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Case study: Development of an in vitro diagnostic (IVD) medical device

Case study: Development of an in vitro diagnostic (IVD) medical device : 작성자, 카테고리, 작성일, 조회수, 원문,출처, 정보 제공
작성자	관리자	카테고리	전문가 인사이트
작성일	2016-05-25	조회수	2,679
원문
출처

글 Agustin de la Calle (아구스틴 델 라 카예): 해외제약전문가
상임 컨설턴트

컨설팅 분야

북미 및 유럽지역 의약품 해외수출 전략 및 시장개척
기술사업화 및 제품 공동개발과 제휴관리

주요 약력

2006-2015 글라이코넥스, 스타라젠, 비스타젠테라퓨틱스, 싸이클론 등 사업개발 컨설턴트
2005-2006 이네이트파마 사업개발 담당이사
2002-2005 마이크로메트 사업개발 담당이사
2000-2002 이오스 바이오테크놀로지 과학분야 전문가(단백질 연구)
더 멘델 그룹 팀리더
1997-1998 MIT공대 박사 후 연구과정

KHIDI

In this article the development options of a healthcare product are discussed on the example of an IVD device. While some aspects are specific to diagnostic medical devices, most can be also applied to the development of other medical devices and even therapeutic products. Many of the differences are based on the risk profiles and development timelines that determine windows of exclusivity and caution in the risk management of potential exposures of patients. Nevertheless, the principle of risk to benefit ratio fully applies protecting the human being.

This example deals with a cancer diagnostic able to detect even precancerous developments. One reason this is an important product is because it offers an effective early detection of cancer that would allow for much more successful treatments, resulting in many more survivors and much improved quality of life for the patients. If we even can detect it early in a pre-cancerous state, before it becomes a malignant neoplasm, we don’t really treat a full blown cancer, but avoid getting cancer all together. Such a product conveys probably more benefit to humanity than today’s best therapeutics in oncology.

Under the US Food and Drug Administration (FDA) an IVD is a medical device because (1): [1]

In vitro diagnostics (IVDs) meet the definition of a device under the Act. Section 201(h) of the Act defines a device as (2):

“an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is—

(a) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them,
(b) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
(c) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.”

Under the European Medicines Agency (EMA) a medical device is defined as (3): [1a]

1. (a) “medical device” means any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of:
- diagnosis, prevention, monitoring, treatment or alleviation of disease,
- diagnosis, monitoring, treatment, alleviation or compensation for an injury or handicap,
- investigation, replacement or modification of the anatomy or of a physiological process,
- control of conception,

and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means;

2. (b) “in vitro diagnostic medical device” means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information:
- concerning a physiological or pathological state, or
- concerning a congenital abnormality, or
- to determine the safety and compatibility with potential recipients, or
- to monitor therapeutic measures.

Specimen receptacles are considered to be in vitro diagnostic medical devices. ‘Specimen receptacles’ are those devices, whether vacuum-type or not, specifically intended by their manu¬facturers for the primary containment and preservation of specimens derived from the human body for the purpose of in vitro diagnostic examination.

Case Study

A Korean manufacturer of IVDs specific for cancers has secured the approval by the Korean FDA (MFDS) and was granted the class II specification. This marketing authorization allows this product to be distributed and sold in Korea. Additionally, an expansion into a class III medical device has several advantages. However, for this next step the MFDS asks to see more supporting data and if possible it would be better if a peer reviewed publication could substantiate the reliability of this product and even better if it is also backed by an international expert recognition to warrant a class III category. The advantage of the class III category is that it would allow marketing the product for the detection of the indication for which it was designed and developed for. Then this IVD could be advertised as diagnostic for colorectal cancer (CRC) and possibly one day also include small intestine and duodenal cancers and perhaps even gastric cancers for which there are no reliable diagnostics yet that could completely cover this spectrum.

A good product needs to have:

1. A compelling MOA with convincing, reliable results.
2. A market need or defendable position in the market where it will be generating revenues

Factors that make this company’s product a good IVD:

The MOA is simple yet most sensitive and specific for the molecular marker of such cancers. This has several advantages setting it apart from the competition.

1. It is extremely accurate and could compete well with, or, given the right data, perhaps even outperform the gold standard colonoscopy. But from a marketing point of view given the ease for the customer with which the test can be performed it would attract many more new customers to be screened for CRC who would otherwise not be tested. Approximately 30% of people over the age of 50 are reluctant to be tested if it means to undergo the procedure of a colonoscopy. In other words, this product will effectively increase the number of tests for CRC and in many cases so will also the number of colonoscopies steadily increase. For each positive result of this IVD a colonoscopy would be convincingly prescribed and more readily accepted than in the absence of a positive proof of a possible malignancy. For the prescribing physician the patient numbers would increase that would undergo a test for CRC resulting in more patients who would undergo a deserved colonoscopy, while reducing the numbers of unnecessary exposures to colonoscopy, which also bears a health risk for the patient.

2. This test would be a lot cheaper to perform than colonoscopies and still be providing similar certainty to catch the cancer even at an early precancerous stage. Given the typical slow advancement of CRC this test could be performed for instance in consecutive years if it yields negative results and improve the statistical result in terms of sensitivity.

3. This test would also be cheaper to manufacture and execute than other more complex IVD products with similar sensitivity and specificity due to its one marker detection process, which means it will eventually dominate the marked, which is typically the case for products with the lowest COGS (cost of goods sold).

4. This product has the potential to even outperform the more complex CRC IVD products because of the higher sensitivity and specificity.

Important definitions:

The sensitivity is the probability that a diagnostic test will yield a positive result when the disease or the target analyte is present (1). [1]
The specificity is defined as the probability that a diagnostic test will yield a negative result when the disease or target analyte is absent (1). [1]

The development plan

In the case of the Korean regulatory authorities, the MFDS, requires a publication in a peer-reviewed journal to support independently the accuracy of the result in order to protect the patients. While this IVD product would not produce a result that would lead to a treatment decision for a patient, the opposite is the issue: In case this diagnostic delivers a false negative result, the patient would forgo any further evaluation and could possibly walk away with undetected cancer. That is why the authorities are focused on reviewing evidence for safety and reliable efficacy.

