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This Week in Devices [12/14/12]: Obama Says 'No' to Device Tax Repeal While Minnesota Senators Call For a Delay

Obama says 'No' to Device Tax Repeal
In an interview with CBS Minnesota, President Obama has said he will not delay or repeal the device tax. The President states, “The health care bill is going to provide those health care companies, 30 million new customers. It’s going to be great for business and they’re doing really well right now and they’re going to get 30 million more customers as a consequence, so this additional tax essentially comes back to them as new customers.” [CBS Minnesota]

Al Franken and Amy Klobuchar
They may have voted for Obamacare but Minnesota democratic senators Al Franken and Amy Klobuchar have joined others in calling for a delay in the medical device tax. Both believe the tax will be a huge blow to the job market in medtech hub Minnesota and want to provide companies with more guidance on how to comply with it. [Washington Examiner
 
Making Medical Devices Safer at Home
FDA has released a consumer update outlining guidelines for consumer use of medical devices and the agency's efforts to help ensure patients use their medical devices safetly and correctly at home. [FDA]
 
Smart Clothing Technology for Monitoring Rehabilitation
Italian researchers have created clothing containing sensors printed into the fabric that can be used to monitor physiotherapy exercises at home. Their research shows that the wearable device can potentially offer low-cost and unobtrusive means of monitoring trunk motor rehabilitation in patients.
 

New User Fee Law Requires More Manufacturers to Register for FDA’s Establishment Database

The number of FDA-registered medical contract manufacturers, manufacturers, and specification developers and percentages of the U.S. total for each state. Percentages are rounded to the nearest whole number. Source: CDRH Establishment Registration Database.

++++++++++++++++++

On August 2, 2012, FDA sent an open letter to the medical device industry advising companies of significant changes to the establishment registration process. The FDA Safety and Innovation Act (FDASIA) is driving these changes. FDASIA, which was signed into law in July, grants FDA the authority to collect user fees from the industry to fund reviews of drugs, devices, and biologics. The changes to establishment registration went into effect October 1, the beginning of the U.S. government’s 2013 fiscal year. 

As a result of the changes to the establishment registration process, Title 21 CFR, Part 807 has been revised. All registered medical device establishments must pay an annual registration fee—not just device manufacturers. The expanded scope, associated with the change in establishment registration, means establishments such as contract manufacturers and sterilization facilities must file and pay the annual establishment registration fee.

Medical device manufacturers, contract sterilizers, and contract manufacturers must also register their products electronically on the FDA Unified Registration and Listing System (FURLS). Both foreign and domestic device manufacturers should establish an account on the FURLS. The system will be employed to update information regarding device establishment registrations and information pertaining to device listings. Existing product listings from device manufacturers will be migrated into the FURLS, according to FDA.

MDUFA III mandates that an annual registration user fee be paid for all types of establishments. The fee for FY2013 is $2,575. This should result in the collection of approximately $57 million to support FDA operational expenses. Some of this additional funding will be used to add FDA headcount to improve the agency’s efficiency. Mehta hopes the resources will improve the current device application review process and hopefully, a reduction in review times.

—Heather Thompson and Bob Mehta, Principle Consultant of GMP ISO Expert Services

 

Medical Device Manufacturing Statistics 

Country

 

Value
(US$ millions)

 

Average Growth (%)

 

Global Share (%)

United States

18613.3

9.4

23.6

Germany

9761.1

 

7.4

 

12.4

The Netherlands

5080.0

6.4

6.5

Mexico

4687.9

 

10.3

 

6.0

 

Belgium

4623.6

16

5.9

China

4165.0

 

18.5

 

5.3

Ireland

3431.2

13

4.4

France

 

3113.0

 

5.6

 

4.0

Japan

2595.5

9.4

3.3

Switzerland

2414.2

 

9.4

3.1

 

The top exporting countries of instruments and appliances for medical and veterinary sciences in 2010. The total world value of exports is approximately $79 billion. Source: UN Comtrade, International Merchandise Trade Statistics.

 

Country

 

Value
(US$ millions)


Average Growth (%)

 

Global Share (%)

United States

9426.0

5.7

24.9

Germany

7830.7

 

6.1

 

20.7

The Netherlands

3758.2

6.7

9.9

Japan

3404.2

 

2.7

 

9.0

France

1980.8

7.0

5.2

China

1946.7

21.4

 

5.1

UK

1460.1

7.7

3.9

Israel

920.3

 

5.8

 

2.4

Rep. of Korea

757.6

12.9

2.0

Italy

581.3

 

0.8

1.5

The top exporting countries of instruments and appliances for electromedical and radiological equipment in 2010. The total world value of exports is approximately $38 billion. Source: UN Comtrade, International Merchandise Trade Statistics.

