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Clinical Trials Go Global

BUSINESS PLANNING & TECHNOLOGY DEVELOPMENT

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The practice of medicine is constantly evolving, and medical practitioners and researchers around the world continue to develop and evaluate new ways to treat human illness. At any given time, thousands of pharmaceuticals and medical devices are being evaluated for potential benefits to patients. In fact, the registry of federally and privately supported clinical trials maintained by the National Institutes of Health, www.clinicaltrials.gov, currently lists approximately 50,000 clinical trials taking place in more than 150 countries around the world.

For pharmaceutical and medical device companies in the United States, clinical trials are increasingly taking place overseas as a prelude to the extensive FDA approval process at home. Ten years ago, 86% of all clinical trials were conducted in the United States. Today, only 57% are conducted in the United States, with almost a third of the trials being conducted in countries outside of the United States and Europe.1

Photo by ISTOCK
As with many business ventures in today's globalized economy, pharmaceutical and medical device companies see lower costs as a major benefit of taking clinical trials overseas. Manufacturers that take their trials beyond U.S. borders also stand to reap other benefits associated with efficiency and patient access.

At the same time, there are potential drawbacks to conducting clinical trials overseas that must be weighed against the benefits. Among such challenges are the myriad regulations that may trip up unwary companies with unfamiliar requirements, both medical and nonmedical. Failing to pay appropriate attention to both types of challenges may result in delays or even the derailment of an overseas clinical trial.

Taking Trials on the Road

The popular perception among the public is that every clinical trial is focused on validating the next new wonder drug or device. However, at any given moment, thousands of trials being conducted around the world are focused on testing slight differences in treatment protocols, experimenting with new ways to use existing devices, and measuring the impact of different drug combinations.

Over the past decade, the number of medical companies taking trials overseas nearly doubled, increasing from 956 in 1997 to nearly 1800 in 2006.1 Medical device clinical trials being conducted by U.S. companies vary greatly in scope, encompassing both large studies in multiple regions of the world and smaller operations in one or two countries. For example, current studies of medical devices listed at www.clinicaltrials.gov include the following.

  • A postmarket evaluation by Abbott Vascular (Redwood City, CA) of the Xience V everolimus-eluting coronary stent system in up to 150 study centers. Locations include countries in Europe (Austria, Belgium, France, the Czech Republic, Germany, Greece, Italy, Ireland, The Netherlands, Poland, Portugal, Spain, Sweden, Switzerland, and the United Kingdom), as well as Canada, China, India, Israel, Jordan, Kuwait, Malaysia, New Zealand, the Russian Federation, Saudi Arabia, Singapore, South Africa, and Thailand.
  • A study by Light Sciences Oncology (Bellevue, WA) of the use of interstitial light-emitting diodes to treat hepatocellular carcinoma compared with standard-of-care therapies. Locations include Hong Kong, India, South Korea, Malaysia, the Philippines, Singapore, and Thailand.
  • An analysis by Serica Technologies Inc. (Medford, MA) of the benefits of the SeriACL device for anterior cruciate ligament reconstruction compared with ligament autografts. Investigations are under way in Germany and Norway.
  • A registry in Belgium sponsored by Cordis Corp. (Miami Lakes, FL), a Johnson & Johnson company, to demonstrate the safety of the company's Enterprise vascular reconstruction device and delivery system.

Although Europe has long been a setting for U.S. clinical trials, China and India are the currently recognized hot spots. Large drug companies spent $2.2 billion in China and India on research and development during 2006—double the amount spent during the prior year.1 And China recently edged out India, which had been leading multinational clinical trials. In November 2007, China had 510 studies under way or completed for the year, compared with 471 in India.2

Central and Eastern Europe is another growth area for clinical trials. While clinical trials in Asia increased 29% annually between 2001 and 2006, Central and Eastern Europe increased 16% annually during the same period, outpacing Latin America's 13% annual growth.3

The Pros and Cons

Companies can realize a number of advantages by using overseas locations for clinical trials, with perhaps the most notable benefit being lower costs. A report by consultant A. T. Kearney estimated that using China as a clinical trial locale may cut costs in half compared with the United States.4 Consultant Frost & Sullivan puts the cost even lower, estimating clinical trials may cost as little as 15% of the tab in the United States or Europe.5 For example, a 2007 article in BusinessWeek cited a Chinese clinical trial of an artificial liver as an example of such cost savings.5 The trial's sponsor, Vital Therapies Inc. (San Diego), reported a per-patient cost of $15,000 in China compared with $50,000 in the United States (see Table I).