Generally the approval of medical devices can be done taking the equivalence route as a me-too product or the clinical evaluation route as an innovative product. Of course an innovative product cannot be approved via the equivalence process.

What is now most appropriate, bench testing or performing clinical studies? It boils down to a risk-based approach. (4) In Europe the MEDDEV 2.7/4 describes the requirements of a clinical investigation.

The Conformity Assessment process for class III, active and implantable medical devices requires that a clinical investigation is undertaken unless it is duly justified to rely on existing data (5) (6). However, depending on the actual risk profile and clinical claims, it is possible that even class I, IIa, and IIb need to perform clinical investigations.

For situations like these, where a body of evidence exists that was produced in a foreign country, Korea in this case, it is likely that additional clinical investigations are required to corroborate the existing clinical evidence with regards to the specific aspects of clinical performance, safety, benefit/risk-ratio to determine the relative effectiveness vs. a suitable comparator according to the state of the art. The main key for regulatory success is to have a robust risk management process in place and to show a flawless risk mitigation for the patient’s protection (7). The three areas are:

Risk identification methods
Risk mitigation methods and
Residual risk acceptability

These will be specifically inspected.

A study performed in the way that would satisfy regulatory authorities, for example in Europe, should be also generating a peer-reviewed publication, which would strengthen the support of the Korean re-classification to the next level, to reach class III medical device status in Korea. With the choice of Germany the company has chosen a strong and yet reliable regulatory challenge that can deliver also the credibility to not only open most other European doors, but also be widely recognized in the rest of the world. The only European country that might challenge the German results could be the UK with their own yet similar set of regulatory requirements.

The German regulatory path results in the CE mark, which is accepted in the rest of the European countries and also in many other countries, such as the countries of the Middle East and Turkey. Given the Korean approval as the country of origin this can open many doors in new countries. Not all European countries even call for the same information. This can vary in the requirements for premarket studies, postmarket studies and even triggering different fees. But so is also the resulting level of appreciation and international acceptance of the resulting approval for the product depending on which country was chosen for European market approval.

The documents evaluated by the EU Notified Bodies are:

Clinical Investigational Plan (CIP)
Letter of No Objection – Approval of Competent Authority
Ethics Committee opinion
Signed and dated final report

In order to receive the CE mark for the IVD product it is very helpful to have already the company certified under ISO 9001 and better even the ISO 13485, which certifies the company’s compliance with the CE norm.

However, most important for advanced or late stage/pivotal clinical trials is to choose wisely which product our diagnostic product will be compared to. This is also applies for therapeutic products that especially in the EMA are running against the standard of care or other most appropriate competitors and if the wrong comparator is chosen, it will determine at what price this product will be reimbursed. It has to be pointed out, that the approval of an IVD/medical device is probably not the most important or difficult step in Europe, but it is more important to secure the favorable market position by receiving the reimbursement rate that is fair based on the results of the late-stage clinical comparison. Many products were run against inexpensive generic products, to show the applicability to therapeutics, and resulted in getting only reimbursed at the level of such generic prices. This can certainly ruin the business model of the product.

How does the medical device perform in the long term? (8) As part of the risk/benefit ratio profile the post-market clinical follow-up studies (PMCF) should be appropriately considered by the manufacturer as part of the post-market surveillance while looking at residual risks as mentioned above as part of the risk management aspects. While the risk for patients won’t change over time it could be beneficial to design an adequate post-market data collection plan to be able to re-evaluate the strength of the IVD product and to be able to improve the body of evidence that could justify further regulatory approvals possibly in other geographies.

The Clinical Evaluation Report (CER) under European regulations should confirm in its summary that:

The device is safe, it is performing well as intended and it has a benefit/risk ratio that is positive.

This stand-alone document must comprise:

Product description
Background regarding device technology
Intended use, indications, contraindications
Claims regarding performance and safety
Relevant bench- and preclinical data
Nature and extent of clinical data
Suitability of the referenced information
Acceptability of the risk/benefit ratio
PMCF plan
Signed and dated by the evaluator who must be experienced in the field the medical device is going to be used. The evaluator’s clinical expertise is relevant in the field.
Justification for the choice of the evaluator

Financing the development

Figure 1: Starting from a strong position of regulatory accreditation the next steps in global commercialization are clearer but could benefit from partnering or alternatively dedicated financing especially if we consider different global territories. This support could of course also cover the expenses for clinical validations

The path in Figure 1 delineates a possible way for a successful global market development. While this process is not as cost intensive as the average therapeutic development it still includes the typical global approach that could benefit from strategic and financial partnerships, i.e. it is important to design a strategy of building coherent alliances and directed financing where appropriate. A frequent point of friction is the data generation, ownership and quality to which it can be applicable to enable commercialization of other territories or even expansion of the overall label. If these aspects are considered from the beginning of forming strategic commercial partnerships many future issues can be resolved in productive ways.

Licensing out

In order to conserve resources and yet increase the commercial success, it is useful to look at which geographies can be licensed out to corporate development partners. The choice of teaming up with local companies adds a de-risking step by including the support of an established partner who could greatly speed up the regulatory process, structure the distribution, organize the sales force and do this according to the regionally customary ways. Here again a contributing factor for successful out-licensing of commercial rights or perhaps retaining an option for co-promotion is the ability to enjoy hopefully a level of patent protection and contribute with supporting data that would help in the regulatory processes of other countries, including relevant comparable studies.

Generally, the factors that influence the company’s position in an out-licensing effort are:

1. A strong convincing MOA
2. Strong supportive data, including a defendable IP position
3. Where a market opportunity exists, i.e. the right reimbursement level would be fundamental

These items form part of the main marketing documents, some of which are used to initiate the licensing discussions.

