacturer was able to charge a premium due to purported superiority over traditional coils without any prospective evidence confirming superiority. When a prospective trial was performed, equivalence was confirmed but superiority was not, indicating that patients had been charged an increased cost for years for a device that was no more effective than its cheaper alternatives.

The HDE approval process may not adequately require substantial proof of efficacy. Nevertheless, the majority of these concerns are addressed at individual devices, not at the fundamental principles of the HDE approval process. Concerns have arisen due to the recent SAMMPRIS results regarding the Wingspan System[13–15] as well as devices for other treatments such as deep brain stimulation in obsessive-compulsive disorder.[32]

Critics note the differing level of requirement for the introduction of drugs versus medical devices. Ironically, the FDA is being criticized at both ends of the spectrum while remaining substantially under-funded for the difficult tasks that it must oversee. On the one hand, there are concerns over the seemingly slow pace of introduction of new devices and drugs to the US medical market. Simultaneously, the FDA faces criticism for allowing drugs and devices to enter the market prematurely. Finally, some critics argue that the FDA and the Centers for Medicare and Medicaid Services (CMS), who are responsible for reimbursement for devices, play a critical role in the speed at which enrollment occurs in important randomized controlled trials based upon reimbursement patterns, and whether or not devices are reimbursed outside the context of a clinical trial. One example of this phenomenon is new acute ischemic stroke devices, which some argue are enrolling patients for randomized trials very slowly due to the fact that these devices are being reimbursed prematurely by CMS without Class 1 evidence supporting their use.[33, 34] In addition, poor coordination between the FDA and CMS with regard to physician reimbursement for FDA-approved devices (eg, foreign body retrievers with a stroke indication) further contributes to this issue. Finally, an inefficient FDA approval process is resulting in an increasing number of device manufacturers outsourcing their randomized trials to Europe or other countries in an effort to expedite accrual and trial completion. This fact may be a further indication that flaws inherent to the current FDA regulatory processes may be beginning to undermine the ability of the USA to remain competitive in the medical device industry.

The Role of Experience in Device Effectiveness and Safety

An important issue that has so far been left out of the FDA clearance debate is the role of operator experience in determining device safety and effectiveness. Most new medical technologies have a learning curve wherein clinicians receive initial training once the device is released for use and then subsequently improve with experience. Logically, practitioners using new devices are more likely to cause patient harm when first learning how to use the device than after proficiency has been obtained. The ‘learning curve’ effect plays a significant role in those devices that require new advanced skill sets and, through its effect on patient outcomes, may be a substantial contributor to the early results of mandated safety and effectiveness trials for devices. Recognition of this learning curve effect by the FDA has led to important FDA-manufacturer agreements regarding training for some new devices such as the Pipeline Embolization Device, wherein clinicians must undergo course training and then be supervised by a proctor for a designated number of cases before being able to use the device independently.

An excellent example of the learning curve effect comes from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), a randomized trial comparing carotid endarterectomy to carotid angioplasty and stenting with the primary outcome of stroke, myocardial infarction or death.[35] Although carotid angioplasty and stenting was first described in 1994, significant improvements in device technology, such as distal embolic protection devices, were not widely available until the beginning of the 21st century. The fundamental goal of CREST was to compare a new and exciting technology—angioplasty and stenting (with which most clinicians having only limited experience)—with a tried and tested technique—carotid endarterectomy, a commonly-performed procedure introduced in the 1950s. CREST began enrolling patients in 2000 and finished in 2008, with 50% of total enrollment reached in 2006. The final results of the trial demonstrated statistical equivalence of stenting with endarterectomy for the primary outcome, with a higher risk of stroke in the stenting group and higher risk of myocardial infarction in the surgical group. Interestingly, the risk of major stroke or death in the stenting group was 2.5% over the period 2000 to 2005 (n=361) and <1% from 2006 to 2008 (n=770).[36] The substantial reduction in serious complications during this time period for the endovascular treatment arm is most likely secondary to improvements in technique from gained operator experience at the treatment centers, but may also be partly due to changes in enrollment criteria during the study period. The learning curve effect is well illustrated in this example because of the longevity of the trial, which provided ample time for operators to develop proficiency with the devices and techniques. Had the trial been halted before 2005, the results from stenting would have appeared worse than endarterectomy because operator experience was poor and complications were high. However, we now know that carotid stenting is a safe and effective option for patients with carotid stenosis because the trial allowed ample time for operators to become proficient and for associated technologies to be developed and widely implemented, with the lower complication rate towards the end of the trial nullifying the higher rate of poor outcomes at the beginning.