Cost in China ($)
Cost in United States ($)
One-day stay in hospital
40–100
750–1000
Magnetic resonance imaging
150–300
1500–3500
Yearly salary for senior oncologist
40,000
225,000
Typical cost to develop new drug
120 million
1 billion
Table I. Comparative costs of clinical trials in China and the United States.5

Benefits of overseas clinical trials extend beyond the financial realm as well. In particular, China and India offer large populations with a wide variety of diseases when compared with populations in the United States, where clinical trials often compete for a limited number of the same—and sometimes reluctant—patients. In countries with poor populations that lack access to routine, affordable medical care, clinical trials represent an opportunity for improved health. Thus, enrollment proceeds quickly. In addition, some countries have streamlined processes so that bureaucratic barriers are fewer or less time-consuming, contributing to a faster time-to-market cycle for new technologies.

Conducting clinical trials in other countries can also facilitate product approval in those countries, thereby generating sales more quickly. In fact, approval of a drug or device in a foreign country can spur sales and generate revenue that can then be used to fund U.S. clinical trials.

In clinical studies involving seasonal diseases, international sites can help shorten the time needed to obtain results by spanning climate zones and enabling year-round testing. International sites can also give companies access to uncontaminated populations in which patients have not been given other treatments that might interfere with testing. Likewise, certain conditions may be more widespread in international locations than they are in the United States. China, for example, is reported to have 160 million cases of hepatitis and 44% of the world's cancer cases.5

Despite the long list of potential benefits, there is an equally lengthy list of potential drawbacks to conducting overseas clinical studies. Some include questions related to the medical usefulness of studies. For example, it may not be possible to generalize results if the clinical study population base is different from that in the United States. In addition, cultural, environmental, or other factors may potentially skew a study's results. Likewise, certain countries may lack adequate clinical facilities and medical expertise to conduct the trial properly and with accuracy. They may also lack an adequate population base that presents the disease or condition being studied, thereby making it difficult or impossible to recruit the appropriate number of volunteers.

Furthermore, the standards imposed by certain foreign settings may not be rigorous enough to pass FDA scrutiny, eventually requiring the trial work to be repeated.

(click to enlarge)
Figure 1. Geographical comparison of time required to secure approval to begin a clinical trial. Source: Wyeth Research and Development.
Other potential pitfalls include various nonmedical considerations. For example, some foreign destinations have lower levels of protection for intellectual property and data confidentiality than those found in the United States. (To address such concerns, both China and India recently revised their laws to provide more protection for companies conducting clinical studies on their soil.) Other potential pitfalls include unstable political environments, ever changing regulatory processes, language barriers, and lengthy review times (see Figure 1). There are also ethical concerns about the possible exploitation of low-income, less-educated, unsophisticated populations and the potential lack of rigor regarding informed consent.

However, perhaps the biggest stumbling block to overseas clinical trials is the wide variety of regulations and requirements that medical companies must take into consideration when they take their trials on the road.

Daunting Complexity despite Standardization

To reduce inconsistency among standards for clinical trials, in 1964 the World Medical Association adopted what is known as the Declaration of Helsinki.6 FDA incorporated the document into its clinical trial standards in 1975. The World Medical Association updated its standards in 1975, 1989, and 2000. Currently, FDA is considering the 2000 revisions but has not yet adopted them.

In addition, the European Union issued a clinical trials directive in 2001 with the goal of reducing red tape, speeding up research, harmonizing procedures across Europe, enforcing patient protection measures, and increasing the transparency of the clinical research process. However, the goal of uniform standards is somewhat undercut by the fact that clinical trials are still subject to the legal codes of each member state of the European Union.

Despite efforts toward clinical trial standardization, much variation remains. Thus, conducting clinical trials overseas requires special attention to pertinent details in each host country. Some areas requiring attention involve medical issues, such as arranging for appropriate informed consent, providing investigators with standardized protocols, and arranging for on-site monitoring. None of these factors is likely to be overlooked when an experienced company is in the early stages of planning its clinical trial.