Furthermore, it is important to be able to contact the right people at the right companies. These networks are the promoters for successful business development. Much like it would be the case when contacting investors, it is useful to be located either at a strategically useful location and/or to use every chance to do business outreach in industry events and attend the meetings. Key is to get on their radar and stay there as a trusted company building a strong reputation.

Attracting investors

As we can see a lot can be done in the field of in vitro diagnostics with humble financial resources. However, this is not necessarily true for all markets. For example the FDA requirements are probably the most onerous in the world and yet they control the most lucrative market in the world. Many diagnostic companies therefore go and develop their products in Europe and other countries first, gather substantial data and then use this to penetrate the US market. Going first to the USA is under such conditions considered brute force that can be quite costly. However, this opinion is not necessarily meant as a complete discouragement, but rather a warning to carefully consider the globalization strategy with respect to the USA.

Funds can be raised from investors who are savvy in the area of medical devices. See Appendix on p.14 for a selection of investors in the medical device field.

For successful fundraising these factors are of importance:

1) MOA, science works well, the product has clear scientific merits
2) There is a clear market need
3) The management of the company is worth investing in. The management accumulates experience and infectious enthusiasm in the areas of

a) Science experts
b) Business experience
c) HR: human resources that work to build high performing teams – further explained below.

Excurse on management and corporate culture

This last point, management, is often a crucial one, because of the general opinion in investor’s circles that a good team can rescue a bad product while a bad team can ruin even a good opportunity. Furthermore, to illustrate what effects a good management team can have on the performance, satisfaction level, productivity and its long term success, the aspects of fostering a productive and healthy corporate culture is shown for its implications on team building. Of course this management expertise is also important for scientific and operational leadership.

The proven principles of building high performing teams can be seen in a recently published study done at Google around the world (9) (10) [3,4]. It is not important who is on the team and who are the stars that have been recruited to work for the company, but much more important is how the team interacts, which determines much more how they function as a team.

High performing teams can be found that share these 5 main characteristics:

1) Psychological safety: Failure is possible and not used against a person, but as a lesson for everybody to improve. Nobody is punished for having tried and failed. Errors are a great tool for improvement.
2) Dependability: You can rely on the fact that the work will get done.
3) Structure and clarity: People should know what their job is and this should be shared across the team.
4) Meaning: The job should be personally meaningful to the team members.
5) Impact: People in the team should know that their job really matters and creates change.

Furthermore, it is important to have regular one-on-one meetings with every member. Invite in the quiet people that normally don’t like to contribute much. Keep the team happy and improve continuity. This will ensure that the company stays productive, employees are loyal and valuable expertise does not move away. Last but not least, the partnerships and funding efforts will probably develop smoother. For example, in an important partnering process the due diligence (DD) of a big partner can take several days depending on the size and importance of the opportunity, during which the DD team interacts often with many departments of your company to get a good view of the opportunity and what it would be like to get “married” to your company. These are the talks at the coffee machine or water cooler or over lunch and dinner that will reflect the satisfaction, loyalty and support for the management team reflecting the healthy corporate culture. Nothing is a more effective show stopper than the impression that the company is not what they say they are or that they are trying to hide something.

In order to get funded by VCs the company needs to be actively looking for ways to establish the dialog with the investors and meet them to build personal relations. In this aspect the location of the company is obviously remarkably important. Why otherwise do Korean investors mostly fund Korean companies? A few respectable exceptions of this rule of course can be found everywhere.

The strength of a geographic region in terms of finding there a critical mass of life science startup companies is directly related to the proximity to smart money in form of savvy venture capitalists. This smart money of course funds the biotech companies, but also can advise in strategy and helpful contact networks within the industry. A close proximity to investors is basically essential for getting funded and exposed to good opportunities.

Attracting other opportunities

There are situations where a company wants to also be able to grow their product pipeline and forge different types of partnerships. For example a quid pro quo where not exactly money changes hands in return for product rights, but where other strategic advantages are traded that sometimes can have very substantial ramifications for the future of the business. One example for such a need is a difficult situation that is impeding the progress in a field littered with “IP minefields”, as we can now see in the case of the enabling technology in the gene editing field around the CRISPR-Cas9 patent disputes. The best solution for all involved parties is a cross-licensing agreement that specifies the rights of all involved parties. These agreements can also be designed in many different ways depending on what the real goals of the parties are. Nobody really wins if such a dispute escalates through the courts – except of course the lawyers.

As another example it could make sense to license out a product to be developed for the Latin American market to a company that has an established salesforce targeting the same customer base and as an exchange to receive a product of their portfolio for the sale in the home territory where one would have an established salesforce. The agreement specifies that one product goes out for one territory and the other product comes in for the home territory. None of these scenarios is actually as simple as they first seem, but in the end the goal is to enable two or more parties with what they need.

The conditions to drive such a transaction are very similar to the scenario of endeavoring to license-in a product or patent portfolio.

1. Solid patent position
2. Deep war chest: long financial runway
3. Matching expertise and capacity to capably develop a product to commercialization, including established distributor network and salesforce
4. Corporate match that would distinguish them as a preferred partner in terms of financial structure and culture

Summary

In our case we have a simple IVD medical device that can be achieving regulatory approval in a less stringent process than medical devices with potentially more risk profiles.
Generally diagnostic medical devices are approved in the USA via several paths.

For instruments and IVD kits:

510(k) as equivalency route,
Premarket Authorization (PMA)

For homebrew tests provided in a central laboratory as service

Laboratory Developed Tests (LDT),
Clinical Laboratory Improvement Amendments (CLIA),
Alternative Summary Reporting (ASR)

In Europe the market approval is decided on a country by country case since the EMA does not regulate medical devices. Yet there are EU regulations that honor the CE mark in the territory of the European Economic Community (EEC).