Medical device export sales for five categories in the medical device field. Source: U.S. Census Bureau, U.S. International Trade Statistics.
 
Employment in the medical equipment supplies and manufacturing industry rose 1.7% from 2010 to 2011. Source: U.S. Department of Labor, Bureau of Labor Statistics.
 

Biomedical Engineers

Medical Appliance Technicians

Rank


Metropolitan area


Employment

Metropolitan area


Employment

1

 

Boston-Cambridge-Quincy, MA, NECTA Division

 

1,010

 

Salt Lake City, UT

550

 

2

Minneapolis-St. Paul-Bloomington, MN-WI

810

Chicago-Joliet-Naperville, IL, Metropolitan Division

490

3

 

Philadelphia, PA, Metropolitan Division

630

 

Philadelphia, PA, Metropolitan Division

 

470

4

San Francisco-San Mateo-Redwood City, CA, Metropolitan Division

600

Boston-Cambridge-Quincy, MA, NECTA Division

450

San Jose-Sunnyvale-Santa Clara, CA 

590 

Minneapolis-St. Paul-Bloomington, MN-WI 

440 

6

Santa Ana-Anaheim-Irvine, CA, Metropolitan Division

550

Pittsburgh, PA

350

7

 

Los Angeles-Long Beach-Glendale, CA, Metropolitan Division

500

Los Angeles-Long Beach-Glendale, CA, Metropolitan Division

 

270

8

San Diego-Carlsbad-San Marcos, CA

480

Dallas-Plano-Irving, TX, Metropolitan Division

270

9

 

Houston-Sugar Land-Baytown, TX

 

420

 

Phoenix-Mesa-Glendale, AZ

250

10

Salt Lake City, UT

420

New York-White Plains-Wayne, NY-NJ,
Metropolitan Division

200

The metropolitan areas with the highest employment levels for two industry occupations as of May 2011. 

Source: U.S. Department of Labor, Bureau of Labor Statistics.

More from 2012 Medtech Snapshot:

Top 40 Medical Device Companies

Medtech Industry Still Feeling Fallout from Recession

FDA Continues Push Toward Efficiency and Transparency

Medtech Industry Still Feeling Fallout from Recession

It should come as no surprise that the medtech industry has acknowledged and is acting on the effects of the recession. As the industry moves through this transitional period, companies are pushing to improve overall productivity.

With 30–35% of profits tied to sales effectiveness, companies need a more effective sales operation model, says Sharad Rastogi, principal of PricewaterhouseCooper’s pharmaceutical and life sciences practice.

Medtech firms are closely examining how they manage their supply chains and inventory. One big issue is reducing waste—especially waste related to inventory that sits on shelves for months in a warehouse. In these tough economic times, operational excellence has become critically important for medical device manfuacturers.

Before the recession, the growth rates of medtech companies were in the mid to upper teens. During the recession, growth rates dropped to the single digits.

“Industry is still growing but at a much slower rate,” Rastogi told MD+DI at the AdvaMed 2012 conference this past October.

Still, given the challenging economic climate, analysts have been impressed by the medtech industry's growth. Last year revenue for U.S. and European nonconglomerates increased 6% over 2010, totaling nearly $320 billion, according to Ernst & Young’s 2012 Pulse of the Industry report.

Funding has also stayed relatively strong. From June 2011 to June 2012, public medtech companies in the United States and Europe raised $27.4 billion, a 26% increase over the prior 12-month period. In addition, domestic venture capital investment grew 11%, to $3.7 billion. However, venture capital investment took a hit in Europe, decreasing 5%, to $676 million.

—Maria Fontanazza

 

Related Content

Top 40 Medical Device Companies

FDA Continues Push Toward Efficiency and Transparency

The winds of change are still blowing at FDA in 2012. The year has seen not only an extension of efforts to reform and improve FDA but also new policies and regulations that will affect FDA procedure. July 2012 saw President Obama sign the Food and Drug Administration Safety and Innovation Act (FDASIA) into law. FDASIA’s overall goal is to improve FDA and industry partnership. Key provisions include an expedited supervisory review appeal process, allowing FDA to reclassify devices by administrative order rather than regulation, and adjustment to the Sentinel program, which will allow FDA to use commercial and insurance data to monitor devices on the market. Most prominent, however, is FDASIA’s increase in user fees. Under the new act user fees will increase to $609 million in 2013-2017, up from their current level of $277 million from 2008–2012. The aim is to assist FDA with additional funding and help device manufacturers get to market faster. 