Other less-obvious issues, however, may catch companies by surprise. Insurance is one such area. Each country has its own standardized protocols and requirements for how insurance is handled and for covering the liability involved in running a clinical trial. International requirements include the following.

  • Germany has two laws addressing clinical trials for medical products: one for devices and one for drugs. The laws stipulate the type and amount of insurance a sponsor organization must carry—?500,000 per patient and ?5 million per trial for trials involving medical devices—and require the coverage be provided by a German insurer.
  • Switzerland requires coverage by local insurers. Most ethics committees within the country require a minimum of 1 million Swiss francs per patient and 10 million Swiss francs per trial. The local center where the trial is conducted must be included as a legal entity on the policy.
  • Australia has no compulsory insurance law. However, most hospitals and other sites where trials are conducted may require that coverage be placed through an Australian insurer, with coverage of $10 million Australian.

As these examples demonstrate, even countries with consistent, high standards for conducting clinical trials may differ greatly in their rules governing insurance coverage and other nonmedical issues. Therefore, when dealing with insurance and other considerations, it is critical that companies undertaking overseas clinical trials get started early with their planning. Arranging for insurance through foreign carriers is not always a speedy process, and failure to obtain the right kind of coverage may delay a trial or prohibit a trial from commencing.

In addition, insurance for overseas clinical trials must go beyond the entity conducting the trial. Coverage must be considered for employees who travel to foreign countries to monitor the site, as well as for the expensive equipment that might be shipped overseas as part of the trial or for local offices that are maintained while the trial is being conducted.

Conclusion

The advantages of going overseas as part of the clinical trial process outweigh the challenges for many companies; the rapid growth in globalized trials is testament to the many benefits. However, the complexity of meeting a variety of local requirements while still holding trials to the rigor required to pass U.S. regulatory scrutiny means that medical companies must plan early and thoroughly. This is especially true for nonmedical considerations that can easily be overlooked in the rush to secure sites and get a trial started. The end result of proper advance planning is not only good medicine, but also good business.


References

1. G Lopes, “Drug Makers Look East for Testing,” The Washington Times (December 8,, 2007): A01; available from Internet: www.washingtontimes.com/apps/pbcs.dll/article?AID=/20071208/BUSINESS/112080024/1001

2. “India Industry: Slipping to Second Place for Clinical Trials,” The Economist Intelligence Unit: Country ViewsWire [subscription data service] (5 November 2007).

3. K Getz, “Global Clinical Trials Activity in the Details,” Applied Clinical Trials, vol. 16, no. 9 (2007): 42; available from Internet: www.pharmainfo.net/global-clinical-trials-activity-details.

4. W Bailey, C Cruickshank, N Sharma, “Make Your Move: Taking Clinical Trials to the Best Location,” Executive Agenda (Chicago: AT Kearney, 2006); available from Internet: www.atkearney.com/main.taf?p=5,1,1,116,3,1.

5. “The Rush to Test Drugs in China,” Business Week vol. 4036, (2007): 60; available from Internet: www.businessweek.com/magazine/content/07_22/b4036076.htm.

6. Ethical Principles for Medical Research Involving Human Subjects (Ferney-Voltaire, France: World Medical Association, updated 2004); available from Internet: www.wma.net/e/policy/b3.htm.

Michael Thoma is assistant vice president for global technology underwriting at Travelers (St. Paul, MN).

Copyright ©2008 MX

FDA Needs More Money and More Ideas

FROM THE EDITORS

It is no longer a question whether FDA has the resources to accomplish its mission. It does not. This message was brought home again in late January, with the release of a report by the Government Accountability Office (GAO). It concluded that CDRH is so far behind on its inspections of foreign plants that produce medical devices for the U.S. market that it would take 27 years to get to them all. The backlog for foreign food and drug plants is similarly shocking.

The agency is so far behind in computer technology that it cannot track how many foreign plants there are, nor can it produce a list of those that need to be inspected. This is particularly a problem in China, where the number of medical device plants has grown sharply in recent years, and more and more of them are starting to produce exports to the United States. Over a six-year period, the agency inspected all of 64 medical device plants in China, yet there are believed to be at least 700 of them.