In Vitro Diagnostics Medical Device Directive (IVDD) 98/79/EC
CE
ISO
- 510(k) as equivalency route,
- Premarket Authorization (PMA)

All these regulatory directives are more or less onerous, but have the common goal to make sure the products pose no risks to patients and are as effective as they claim. The manufacturer is responsible for ensuring that their products comply with the regulations before affixing the CE mark and gaining free access within the European Economic Area (EEA). The same is valid for the products in other jurisdictions. Yet there is often a big difference between the regulatory requirements in USA vs. Europe. For this reason many US diagnostic companies go first to Europe and come back to see the FDA after their approval in Europe with data for the FDA.

For our case study of the IVD medical device that was going to be offered as LDT and no medical decision or intervention was going to be based directly upon its result, it will undergo a simple CE marking process with a clinical study, resulting in the Clinical Evaluation Report (CER) to demonstrate adequate sensitivity, specificity and reproducibility, which would follow the simpler CE registration according to the European Directive on In Vitro Diagnostic Medical Devices, Annex III self-declaring conformity for General IVDs (11) (12). Further registrations in other countries can then be approached including a plan for the FDA approval.

References

1. 21 U.S.C. § 321(h). Definitions.
2. ResearchDepartment of Health and Human Services food and Drug Administration Center for Devices and radiological Health Center for Biologics Evaluation andU.S. In Vitro Diagnostics (IVD) Device Studies - FAQ. “Guidance for Industry and FDA Staff. ”2010.
3. devicesEuropean parliament and of the council of in vitro diagnostic medicalthe. DIRECTIVE 98/79/EC. “Amendment M3 Commission Directive 2011/100/EU. ”2011.
4. ConsumersGeneral for Health andDirectorate. Guidelines on clinical investigation: a guide for manufacturers and Notified Bodies. CommissionEuropean. “Guidelines on medical devices. ”2010.
5. Section 1.2 of Annex 7 of directive 90/385/EEC.
6. Section I.2a of Annex X of directive 93/42/EEC.
7. MEDDEV 2.7.1 Rev. 3.
8. MEDDEV 2.12/2 Rev. 2.
9. “Google searches itself to build more productive teams. ”Mendoza and Liedtke, M.M. Associated Press, Nov. 18, 2015.
10. “The five keys to a successful Google team. ”Julia Rozovsky, Google People Operations. Rework With Google, November 17, 2015.
11. Quality Guidance | Q 3 | Issue no: 4.3 | Issue date: 09.10.13 | Page: 19 of 22. “UK Standards for Microbiology Investigations | Issued by the Standards Unit, Public Health England."
12. European Directive on In Vitro Diagnostic Medical Devices (98/79/EC).

Appendix – Investors in the Medical Device Field

Published on MDDI Medical Device and Diagnostic Industry News Products and Suppliers (http://www.mddionline.com)