Figures 1–3. PMA and 510(k) submissions were at or near five-year highs in 2011. Source: FY 2011 MDUFA Performance Report to Congress.


Medical device user fees were first authorized in 2002, under the Medical Device User Fee Modernization Act (MDUFMA I) for fiscal years 2003–2007. Now, under the amended MDUFA II, which is in effect through fiscal year (FY) 2012, FDA has committed to more stringent performance goals to improve the timeliness and predictability of medical device reviews. The two-tiered system divides performance goals based on short- and long-term review times (based on times previously established by MDUFMA I). This two-tiered approach is intended to ensure that a significant number of reports are completed in a shorter number of days by providing quantifiable goals.
FDA’s FY 2011 MDUFA Performance Report to Congress states that, based on preliminary data of completed and pending reviews, FDA has the met or has the potential to meet or exceed 17 of 21 Tier 1 performance goals and 15 of 21 Tier 2 goals. However, the report also shows that, despite these goals being met, the total time for review (FDA time combined with industry time) has been increasing. In her commissioner’s report, FDA commissioner Margaret A. Hamburg states that in January 2011 FDA announced a plan of action for improvement. Hamburg states the aim is to “create a culture change toward greater transparency, interaction, collaboration, and the appropriate balancing of benefits and risk; ensure predictable and consistent recommendations, decision-making, and application of the least-burdensome principle; and implement efficient processes and use of resources.” 
 
The FY 2011 MDUFA report shows (Figure 1) that PMA, panel-track PMA supplement, and premarket report MDUFA cohort submissions reached the second-highest level in five years in 2011 (2010 being the five-year high). From FY 2008–2012, for nonexpedited filed submissions, 60% of decisions were issued on time for Tier 1, with this number increasing to 90% for Tier 2 (Figure 2). The number of 510(k) submissions under the MDUFA cohort portion (representing 94 of every 100 submissions) reached a five-year high in 2011 and decisions for 501(k)s were delivered 90% on time for Tier 1 and 98% for Tier 2 (Figure 3). 
 
Overall, FDA has reported consistent year-to-year performance with regard to the expectations set by MDUFA II. However, FY 2012 marks the final year under the current amendment. Based on future performance and overall performance in FY 2008 through FY 2012, it will be interesting to see if FDA makes further revisions to create more lenient performance goals or perhaps to push itself further. 
 
Goal Tier Performance Goals Fiscal Year Received Pending Within
Goal
Overdue On Time Percent On
Time
Met Goal
Issue a decision for non-expedited
Filed submissions
1 Issue 60% within 180 days 2008 33 0 12 21 64% Y
  1 Issue 60% within 180 days 2009 41 0 9 32 78% Y
  1 Issue 60% within 180 days 2010 54 7 12 35 74% Y
  1 Issue 60% within 180 days 2011 42 28 3 11 79% P
  2 Issue 90% within 295 days 2008 33 0 7 26 79% N
  2 Issue 90% within 295 days 2009 41 0 6 35 85% N
  2 Issue 90% within 295 days 2010 54 12 2 40 95% P
  2 Issue 90% within 295 days 2011 42 30 0 12 100% P
 

Performance indicators for FY 2008 through FY 2011 show that FDA has met, or is capable of meeting, performance goals for decisions issued for non-expedited filed submissions. Source: FY 2011 MDUFA Performance Report to Congress.
 
 
Goals Tier Performance Goals Fiscal Year Received Pending Within
Goal
Overdue On Time Percent On
Time
Met Goal
Issue a decision for 510(k)s 1 Issue 90% within 90 days 2008 3310 2 208 3100 94% Y
  1 Issue 90% within 90 days 2009 3444 1 357 3086 90% Y
  1 Issue 90% within 90 days 2010 3224 72 303 2849 90% P
  1 Issue 90% within 90 days 2011 3660 1697 104 1859 95% P
  2 Issue 98% within 150 days 2008 3310 2 53 3255 98% Y
  2 Issue 98% within 150 days 2009 3444 1 83 3360 98% Y
  2 Issue 98% within 150 days 2010 3224 90 56 3078 98% P
  2 Issue 98% within 150 days 2011 3660 1740 8 1912 99% P
 

In 2011 510(k) decisions were delivered on time 90% of the time for Tier 1 and 98% of the time for Tier 2. ?Source: FY 2011 MDUFA Performance Report to Congress.
 