The GAO report comes on the heels of a report by FDA's own Science Board that concluded the agency cannot keep up with the growing number of imports, and thus cannot guarantee that they are safe for U.S. consumers. (MD&DI had more on that story in the NewsTrends section of last month's issue.)

Since 1987, the agency has lost 1311 employees. The talent drain and high turnover rate among scientists are reasons why the agency is having trouble keeping up to speed on emerging technologies. And more attrition is coming: A number of long-time agency employees are expected to retire rather than endure the aggravation of moving when the agency's new White Oak facility in Silver Spring, MD, is fully up and running.

Adjusted for inflation, FDA's appropriation from Congress is $300 million less than it was in 1987. Yet, since that time, Congress has passed more than 100 laws expanding or redefining the agency's responsibilities.

The math doesn't add up. If you tell an agency to do more things with less money, fewer people, and inadequate technology, you shouldn't be surprised when it does a poor job and scandals such as the Guidant defibrillator fiasco happen.

Something has to change.

Not surprisingly, more people are starting to notice the agency's plight. Reaction to President Bush's proposed fiscal year 2009 budget for the agency was mixed at best, as most of the increase comes from user fees. The Alliance for a Stronger FDA, an advocacy group formed from the merger of the FDA Alliance and the Coalition for a Stronger FDA, was particularly vocal. The group suggested adding $380 million to the president's proposal. Peter Barton Hutt, a former chief counsel for the agency, went further, telling Congress that FDA's appropriation should be doubled and its staff increased by 50% over the next two years.

It is clear that FDA does not have enough money for its mission. Much thought must be given to what it would take to ensure that it does. But because funding resources are finite, the debate should not end there. Much thought must also be given to what exactly the agency's mission should be, and which, if any, tasks it performs now can be streamlined or eliminated. For example, a CDRH inspection has requirements that go beyond those in ISO 13485, which is used by much of the rest of the developed world. Do they really make us that much safer than patients in Europe or Canada? Imagine the cost savings that could happen if the United States used the same inspection system as its Western counterparts. And shorter inspection time means that more plants, domestic and foreign, get inspected in a timely manner. I'm not saying this is the route FDA needs to go, but it's the kind of thing that needs to be considered. It's obvious the status quo isn't working. The agency not only needs to be revitalized, it also needs to be reengineered.

Erik Swain for The Editors

Changing Perception of Industry a Priority for AdvaMed

NEWS TRENDS

The idea that slowing medical technology can help control healthcare costs is a flawed mindset, says Stephen Ubl of AdvaMed.
AdvaMed has made several issues a priority this year, but none may be more urgent than changing the perception that medical technology is the biggest driver of increased healthcare costs.

“We still have a challenging healthcare policy environment around the world,” said Stephen Ubl, president and CEO of AdvaMed. He spoke to the media about device industry concerns during a briefing in February.

Ubl said a report by the Congressional Budget Office, “Technological Change and the Growth of Health Care Spending,” could be a threat to innovation. The report was released before the U.S. Senate Budget Committee in January.

Ubl disagreed with the report's assertion that medical technology is primarily responsible for the increase in healthcare spending. He also called its model for estimating healthcare costs flawed and questionable.

“It implies that slowing the diffusion of advances in technologies is the right approach to controlling costs,” said Ubl. “The American people will not—and should not—accept a so-called solution to the cost problem that sacrifices longer and healthier lives for slower [technological] growth and medical costs.”

Ubl suggested controlling costs by examining drivers such as poor quality and other inefficiencies. He also said that more-effective prevention measures and better management of diseases should be analyzed.

Additional Medicare legislation is anticipated this year, and AdvaMed is working with Congress and CMS to ensure that any changes will be beneficial to the device industry.

Ubl also touched on areas that Adva­Med hopes to see changes this year.

  • Remote monitoring. Right now, doctors aren't reimbursed for remotely interacting with a patient or a device.
  • Molecular diagnostic testing. Adva­Med has been working on a demonstration project for incorporating the value of such new tests. Ubl thinks molecular diagnostics has a good chance of being included in Medicare legislation this year.
  • Imaging. Reimbursement cuts could be part of the Medicare package.
  • Hospital inpatient prospective payment system. There will be a key rule addressing charge compression, according to Ubl, who said the current inpatient rate is distorted.
  • Patents. As patent reform talks heat up, AdvaMed has been working with committee leaders and has planned advocacy in key states.
  • Global environment. Issues include partnering with local associations in countries to demonstrate the value of technology, foreign reference pricing, and the harmonization of emerging regulatory systems.