Accuitive Medical Ventures	Is a $160 million fund that invests exclusively in early stage medical device technology opportunities nationwide. The group invests up to $10 million per company over the life of a deal.
Adams Capital Management's	Focus in the medical arena seems to be on software-based diagnostic equipment.
Advanced Technology Ventures	Focuses on early-stage companies. Portfolio includes a number of diagnostics manufacturers as well as makers of minimally invasive surgical instruments and intracoronary radiation systems.
Advent International	Invests in companies at all stages of development, from emerging growth enterprises to large profitable businesses. The group can provide up to $200 million in equity for a single transaction and will consider a variety of investment structures, including minority equity positions, leveraged recapitalizations, and management buyouts. Current portfolio includes companies in the cardiovascular, orthopedic, imaging, and diagnostics fields.
Alliance Technology Ventures	typically invest between $500,000 and $2 million in early-stage companies, particularly those in the Southeast. About a half-dozen device firms are currently supported, including some pursuing cardiovascular technologies, surgical devices, and organ repair.
Alpha Capital Partners	provides equity financing for promising growth businesses and buyouts or recapitalizations of established companies. Investment typically ranges from $500,000 to $4 million per enterprise, with concentration in the greater Midwest. The portfolio includes developers of automated immunoassay instruments, digital interconnect systems for medical imaging equipment, and surgical cable and instruments.
Alta Partners	prefers to act as the lead investor, taking a board seat, and assisting the company as it develops. Typically, between $2 million and $8 million is invested in a company throughout the life of the investment. Focus is on the West Coast.
Ampersand Ventures	focuses exclusively on the specialty material and chemical industry. Portfolio includes companies developing microfluidics systems for genetic analysis, automated cancer diagnosis, and reagents and electrophoresis systems for research applications.
Anthem Capital	is a $43 million VC partnership focusing on investments in Virginia, DC, Maryland, Delaware, Southeastern Pennsylvania, and Southern New Jersey. The group expects to help develop the financial marketing and overall strategic plans and to oversee their tactical execution by management. Products covered in the portfolio include a microprocessor-controlled CPR vest, products for cancer screening, a miniature optical sensor with applications in glucose and oxygen sensing, and products for diagnosing and treating chronic pain.
Asset Management Associates	lists a few diagnostics manufacturers on its portfolio of life sciences companies. Usually invests about $2 million to $3 million during the seed or early stages.
Atlas Venture's	portfolio seems to emphasize genomics and biopharm, but also includes manufacturers of cardiac-mapping systems, a cardiac assist device, disposables, diagnostic endoscopes, surgical instruments, medical lasers, and separation products. Initial investment is usually between $500,000 and $5 million, although seed investments of less than $500,000 can also be arranged.
Aurora Funds	They are invested primarily in North Carolina and the Southeastern US. Typical investments range from $250,000 to $1,500,000. The portfolio lists manufacturers of 3-D imaging systems and diagnostic instruments.
Bancorp Piper Jaffray Ventures	organizes venture funds and invests the capital into emerging-growth companies in the areas of medical devices, healthcare services, and technology. Healthcare funds have approximately $80 million under management. Areas of focus in the medical device arena include cardiovascular surgery, interventional neuroradiology, minimally invasive orthopedics, urology/women's health/oncology, and tissue engineering/biological.
Bessemer Venture Partners	invests between $1 million and $5 million in private companies at any stage. The small number of device firm investments includes MRI and diagnostics companies.
BioAsia Investments	is a California-based VC firm. Average investment ranges from $1 million to 3 million, although investments from $0.5 million and $5 million can be considered. Generally, a BioAsia representative will serve on the board of directors. Strength seems to be in drug discovery and diagnostics; investments include companies developing clinical diagnostic reagents and enzyme-based immunoassays, a portable device for measuring blood glucose and glycated protein, and blood processing and cryopreservation equipment.
BioMed Discoveries Inc.	focuses on projects that helping startups meet unmet clinical needs. Funded by Stowers Institute for Medical Research, the firm pursues projects across a range of diagnostic areas but focuses on therapeutics and diagnostics.
Brentwood Venture Capital	invests equity capital in start-up, early-stage, and emerging-growth companies, preferably in a market that will support revenues of greater than $50 million within five years. Current portfolio includes more than a dozen medical device companies and covers the cardiac, surgical, and imaging areas, among others.
Canaan Partners	can invest in any stage of development, from early through expansion stage, and will consider other growth opportunities such as private placement in public companies, management-led buyouts, and recapitalizations. Funds ranging from $0.5 million to $15 million are available for individual companies. Portfolio companies include makers of hemodialysis equipment, patient monitors, infusion pumps, and orthopedic products.
Capital Southwest	provides capital for early-stage financing, expansion financing, management buyouts, recapitalizations, and industry consolidations. Representative investments include a manufacturer of surgical masks and other disposable products, a manufacturer of medical x-ray imaging film and direct radiography systems, and a manufacturer of hematology and blood-chemistry analyzers.
Cardinal Health Partners	manages an initial capital pool of $62 million, and typically invests between $2 million and $5 million per company. The group focuses on early-stage companies developing medical devices, healthcare information systems, healthcare services, and life science technologies. Group principals have been the co-founding investors in over 100 start-up companies and have played interim management roles in more than ten.
Charter Life Sciences	invests in technology-based companies at the seed and early stages of development. The group frequently serves as lead investor, contributing resources and management support. Half of business is life sciences, including manufacturers of controlled-release delivery systems, diagnostics, electrophysiology devices, orthopedics, cancer therapeutics, computer-aided surgical systems, infusion pumps, and hearing aids.
Clarus Ventures	Founded by a team of accomplished investment professionals with extensive and complementary industry backgrounds, Clarus Ventures is a life sciences venture capital firm with a team that has a unique and long history of success in creating value. Deep relationships with thought leaders and decision makers allow this team to identify unique investment opportunities and shepherd them to maturity. Clarus augments its core expertise of investing in biopharmaceuticals, specialty pharma and medical technology with the deep and diverse experience of the team in research and development, commercialization, business development and operations management at a global level. Clarus has offices in Cambridge, MA, and South San Francisco, CA.
Collinson Howe & Lennox	Founded in 1990, Collinson Howe & Lennox invests principally in start-up and early-stage companies in the medical sector. Current portfolio companies are active in the areas of women's health, minimally invasive surgery, drug-delivery catheters, treatment of in-stent restenosis. Investments range in size from $100,000 to $5 million.
Cordova Ventures	prefers companies located in the Southeast with the potential to serve national markets. The portfolio includes a manufacturer of vascular access products.
Crosslink Capital	invests in emerging-growth companies with proof-of-concept. In the medical arena, the company has supported biotech, equipment, and software firms.