Performance Indicators FY 07 FY 08 FY 09 FY 10 FY 11
BLA Supplements (CBE/CBE-30) – Percent
Reviewed and acted on within 6 months
100% 100% 100% 100% 100%
IDEs – Percent of decisions made within 30 days 99% 99% 99%a 98% 100%
IDE Amendments – Percent of decisions made
Within 30 days
98% 98% 99%a 99% 99%a
IDE Supplements – Percent of decisions made
Within 30 days
99% 100% 99% 99% 99%
PMA Supplements (CBE) – Percent of decisions
Made within 180 days
100% 100% 100% _b 100%
PMA Supplements (135 day) – Percent of decisions
Made within 135 days
100% 86% 100% 100% 100%
PMA Supplements (CBE - 30) – Percent of decisions
Made within 30 days
100% 100% 100% 100% 100%
           
           
Percentages above 99%, but below 100% are
Rounded down to 99%
         
b No PME (CBE) supplements were received in FY 2010          
 A review of FDA performance for submissions that do not have explicit MDUFA II performance goals. Source: FY 2011 MDUFA Performance Report to Congress.
 
Goal Tier Review Time Performance Level
FY 2008 – FY 2012
Submissions
Issue a decision for 180-day PMA supplements 1 180 85% on time
  2 210 95% on time
Shown is a summary of Tier 1 and 2 performance goals for 180-day PMA supplements. Performance goals are appllied to MDUFA cohort submissions. Source: FY 2011 MDUFA Performance Report to Congress.
 
 
—Chris Wiltz is the Associate Editor at MD+DI 

Kappos' Successor to Oversee Implentation of Patent Reform

In 2009, the United States Patent and Trademark Office (USPTO) found itself in a crisis. In the latter part of the year, IBM assistant general counsel David Kappos took charge of the agency, which was faced with lengthening patent review timelines and a tough fiscal situation. As he explained in his remarks in the USPTO’s Performance and Accountability Report that year, the agency was forced to work with “an outdated financial model.” The economic downturn had resulted in fewer patent filings, forcing the agency to “freeze hiring, curtail mission critical programs, and cut back in key efforts relating to the Agency’s mission,” he explained in the remarks.

Since taking charge, the agency’s finances have improved but, perhaps more importantly, Kappos pushed forward bold patent reform efforts and made other improvements to improve the speed with which patents are granted. Kappos has announced that he will step down from his role in January 2013.

While in the office, Kappos has implemented an ongoing push to accelerate both the speed and quality of patent processing. As medical device patent attorney David Dykeman of international law firm Greenberg Traurig LLP explains, “Director Kappos was a strong proponent of patent reform and an advocate for reduced pendency times of patent applications. Under his leadership, the USPTO made progress on the large backlog of patent applications waiting for examination. He will be a hard act to follow.”

In September 2011, the Leahy-Smith America Invents Act was signed into law, marking the most significant update to U.S. patent law in decades. "The next Commissioner of the USPTO will be tasked with implementing the significant America Invents Act change from ‘first to invent’ to ‘first to file’ for patent applications that is slated to take effect in March 2013 and with integrating the USPTO's new satellite patent offices in Detroit, Silicon Valley, Denver, and Dallas,” Dykeman says. “Hopefully, the next Commissioner will be as mindful of industry's need for thorough but fast examination of patent applications.” The regional offices will be staffed with roughly 120 patent examiners apiece and be supplemented with a number of administrative patent judges. In addition, Kappos also has announced a multi-year strategy to overhaul USPTO's IT infrastructure, upgrading it with cloud computing technology.

Brian Buntz is the editor-at-large at UBM Canon's medical group. Follow him on Twitter at @brian_buntz

Related Content:

Medtronic Sued for Alleged Deceptive Business Practices

Medtronic, a medical device manufacturer based in Minneapolis, Minnesota, was named as the defendant in a federal lawsuit over its allegedly deceptive business practices. According to the three plaintiffs named in the federal lawsuit, Medtronic used deceptive business practices to market defective and dangerous products. This lawsuit follows accusations of illegal marketing practices like doctor kickbacks for its defibrillator products. Medtronic has already settled that case. According to the Star-Tribune, the three men named in the federal lawsuit are seeking $427,000 in damages plus an undisclosed amount in compensation. The plaintiffs allege that the company distributed faulty devices and paid physicians to use them. One of the plaintiffs started a website called MedtronicMurders.com. The plaintiff claims on the site that the company's board is guilty of third-degree murder. He also states that the company ignored clinical risk of death information to boost profits. Medtronic believes the lawsuit is without merit. The company claims that it paid $268 million over its Sprint Fidelis lead recall. According to information shared with reporters at Star-Tribune, the company believes all new claims were resolved in this previous litigation. While the plaintiffs and Medtronic are both suffering at the moment, one party did benefit from this. Medtronic's litigation and fines paid almost half of the Minnesota U.S. Attorney's haul for the year. The $53 million haul is four times the agency's annual operating budget. References medtronicmurders.com/ www.startribune.com/business/183094501.html?refer=y www.bizjournals.com/twincities/blog/law/2012/12/minn-us-attorneys-office-collects.html