Despite the potential obstacles that Ubl discussed, he feels that 2008 is a year of tremendous promise. AdvaMed can move forward with its Medicare agenda on issues such as remote diagnostics, and the group is also building the foundation for innovation and improving reimbursement in foreign markets. The association will continue to broaden the reach of its industry-standard code of ethics.

Copyright ©2008 Medical Device & Diagnostic Industry

Creganna Expands Facility, Focuses on Strength

OUTSOURCING NEWS

Less than a year after its plant in Massachusetts opened, Creganna has expanded the facility. Creganna is a specialty needle and catheter development company. Its Malborough, MA–based plant doubled in size to 20,000 sq ft.

The expanded space enables Creganna to add staff to accommodate increased demand, according to company spokesperson Maura Leahy. The facility expansion was completed in January.

The facility serves as the global manufacturing base for all of Creganna's specialty needle manufacturing services.

“[With this expansion], we can fulfill all the requirements of customers seeking full manufacturing services for specialty needles,” says CEO Helen Ryan.

It's the Economics, Stupid

EDITOR'S PAGE

Considering the many steps that medtech manufacturers must accomplish before a new product sees the light of day, it's little wonder that they haven't been eager to undertake further studies once their products have been launched. Nevertheless, many device companies report that they are conducting more postmarket research about their products today than ever before, including studies required by FDA as well as studies designed to examine the clinical outcomes and costs related to the use of those products.

Now, with an infusion of funding expected to peak at $200 million annually, U.S. Senate Finance Committee chairman Max Baucus (D–MT) and Budget Committee chairman Kent Conrad (D–ND) hope to push healthcare research to new levels. At the beginning of March, the two senators introduced the Comparative Effectiveness Research Act of 2008, which would establish a private, nonprofit research institute to compare the clinical effectiveness of alternative treatments for specific medical conditions. In a press release, Conrad stated, “Our goal with this bill is to give Americans and their doctors accurate and objective information to help them make medical decisions. Healthier people should mean lower healthcare costs.”

While noting its support for the principles of evidence-based medicine, industry organization AdvaMed (Washington, DC) was quick to caution against using the institute as a means to study health economics. “Research should focus on comparative clinical effectiveness, and not on cost-effectiveness—which could lead to decision making that may not be in the best interest of patients,” said AdvaMed president and CEO Stephen J. Ubl.

Considering the cost pressures being exerted on healthcare systems worldwide, however, it may be tough to keep that genie in the bottle. In spite of industry opposition, when researchers are given an opportunity to compare the effectiveness of different therapies, the temptation to take cost factors into account could prove overwhelming.

Copyright ©2008 MX

Quick Sources

BUSINESS PLANNING & TECHNOLOGY DEVELOPMENT

The following are resources for understanding different clinical trial standards around the world.
Copyright ©2008 MX

Portable Devices: Optimizing Diaphragm Pumps and Solenoid Valves

PUMPS AND VALVES

Miniature diaphragm pumps and valves can be tailored to meet market objectives. Photo by RONI RAMOS
The increased demand for medical therapies and treatments to be administered at home—or even on the go—has sparked a new generation of portable devices. Many of these systems incorporate fluidic modules consisting of miniature diaphragm pumps and solenoid valves.

These components need to be optimized according to the system criteria that best achieve the market demand objectives. Medical device developers benefit from understanding how these components can be tailored to meet their application-specific requirements.

Healthcare Market Drivers

Pressures from payers and employers to contain healthcare costs have been associated with the shift to less-costly outpatient procedures. Procedures that were once performed only on an inpatient basis are increasingly performed in a variety of outpatient and ambulatory (when a patient must travel to a location to receive services that do not require an overnight stay) settings. Advances in medical technology and the development of noninvasive and minimally invasive surgical procedures have contributed to this growth in outpatient ambulatory care.

The trend for medical practitioners to have patients reduce hospital stays and continue treatments at home has required medical device companies to engineer systems that are portable, quiet, and cost-effective. Several high-technology diagnostic and therapeutic services now available in the home include transfusion therapy, dialysis, oxygen therapy, mechanical ventilation, compression therapy, and wound therapy.