De Novo Ventures	was formed in 2000 by experienced investors and medical device entrepreneurs with the mission of helping budding medical device companies to find funding. With $650 million under management, the firm has made more than 40 investments in healthcare.
Domain Associates	provides $30 million to $40 million annually to US-based ventures concentrating in the life sciences. Current portfolio includes some well-known device firms, including developers of tumor-ablation devices, wearable defibrillators, minimally invasive surgical instruments, and surgical vision systems.
Edison Venture Fund	actively investing since 1986, partners with entrepreneurs, service providers and other financing sources to build successful companies. They provide private equity and value-added services to expansion stage ($5 - 20 million revenue) information technology businesses located in the Boston to Washington, DC corridor. Edison has realized many successful exits generating substantial proceeds for founders, management, employees and investors.
Emergent Medical Partners	is a life sciences investment firm that works with medical device and healthcare companies. The company has more than 50 years of experience in the field. The firm works with early-stage manufacturers from a diverse background encompassing and our expertise encompasses all areas of medicine.
Enterprise Partners	Located in Southern California, Enterprise Partners invests in privately held early-stage and emerging-growth companies, particularly in the area of medical technology and healthcare services. An extensive portfolio includes manufacturers of gynecological instruments, cytometers, medical-records management software, minimally invasive devices for orthopedic surgery, patient monitors, noninvasive blood-pressure monitors, and nerve stimulation devices.
ePlanet Capital	ePlanet Capital , which is based in Silicion Valley, is an international firm that invests in a variety of industries including healthcare and medtech, Internet and e-commerce, electronics, wireless technology, and green energy. Formed in 1999, the firm employs thirty professionals
Finistere Partners LLC	is a San Diego, CA-based venture fund, focusing on early stage investments in medical devices, and non-therapeutic biotech (particularly Agbio) ranging from $0.5m to $5.0m. The fund has existing investments in the cardiovascular space, and is also interested in orthopaedic and drug delivery systems. Finistere is actively seeking new investment opportunities.
Fluke Venture Partners	makes equity investments in developing and expanding companies based in the Pacific Northwest. Prefers to hold minority equity positions in its portfolio companies and to maintain a close yet hands-off relationship with management. The group typically invests between $500,000 and $2 million in a round of financing, although the minimum investment can be lower. Given the Northwest focus, it's perhaps not surprising to see software companies, coffee wholesalers, and microbrewers alongside manufacturers of wound-care products and medical lasers in the investment portfolio.
Forward Ventures	pursues a mix of early-stage portfolio investments focused in biotechnology and healthcare, with an emphasis on seed and start-up investments. Over the last decade and a half, the partners have founded 14 life-science and healthcare companies. Geographic preference is the West Coast, and initial investment size ranges from $500,000 to $1,500,000.
Galen Partners	is a private equity firm specializing in the healthcare domain. The firm has invested in more than 70 firms since it was founded and has had almost $1 billion in assets since it was founded.
Golden Pine Ventures	is a venture capital company focused on discovering and developing exceedingly rare early-stage technologies which can form the basis of promising biotechnology and biomedical companies. The management and directors of Golden Pine Ventures have a history of past successful ventures in the biotechnology and biomedical fields. In total, they have successfully launched over two dozen companies, raised over a billion dollars for portfolio companies, and have taken seven of these companies public.
Greylock	Greylock, a Boston-based VC firm founded in 1965, invests at all stages of corporate development—from supplying the initial capital to providing expansion capital to growing private companies. Portfolio includes manufacturers of dialysis equipment, disposables, filtration equipment, orthopedic devices, monitoring equipment, diagnostic, C02 analyzers, hospital information systems, neurological therapeutics, and others.
Hambrecht & Quist Capital Management	manages the H&Q Healthcare Investors fund, which invests in smaller, emerging biotechnology, pharmaceuticals, and medical devices and services companies. HQCM focuses on later-stage and mezzanine financings, with initial investments in the $2 million – $5 million range. The fund may invest up to 40% of assets in restricted securities of both public and private companies.
Hickory Venture Capital	provides long-term venture capital financing to small but rapidly growing private companies throughout the Southeast, Southwest, Mid-Atlantic, and Midwest. The firm typically invests $1 million to $2 million initially, and may fund up to $6 million over time. The group does not seek control, but instead backs strong management teams.
Highland Capital Partners	works with entrepreneurs and growing businesses in the information technology and healthcare industries. Portfolio companies include manufacturers of anesthesia monitors, DNA-based cancer screening, minimally invasive urological surgical instruments, stents, urology products, and healthcare information systems.
IVP-Institutional Venture Partners	invests primarily in seed or early-stage technology companies with as little as $50,000 and as much as $4 million. Extensive portfolio includes manufacturers of POC clinical chemistry analyzers, blood-glucose monitoring, revascularization devices, stents, therapeutic ultrasound devices, cytology equipment, infusion pumps, and more.
InCube Ventures	specializes in funding innovative medical projects that fulfill unmet clinical needs.nt outcomes.
InnoCal	focuses is on early- and expansion-stage companies with proprietary technology. Businesses in California receive preference, although the group will consider investment opportunities anywhere in the country. Technologies currently supported include orthopedic implants, infusion devices, and urology products.
Intersouth Partners	invests primarily in the Southeast. The firm prefers to be the lead investor in the first institutional round of financing. Focus is on seed and early-stage companies with reasonable initial capital requirements and sales potential exceeding $20 million in 3–6 years. Technologies represented include POC diagnostics, implantables, laparoscopic instruments, and drug-delivery systems.
InterWest Partners	invests an average of $5 million over the span of involvement with each portfolio company. The group supports companies in all investment stages, and investments may be staged over several rounds of financing. An extensive healthcare portfolio includes a number of well-known companies in areas ranging from ultrasound imaging to orthopedic surgery to DNA probes to vascular intervention.
JP Morgan Partners	is the venture branch of J.P. Morgan Chase Bank. Very deep pockets, fairly conservative investments. Portfolio companies in the healthcare area include manufacturers of cardiac catheters, diagnostic systems, orthopedics, liver-assist devices, urological surgery products, blood-glucose monitors, external defibrillators, IV components, and plastic components.
KBL Healthcare Ventures	is a physician-run VC firm. Focus is on start-up, early-stage, and emerging-growth companies. Current investments cover noninvasive cardiac diagnostics, women's health, cytology, and healthcare software.
Kleiner Perkins Caufield & Byers	seems to focus on Internet technologies, but the portfolio does list one or two device manufacturers in the fields of orthopedics and neurology.
Kline Hawkes & Co.	provides equity capital for later-stage venture deals, changes of control, and industry consolidations. Typically, investments range from $3 million to $6 million.
Latterell Venture Partners	was formed in 2001 with the sole mission of investing in early-stage healthcare companies. The firm has more than $300 million of committed capital.