Drawing Inspiration from Cork, Researchers Develop Superelastic Graphene Material

Few materials in recent memory have gotten as much attention as graphene, a material composed of a sheets of carbon that is one atom thick. On the pages of MPMN, we have written stories on the materials impressive materials with titles such as Going Gaga Over Graphene and Graphene Arrays Could Revolutionize Electronics.

The graphene monoliths have a density that is much less than that of conventional materials. 

For a crystal, the material is relatively elastic, capable of stretching up to 20% of its length. The materials' usefulness, however, is limited when graphene is stacked, as it becomes brittle. For that reason, much of the research that has been done on the material has focused on applications of individual sheets of the material.

Researchers at Monash University in Victoria, Australia have developed a superelastic 3-D graphene-based material with a structure resembling that of cork. The ultralight graphene monoliths could withstand loads of more than 50,000 time its weight and can recover from deformation exceeding 80%. The novel material could be used in conductive biological implants, tissue scaffolds, and flexible electronics.

The scientists were able to create the material by using a technique known as freeze casting, which molded chemically modified graphene into a multidimensional structure that is extremely light.

Brian Buntz is the editor-at-large at UBM Canon's medical group. Follow him on Twitter at @brian_buntz

Study Abroad: Tips for Successful Clinical Trials Outside of the United States

Study Abroad: Tips for Successful Clinical Trials Outside of the United States

Introduction

An increasing number of medical device companies are going overseas to trial their technologies. As of July 2012, the U.S. National Institutes of Health’s ClinicalTrials.gov registry contained 129,291 clinical trials in 179 countries with 10,618 trials currently being conducted in East Asia and 2281 in South Asia.1 Many in the industry believe this trend will continue in the coming years. During a 2012 survey of leading U.S. medical devices companies conducted by research and consulting firm Best Practices LLC, 86% of respondents expressed their belief that the number of trials run in emerging markets will increase in the years ahead as companies look for efficient and cost-effective ways to bring new technologies to market.

The number of trials run in emerging markets is likely to continue to grow for the foreseeable future. Image from Glyn Lowe Photoworks.

This article explores the challenges and opportunities of conducting clinical trials overseas based on GlySure’s experience conducting human use trials for its continuous blood glucose monitoring system in India. It presents the realities of conducting trials abroad, tips for the contract research organization (CRO) and site selection processes, and suggestions on how to successfully position technology for future clinical regulatory trials in the United States and Europe.

Prior to conducting our trials in India, the GlySure management team had experience running clinical trials in the United States and the United Kingdom for both Fortune 500 and venture start-up organizations. This was, however, the first experience that any of us had in conducting trials in the developing world. The outcomes far exceeded our expectations, with direct trial costs savings of 50–70% compared to U.S. or EU study costs and, more importantly, savings of 9–12 months in development time due to faster regulatory approval processes. At the same time, there were multiple challenges and learning opportunities throughout the course of the study.

Getting Started: Trial Preparation

Any medical device trial requires extensive planning but trials conducted outside of the United States and Europe, particularly those in emerging markets, add a new layer of complexity because of the unique challenges of distance, basic logistics, foreign regulatory paths, and cultural differences that come with the territory. 

CRO and Site Selection. Being hundreds or even thousands of miles away from your trial site, as we were in the case of GlySure’s Intensive Care Unit (ICU) Pilot Trial in India, a medical device company does not have the ability to provide daily hands-on support. It must thus lean heavily on its Contract Research Organization (CRO) and primary investigator (PI). Therefore, the success of a company’s trial often hinges on choosing the right CRO and PI to meet its specific needs.

The good news is that a growing number of CROs have the ability to conduct medical device trials overseas. To choose a CRO for our trials in India, we partnered with Technomark Life Sciences in the United States. With corporate offices in the United States and the United Kingdom and a regional office in India, Technomark was able to bridge the gap between East and West, helping us overcome challenges and capitalize on the opportunity.