Expanding the concept of a learning curve effect to the approval process makes the situation even more complicated. Assuming this process occurs universally for most new technology, early trials evaluating the effectiveness of a new device are likely to overestimate complications and underestimate effectiveness because clinicians have limited experience with the device and are more prone to error. Consequently, early studies are likely to show no difference in outcomes (or potentially worse) compared with standard of care therapies. Studies performed years after approval of a device, after clinicians have gained experience with the technology and acquired proficiency, are more likely to report lower complication rates and a better safety profile. Extrapolating this argument further, one can predict how rigorous early testing of new technology, such as in a PMA, has a bias towards device rejection. Conversely, continued post-marketing monitoring of device safety and effectiveness in the years that follow approval is likely to show improved results as time progresses. Therefore, while early tests are crucial in detecting devices that are unsafe, post-marketing monitoring may be just as important in capturing the true risks and benefits of new technology.

There certainly exists a subset of newly-approved devices with inherent flaws that will continue to show inferior results regardless of advancements in proficiency (eg, the Depuy ASR). However, there are probably devices approved by the FDA with mediocre initial results that could show improvements in safety and effectiveness with time, and eventually become a standard of care therapy with profound benefits to patients with a particular condition.

Optimizing the FDA Approval Process

Recent and major device failures suggest a rationale for change within the FDA device approval framework. There has been surprisingly little argument from neurointerventional physicians regarding the PMA process and the need for rigorous testing demonstrating safety and effectiveness of new high-risk Class III devices. Furthermore, although the HDE process has limitations, the rarity of the diseases for which the devices are designed to treat makes obtaining effectiveness data impractical. In addition, it seems impractical to mandate that new devices with only small iterations upon previously-approved medical devices (ie, 510(k) approved devices) show robust effectiveness and safety data prior to approval. However, it is difficult to support the notion that merely being able to argue that a new device has ‘substantial equivalence’ to a predicate is an acceptable surrogate to actually having demonstrated it through clinical studies.

A potential solution to resolving the problems with the 510(k) and HDE processes does not necessarily lie in a complete overhaul of the system but, instead, lies in the realm of post-marketing monitoring and reporting. Mandatory post-marketing reporting of outcome, safety and complication data on new 510(k) or HDE devices by clinicians using newly-approved devices would provide an additional screening process by which 510(k) devices actually demonstrate equivalence and by which HDE devices actually demonstrate effectiveness. Essentially, this solution would make 522PMS mandatory for all newly-approved Class II or III devices, with most devices requiring active surveillance studies for recording and reporting of all adverse outcomes. As an example, it could be mandated that the first 1000 devices used (or implanted) after FDA approval are monitored closely for early and long-term outcomes. This would allow physicians to treat patients with new technology that they deem to be of benefit and allow manufacturers to continue to profit from their research and development by selling devices, while simultaneously providing a validation process for new technologies that can weed out those that are causing harm. This would not only allow patients to be treated with cutting edge technology but would continue to support technological innovation. If stringent post-marketing monitoring was performed for the Depuy ASR, it is certainly possible that an unacceptably high revision rate would have been detected much earlier and the device could have been removed from the market. Additionally, with mandated ongoing data accrual, it is not unreasonable to expect that the overall field would actually benefit as subsequent iterative advances would be based on valuable newly collected data rather than on anecdotal and marketing projections.

Limitations of mandated post-marketing monitoring for HDE and 510(k) devices largely appear to be related to the additional costs of data collection and data review. Unless strictly regulated, data provided by physicians or industry to the FDA would likely also contain an inherent bias. Strict guidelines for accurate, honest and clear reporting would be an essential element of any post-marketing amendment to the approval process. An adjudication procedure in which unbiased external experts review and evaluate clinical and outcome data in the post-marketing period may be necessary to ensure the quality of the post-marketing monitoring process.

The authors of this commentary are sensitive to the numerous burdens facing healthcare providers and medical device manufacturers. The Affordable Care Act produced legislative changes to healthcare greater than many US-based doctors have experienced in their professional lifetime. As part of the funding for the Affordable Care Act, device manufacturers have had a 2.3% tax imposed on the sale of their products.[37] Physicians have increased demands on their time with diminishing reimbursements. Mandating post-marketing monitoring has the potential to be perceived as an unfunded mandate. We propose it in the absence of an alternative to potential changes of a more draconian nature as could occur by a sensitive or reactive FDA. Neurointerventionists, like other medical specialists with practices closely tied to the availability, safety and effectiveness of cutting edge medical devices, should be involved in designing and refining such processes to ensure that the proposed post-marketing monitoring remains efficient and effective in capturing credible information.


Recent challenges with medical devices suggest a need to reform the FDA medical device approval process. Disbandment of the 510(k) process, as is being suggested by the IOM, with mandatory completion of safety and effectiveness trials before device approval for all new devices is impractical and may harm technological innovation and, indirectly, patients. Instead, measured consideration of mandatory post-marketing surveillance for all newly-approved HDE or 510(k) devices, such that safety and effectiveness data may be demonstrated and suspect devices be identified and removed from the market expeditiously, may provide a better solution to this problem. Although this approach would certainly add cost, mandatory post-marketing surveillance will continue to promote technological innovation and device profitability while ensuring patient safety, and provide a more reasonable alternative to mandatory expansive comparator-controlled pre-marketing requirements.