Magic Venture Capital	provides seed and first-round funding for healthcare ventures, assisting the majority of its portfolio companies by playing key roles in early management. The group has a modern prototype facility capable of providing working models of most medical devices. The two companies currently supported develop products for treating atrial fib and internal spinal fixation devices.
Mayfield Fund	has $1 billion of capital under management and has invested in more than 300 information technology and healthcare companies since its founding in 1969. The current portfolio of about a dozen device firms includes companies involved in computer-assisted surgery, hearing aids, cardiovascular intervention, and anesthesia monitoring.
MedVenture Associates	specializes in the early-stage financing of companies in the fields of medical devices, medical information technology, and pharmaceutical and biotechnology products. Companies must be located in the Western region of the continental US. An extensive portfolio encompasses the cardiovascular, neurovacular, orthopedic, and women's health specialties as well as instruments and equipment. Some of the industry's most prominent movers and shakers are on the list.
Menlo Ventures	typically invests from $4 million to $10 million in a portfolio company, usually over several rounds of financing. The group serves on the boards of over 80% of portfolio companies. The device division focuses primarily on minimally invasive surgical technologies.
Meritech Capital Partners	which is based in Palo Alto, CA, funds mainly late-stage entities. It works with firms specializing in communications, software development, semiconductors, as well as medical devices. Its healthcare clients include Acclarent, Glaukos, Intralase, and Vantage Oncology.
Mitsui USA Private Equity Group	seeks early-stage investment opportunities in the information technology and healthcare industries. The firm prefers opportunities where pre-money valuations are less than $20 million. The group's Orien Fund supports manufacturers of an implantable nerve stimulator, an infusion pump, and a blood-handling device.
Morgan Stanley Dean Witter Venture Partners	invests in later-stage high-growth companies in the IT and healthcare industries. Although the partners are active investors who seek significant ownership positions, they do not require controlling interest in companies nor desire an operating role. The group's healthcare portfolio covers cardiology diagnostics, automated sample preparation, and computerized diagnostics.
Morgenthaler Venture Partners	invests in medical devices, healthcare services, healthcare information services, and biopharmaceuticals. Focus is on early-stage investments as well as management-led buyouts, build-ups, and recapitalizations. Typical investment ranges from $2 million to 8 million in VC opportunities and $5 million to 30 million in management buyouts. A small but impressive device company portfolio shows particular strength in cardiovascular surgery and neurology.
MPM Capital	is the manager for the $230 million BioVentures family of venture capital funds that are invested in parallel in selected private healthcare companies in the US and Europe. BB Bioventures LP investments range from $5 million to $20 million. The current portfolio includes manufacturers of surgical sealants, diabetes management systems, hearing aids, and transdermal drug-delivery systems.
New Enterprise Associates	provides an initial financial commitment typically ranging from $500,000 to $6 million. An extensive medical portfolio covers ultrasound imaging, endovascular surgery, orthopedics, urology, patient monitoring, cardiology, and just about everything else.
Newbury Ventures	is a private VC partnership providing seed and early-stage financing for communication and healthcare technology companies. Partners will take a position on the portfolio company's board of directors and can provide assistance with management team building, product development, operations and manufacturing, business development, and sales and marketing. The portfolio, though favoring communications companies, lists companies developing cardiac output monitors and waterjet-based surgical instruments.
Norwest Venture Capital	commonly serves as one of the lead investors for its portfolio companies. Total investment in a company can range from $1.5 million to $20 million. The portfolio covers automated sample preparation, blood-gas sensing, minimally invasive surgery, and orthopedics.
Olympic Venture Partners	focuses primarily on companies in the Pacific Northwest. Initial investment is usually about $1 million to $3 million, almost always made with at least one other VC firm. Given their NW focus, it's not surprising to see so many Internet companies on the portfolio list—but there are also manufacturers of cardiology catheters and vascular sealing devices.
Onset Ventures	focuses on seed and early-stage investing. Initial first- or second-round investments may range from $1 million to $4 million. While the amount varies based on the needs of each company, the average investment is $5 million over a company's development. The portfolio includes companies involved in revascularization, molecular diagnostics, spinal implants, and reproductive health.
A. M. Pappas & Associates	manages three investment funds, including TechAMP, an international life science VC fund based in Research Triangle Park, NC. Investments will focus on mid-stage companies developing therapeutics, diagnostics, discovery platforms, biotech toolkits, and drug-delivery technologies. TechAMP's investment scope also includes clinical instrumentation, interventional devices, and regulatory enhancing technologies.
Partech	assists companies at all stages of growth—from the early-stage start-up phase to pre-IPO and beyond. Portfolio companies include device firms active in the cardiology and urology markets as well as manufacturers of surgical sealants and drug-delivery polymers.
Primus Capital Funds	specializes in healthcare services, healthcare information systems, and medical devices. The portfolio includes companies involved in diagnostics, sterilization systems, blood processing, and motor-function restoration. Preferred investment size is $5 million to $10 million
Prism Venture Partners	Within the healthcare field, Prism Venture Partners focuses on medical devices (particularly disposables), healthcare services, healthcare information systems, software, and services. A suitable portfolio company must have the potential to achieve annual revenues of $50 million to $100 million within 5 years. Capital requirements should support an investment of $4 million or more prior to a liquidity event.
River Cities Capital Funds	provide growth equity and business building experience to entrepreneurial private companies, primarily in the Midwest and Southeast. Broad portfolio includes a manufacturer of specialty disposables and a manufacturer of intraoperative surgical navigation systems.
RiverVest Venture Partners	focuses on early-stage life sciences investments. The St. Louis–based firm seeks to build relationships with entrepreneurs and scientists striving to develop breakthrough solutions to unmet clinical needs.
SantéVentures	invests in early-stage life-science and healthcare ventures. The firm's venture partner is Billy Cohn, MD, a heart surgeon who developed a novel artificial heart with the help of Bud Frazier at the Texas Heart Institute in Houston.
Seaflower Associates	makes seed and first-round investments in companies developing biotechnology, medical devices, healthcare information technology, and healthcare services. Geographical preference is for New England and the Great Lakes region. Typical investments range from $250,000 to $1,250,000. Portfolio companies range in focus from computer-enhanced laparoscopy to biomaterials to endoscopic imaging.
Sequoia Capital	prefers early-stage investments in technology-driven companies on the West Coast. Funding ranges from a $50,000 seed investment to $10 million transactions. The group's partnership role can range from intensive involvement in an early-stage company (which can set up shop in the group's offices during initial formation) to a far more detached role once the company matures. A lengthy device company portfolio includes manufacturers of ultrasound equipment, minimally invasive cardiac surgery systems, patient-side diagnostic devices, orthopedic implants, glucose monitors, and BPH treatment systems.