Technomark took a broad approach when working with us to select a site and PI for our Indian trials. They first examined 100 potential sites and then narrowed down the list to three, selecting those best suited to our technology and trial type. Technomark then arranged for us to interview the final three PIs and visit the sites to make our selection.

No One Size Fits All Solution. It’s important to note that a medical device company should select a CRO that has experience with medical technologies and not just pharmaceuticals because the trial process and requirements are vastly different. The CRO should also have experience in successfully managing your specific trial type. There’s a big difference between conducting a regulatory approval trial where the core product design has been finalized compared with a development trial where there are fewer patients but investigators and sites must have the flexibility to work with prototype devices.

An Experienced and Enthusiastic Leader. In regards to site selection, regardless of the trial type and where it is conducted, it is universally true that the ultimate success of the trial depends on the PI and his or her ability to drive patient enrollment and conduct the trial in accordance with study protocols. Therefore, it is critical that a company work with its CRO to find a PI who has a genuine interest in the trial and the right background and experience. During the PI/site selection process, the company should gather information on how many studies the PI has managed, the types of studies, technologies trialed, and his/her patient throughput.

According to Allen Hakimi, managing director of Technomark, the “softer” PI attributes are important as well.

“Personality is key,” Hakimi says. “While it’s important to select a PI with all of the necessary quantitative attributes, such as education and past clinical trial experience, qualitative characteristics are essential as well, including friendliness, enthusiasm for the technology and trial, and flexibility. Because we took all of these factors into consideration when selecting a PI for GlySure’s Indian trials, the PI is now an ambassador for the product and someone who continues to serve as an invaluable asset to the company.”

It is a bit embarrassing to admit, but six months later, with data in hand, we found ourselves incorporating half of the suggestions the PI made on day one, including the switch from the RA to IJ placement.

On our first day in India, we met with the PI and were greeted with a list of half a dozen suggestions for improving the product before we had even run our first case. One of these was to change the location of our sensor from the radial artery (RA) to the internal jugular (IJ). After spending four years and plenty of market research getting the product to the point of being ready for the first ICU test, our response was perhaps a bit subdued. We wanted an eager PI, but had expected to get some data in hand before the suggestions started flowing. It is a bit embarrassing to admit, but six months later, with data in hand, we found ourselves incorporating half of the suggestions the PI made on day one, including the switch from the RA to IJ placement.

This brings up one of the additional challenges of doing emerging market studies, “How do you determine which feedback is geographically specific and which will apply globally?” In our case we benefited from the strong historical British–Indian ties. Our PI had trained and worked in the United Kingdom for a decade before returning to found an anesthesia practice in India. He was quite effective at pointing out where ICU practices were the same or different. In addition, we used our existing U.S. and UK clinical advisory board to confirm the feedback coming out of the trial.

Regulatory Path

Because every country has its own regulatory path for clinical trials, it can be difficult to navigate the waters when conducting a trial overseas. The regulatory bodies are different, the timelines for submitting and receiving approval to conduct a trial vary widely and oftentimes, regulations in emerging markets are not as clear cut as they are in the United States or Europe.

“In the U.S., you submit your trial application to the FDA and, if you do not hear anything back within 30 days, you know you are good to go. The onus falls on the regulatory body to be timely and diligent,” Hakimi says. “This is not the case in other countries. There have been times when we’ve had a four-week trial approval and others where it has taken 14 months. The accountability infrastructure is not always there, which can be frustrating for a U.S. or European company that is used to standard timelines and deadlines.”

A good CRO and PI can help a medical device manufacturer navigate foreign regulatory paths and provide direction on what exactly it needs to do in order to secure the necessary approvals. During GlySure’s trials, every approval came on or ahead of the target date. In the case of local ethics boards, choosing a PI who is experienced and well respected played a critical role in paving the way for an efficient and successful program.

Time is Money

We chose India knowing that conducting trials overseas doesn’t mean that a company has to do less—the product must still be safe for use in humans, patient interests must be protected, and the data must be both accurate and credible. The main benefit for us came in the form of quicker turn around times—timing for both the official regulatory approvals and ethics board approvals were faster, which shaved months off of the time required to get the data we needed.

At first glance, two-to-three months time savings might not sound like a big deal, but this time adds up for a company in the development stage. During GlySure’s clinical program in India, we would conduct patient testing, collect the results, modify the product and then repeat the cycle again. Each time we went through that cycle, we needed to go back through the regulatory approval path. Having gone through that cycle four times, we saved anywhere between nine and 12 months of regulatory submission time.