Sierra Ventures	typically likes to serve on the board of directors of portfolio companies. The group manages six venture capital partnerships, which together have more than $400 million of committed capital. Portfolio companies are involved in vascular intervention, computer-guided surgery, diagnostics, and others.
Sorrento Associates	provides VC funding for emerging-growth companies in San Diego and Southern California with prospects to grow to $25 million to $50 million in revenues within three to five years. The group does not seek to run portfolio businesses or to be involved in any day-to-day management activities. Typically provides between $1 million and $7 million. Current portfolio lists manufacturers of central venous catheters, a solid-state gamma camera, respiratory equipment, infusion pumps, defibrillators, and drug-delivery platforms.
Spray Venture Partners	is a $50 million seed and early-stage healthcare venture firm, with a particular focus in medical devices. Portfolio includes companies developing ultrasound catheters, minimally invasive surgical equipment, microfluidics, AEDs, drug delivery, and other technologies.
Sprout Group	typically invests $5 million to $50 million with a minority interest. More than a score of device companies are on the portfolio list. Diagnostic products seem to be a specialty, although the roster also covers vascular access, minimally invasive surgery, urology, cardiology, and orthopedics.
Split Rock Partners	formerly part of St. Paul Venture Capital, works with emerging companies in the healthcare (medical devices and specialty pharmaceuticals) and software industries, primarily in the Upper Midwest and on the West Coast.
SterlingStart	is a company that provides flexible funding solutions, comprehensive technical support and operational guidance to medical device start-ups and entrepreneurs across the country.
Telegraph Hill Partners	is a life-science and med-tech focused private equity fund that invests in growth-stage companies across the U.S. The firm will invest between $5M to $25M in companies that have: commercial revenue through the sale of products or services, current or near-term profitability, a loyal and expanding customer base, superior economic business models, and a strong management team. Portfolio investments include chemical and reagent companies, orthopedic and cardiovascular device companies, and diagnostic companies.
TGap Venture Capital Fund	is a $20 million venture capital firm formed on August 14, 2002 with its headquarters in Kalamazoo, Michigan. The Fund invests in early stage medical device, medical services, and IT technology companies. TGap’s typical initial investment in a company is between $250,000 and $1,000,000, and is made as part of a larger financing in conjunction with other investors.
Third Rock Ventures	was founded in 2007. The firm focuses on life sciences companies and has raised more than $800 million. Its mission is to launch transforming companies that are developing disruptive technologies.
Three Arch Partners	was formed in 1993 to provide young companies with access to relevant clinical and business resources, as well as capital. Three Arch Partners has helped create, build, and fund more than 100 healthcare companies. The investment focus is on opportunities in medical devices and healthcare services, as well as biotechnology and information technology. The partnership manages over $1 billion in capital.
TL Ventures	mostly covers biopharmaceuticals, but also lists some manufacturers of diagnostics and monitoring equipment in its portfolio. The group initially invests between $3 million and $10 million in companies in the early to middle stages of development.
TVM Capital	is an international VC firm with offices in Munich and Boston. Generally, investments in a given company will range from $3 million to $4 million; however, the group can invest as little as $100,000 in seed financing and as much as $5 million in exceptional cases. A lengthy portfolio includes manufacturers in the fields of urology, orthopedics, and imaging.
U.S. Venture Partners	invests principally in companies headquartered in the Western US. Healthcare investments are primarily focused on companies developing innovative proprietary medical devices to enable less invasive therapeutic procedures. An extensive roster covers diagnostic imaging, fluoroscopy, cardiovascular surgery, implantables, drug delivery, and more.
Vanguard Venture Partners	specializes in seed and early-stage high-tech investments. The firm looks for market opportunities that can return at least 10 times the investment through IPO or acquisition within five to seven years. Expertise in the life sciences includes medical devices, diagnostics, biotech instruments, and medical infotech.
Venrock Associates	is the venture capital arm of the Rockefeller family. In the medical device sector, emphasis seems to be on minimally invasive technologies, particularly in the area of cardiovascular medicine and orthopedics.
Venture Investors Management LLC	Over 80% of the dollars invested by Venture Investors Management LLC have gone to seed and early-stage companies in markets such as biotechnology, instrumentation, and medical services and devices. Usually functioning as the lead investor, the group also enters co-investor relationships. Portfolio companies include manufacturers of cardiac analyzers and biodegradable polymers.
Versant Ventures	currently manages over $1 billion in committed capital having recently raised its third fund and currently managing over 65 companies in its portfolio. Versant's medical device portfolio includes Acclarent, Calypso Medical Technologies, Cameron Health, LipoSonix, NDO Surgical, NeoVista, Second Sight Medical Products and Spiration.
Vertical Group, The	is a venture capital group specializing in medical technology and biotechnology. It makes early- and late-stage investments. The firm is the successor to the venture capital division of F. Eberstadt & Co. and has been independent since 1988.
Welsh, Carson, Anderson & Stowe	focuses on only two industries: healthcare and information services. Healthcare services seem to represent the group's core medical focus, although several investments have also been made in healthcare products. Investments usually focus on medium-sized companies, with revenues typically between $30 million and $200 million.
Western Technology Investment	looks for companies with the potential to generate $25 million in annual sales within 5 years. Investments range from $500,000 to $10 million. Portfolio includes companies active in the cardiovascular, drug delivery, glucose monitoring, and urology markets.
WFD Ventures LLC	provides equity financing and industry expertise to medical device and healthcare technology companies. The principals of WFD have developed and commercialized dozens of technologies and seek partnerships with entrepreneurs, doctors and scientists to improve medical outcomes and maximize the financial potential of their innovations. WFD typically invests between $2 million and $15 million in therapeutic, diagnostic or drug delivery technologies with strong intellectual property rights and exceptional market potentials. WFD targets ventures at any stage, as we have direct experience with prototype development, intellectual property and licensing strategies, clinical trials (US and OUS), regulatory filings (510(k), PMA and drug/device combinations), system and physician economics, reimbursement, distribution strategies and sales management. WFD helps its portfolio companies develop liquidity strategies and orchestrate liquidity events. Successful interaction with potential partners and acquirers requires focus long before the event. To inform exit planning, we have built collaborative, working relationships with all of the major medical device consolidators.
J.H. Whitney & Co.	has been around for over 50 years. Companies supported include manufacturers of minimally invasive devices and separation technology.
Windward Ventures	provides early-stage venture capital for companies in Southern California. The firm generally servesg as lead investor. Typical funding ranges from $1 million and $2 million over the life of an investment. Initial investments may be as little as $250,000. Current portfolio includes companies working in interventional cardiology and infusion therapy.

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Case study: Development of an in vitro diagnostic (IVD) medical device

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