A company must take into consideration not only the time saved, but also the cost savings to which it equates. A development stage company could be burning through $100,000 to $200,000 a month while it awaits regulatory approvals. We just completed our 100th subject in India last month and the direct trial savings are between $500,000 and $750,000. The savings in burn rate, by being able to collect that data nine months faster, is two-to-three times the direct cost savings.

Patient Enrollment: A Question of Ethics

Companies conducting clinical trials abroad are often asked if they are taking advantage of third-world patients in order to save time and money. One way to assess this is to look at patient consent rates: how often do patients decline to consent to participate? In our case, the answer is most definitely the same or more frequently than I have seen in U.S. trials.

For our clinical trials in India, we took pains to ensure that we selected only well-qualified trials sites that comply with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. During the trials, there were plenty of days when our PI told us that we didn’t have any patients because they all refused consent. As frustrating as it was to miss an enrollment, it was always a good reality check that patients were not being coerced to participate in the trials or taken advantage of in some way. If a company is conducting a trial abroad where every patient consents to participate, it must ask itself if its trial is being run in an ethical manner.

Companies are also asked if they are using third-world populations as test subjects for unsafe or unproven devices. One of the reasons that we chose India for GlySure’s initial clinical trials was that its Central Drugs Standard Control Organization (DGCI) enforces ICH GCP guidelines, so products must be proven safe for human use before initiating a trial. Not only does this protect patients from potential harm, it lends credibility to the trial and the results.

At GlySure, we had the upmost confidence in the safety of our technology, to the point where the company’s founder, one of our chief scientists and I served as the first human subjects. Before we started any trials abroad, we had already tested it on ourselves. This isn’t uncommon in the medical diagnostics/monitoring world, particularly among early stage companies with minimally invasive products.

Challenges

While there are clear advantages in terms of time and cost savings when conducting trials in emerging markets, there are countless logistical and cultural challenges as well. My advice to other medical device manufacturers is not to expect a trial abroad to run like a trial in the United States or Europe. This expectation will only leave you extremely upset and frustrated. Be prepared to take the good with the bad and focus on the long-term benefits.

My advice to other medical device manufacturers is not to expect a trial abroad to run like a trial in the United States or Europe.

Time and Distance. We were fortunate with our technology that we were able to go to India at the start of a trial, train for a couple of weeks with the PI and site staff and then go back home knowing they could conduct the study on their own. Issues inevitably arose during the trials but because we couldn’t hop on a plane every time something went wrong, we leaned heavily on our CRO to resolve matters on our behalf.

“Conducting a trial abroad requires a leap of faith,” Hakimi says. “We don’t tell clients not to go abroad. We tell them just don’t go abroad without us.”

Even with a strong team on the ground in India, it was still critical that we hold regular conference calls with the PI and the CRO every two-to-three days in order to track enrollment, discuss progress and answer questions. The time difference was definitely an issue. We had the advantage of being in the United Kingdom where there is a four-to-five hour time change to India, which is half a working day. U.S. companies face an even greater challenge, particularly those based on the West Coast where it is a 12-hour time difference. When managing a trial in Asia from the U.S. or Europe, be prepared to work at odd hours. Somebody is always up early and somebody is working late.

Customs. One of the greatest challenges that we faced during our trials in India was importing and exporting our equipment. Some parts of our technology, such as the sensors, are small, lightweight and relatively inexpensive to insure, making them relatively easy to navigate through the customs channels. Where we ran into issues was with our hardware. Computers, circuit boards and other equipment that are large, heavy, and expensive can trigger multiple red flags in customs, raising questions and resulting in significant delays.

The first time we brought our equipment over from the United Kingdom to India, we encountered a number of unexpected challenges. We arrived in India one week after our equipment arrived but one week before it made it through customs and to the trial site. As a result, we had a one-week unintended holiday stuck in our hotel rooms where the air conditioning cranked on high brought the 115° Fahrenheit temperatures down to a balmy 80°.

Cultural Differences and Language Barriers. One of the advantages of conducting trials in India is that English is a common language for business. As an emerging country for medical trials, India sees its high English literacy rates as a competitive advantage compared with countries such as China.

Cultural differences are always present. A company must be prepared to work with its CRO to ensure that all parties participating in its trials understand what is being asked of them, agree to the protocols and come up with realistic timelines so that there are no surprises and minimal misunderstandings.

“When a problem arises it’s sometimes hard to find the reality of a situation because different cultures communicate in different ways,” Hakimi says. “That’s why it’s important for a trial sponsor to have people on the ground who live and breathe the local customs and are able to communicate effectively across geographical and cultural boundaries to resolve issues.”

Effectively Positioning Technology for U.S. and European Trials

While the U.S. Food and Drug Administration (FDA) and the European Union (EU) ultimately require data on patients within their borders before issuing FDA clearance or a CE mark respectively, a trial conducted abroad in a credible manner can give a company a running start to securing regulatory approvals these markets.

Broad Patient Scope. When conducting trials abroad, there is always the question of whether medicine is practiced in the same way as it is in the ultimate launch markets. Are patients exposed to the same drugs, are they in the same care situations? To address this concern a company must ensure that its trials cover a broad scope of patients—different patient types, conditions and co-morbidities. The broader the patient scope, the more applicable the data.

A Hands-Off Approach. Regulatory bodies take with a grain of salt data from trials where the manufacturer of the product was frequently on-site making modifications. While leaving a device in the hands of site staff thousands of miles away for months at a time can be challenging, it certainly lends credibility to not only device usability but to the trial data itself.

Established Relationships. Now that GlySure has completed its pilot trials in India, we are now preparing for larger, international, multi-center regulatory trials in the United States, Europe, and India. It is extremely beneficial to have an established site up and running in India so that we can put our time and effort into establishing our new sites in the United States and Europe.

Conclusion

While we would have liked to have conducted a trial in our own backyard as opposed to somewhere that was a 10-hour plane ride away, the reality is that conducting clinical trials in India allowed GlySure to secure the data it needed in a relatively short time period. This in turn enabled us to secure further funding and successfully position ourselves for trials in the United States and Europe.

Beyond the strength of our technology platform, the key to our success was having a strong capable team on the ground in India, including the PI, site personnel and CRO representatives, who could drive patient enrollment, follow study protocols and help resolve issues. We knew that GlySure staff could not be on-site micromanaging every aspect of the trials. In the end, this ability to place our trust in this local team added to the strength and integrity of our technology and has enabled us to gather accurate and credible data to fuel the next stage of our development.

Christopher Jones is the chief executive at GlySure Ltd. He has more than 20 years of experience in the medical device and diagnostic industry. Prior to joining GlySure in 2008 he was CEO of Tensys Medical and led the development of the first clinically acceptable, continuous, non-invasive blood pressure monitor. Jones also spent nine years with Nellcor Inc., a division of Tyco, serving most recently as VP of Marketing responsible for the pulse oximetry and critical care businesses. Prior to that, he spent six years in sales and marketing management positions at BioGenex Laboratories. Jones is a graduate of Yale University with a bachelor of science in molecular biophysics and biochemistry. 


References

  1. ClinicalTrials.gov, [online], Washington, D.C., available from Internet: http://www.clinicaltrials.gov/ct2/home.
  2. Clinical Affairs Excellence: Benchmarking Clinical Trial Strategies to Ensure Medical Device Success in a Global Marketplace. [online], Chapel Hill, NC, available from Internet: http://www.best-in-class.com/bestp/domrep.nsf/products/A464580371F5C87685257983006C407F!OpenDocument.

Multiplexed Microbiological Diagnostics Guidance

The guidance recommends studies for establishing HMMD performance characteristics. FDA says it considers the recommended studies to be relevant for premarket notifications that may be required for a particular device.

The scope of the draft guidance includes nucleic acid-based devices that employ technologies such as polymerase chain reaction, reverse-transcriptase polymerase chain reaction, bead-based liquid arrays, microarrays, re-sequencing approaches and the measurement of individual targets determined by separate assays that are reported out simultaneously.

The guidance can be accessed at online.

Clarification Sought on FDA Presubmissions Guidance

In another comment, Johnson & Johnson outlined some of the strengths it sees in the program and says the guidance will give manufacturers the opportunity to obtain clear regulatory feedback before an IDE or premarket review submission to ensure optimal and efficient pre-clinical and clinical design and planning and to assure appropriate positioning of novel technology for regulatory submission. J&J included line-by-line comments.

Finally, Cook Group said that while several specific aspects of the draft guidance are commendable, the company is “seriously concerned that FDA has extended the time frame for pre-submission meetings.” Under the pre-IDE program the target date for meetings was 60 days, the letter said. The draft sets the target at 90 days or within 75 days but no longer than 90 days. “Regardless of whether the target is 75 days or 90 days, and recognizing that in some situations the target date cannot be met, Cook does not understand why FDA would need to extend its previous target date,” the letter said. “Cook specifically requests that the final guidance maintain the target date of 60 days, as stated in the current pre-IDE guidance.”