This changing healthcare landscape is driving explosive growth in the medical device field.1 The market will continue to accelerate as demographics and market drivers increase their pressure for new and innovative product offerings.

To successfully support an increased speed to market of new and innovative products, medical device companies are finding great value in working closely and earlier in the development process with component suppliers to identify key system requirements. Miniature diaphragm pumps and solenoid valves, for example, have become popular with fluidic-systems engineers to provide pressure and vacuum transport of air and gas in a cost-efficient manner. By understanding how key components such as these can be tailored for optimum system performance, medical device developers can speed their time to market by identifying early exactly what they need.

Identifying a System's Performance Criteria

The marketplace for portable medical devices is becoming more segmented and competitive, with each segment offering different features to meet specific end-user demands. The first step in the development process should be to get a clear definition of the criteria for a successful product release from the marketing team. Then, it is important to prioritize these capabilities and select the components and the respective performance specifications needed to best meet the ranked criteria. Because there are usually trade-offs, this step helps to ensure that major product objectives are met and that development timelines don't suffer from project scope creep. Scope creep refers to the tendency of a product's objectives to broaden as the program moves forward.

For portable medical device developers, the following criteria—and how they are prioritized—can make significant differences in the specific components that should be selected.

The compact design of a pump for liquid operations can enable it to operate longer than previous pump designs.
Size and Weight. For medical devices to be truly portable, they need to be much more compact and lighter than their desk-mounted predecessors. The maximum envelope that the fluidic module can fit into needs to be determined. The fit of the module affects the maximum size of the pump and valves that will determine fluidic performance. If space is limited, smaller pumps and fewer valves are needed. Be aware, however, that using small pumps can either limit performance or increase noise. Smaller pumps must often run at maximum motor speeds to achieve similar performance of a larger pump that is run at a slower speed.

Performance. Another key parameter is the required flow at pressure and vacuum at the critical operational points of the medical therapy. It is important to understand how the pressure and vacuum is controlled (analog control, pulse width modulation [PWM] control, PWM with tachometer output, etc.). How they are controlled should be determined to set baselines for key components.

Increasing the performance while shrinking the size of the miniature solenoid valves and diaphragm air pumps has posed several interesting challenges. Advanced designs, materials, and motor technologies have launched new, innovative pumps and valves that can achieve better performance in a smaller package.

Noise. Some medical therapies must account for noise. Such therapies include devices that operate next to a sleeping patient or those that are used in public. Diaphragm pump manufacturers minimize noise by reducing the stroke, optimizing diaphragm shape and durometer, and lowering chamber inefficiencies. Depending on the level of these actions, trade-offs may affect pump efficiency and fluidic performance. Another tactic noted earlier is to use a larger capacity (e.g., a dual-head pump versus a single-head pump) running at a lower rpm. The performance stays the same but the noise level drops significantly. The trade-off, of course, is a larger pump envelope.

New valves have been designed to provide increased flow and to reduce power consumption.
Efficiency. For a battery-powered device, the designer must determine the desired target operational life from the battery. One consideration is whether there would be a market advantage to having the portable medical device run longer from a battery than its competition. As discussed in more detail later, the proper selection of motor technology for the diaphragm pump contributes greatly to the efficiency of the system. In addition, properly matching the orifice size of the solenoid valves ensures that they are not acting as a restriction, which would force the diaphragm pump or miniature compressor to work harder.

Operational Life. A key consideration is whether the device is disposable or requires the fluidic components to run intermittently. Another consideration is whether the pump requires proven high reliability under demanding cyclic operation that can exceed 10,000 hours of operational life. Operational life requirements are affected by selection of the motor technology, diaphragm elastomer, and fluidic loads and cycling, in addition to the maximum temperature environment to which the components will be exposed.

Cost. When cost is placed on the decision criteria for fluidic components, it greatly affects the ability to maximize the advantage of each of the preceding factors. It should be noted that too strong an emphasis to cut costs of the diaphragm pumps and solenoid valves could actually increase overall costs and decrease marketability of the device. For example, advanced, high-efficiency and high-reliability motor technology and solenoid valves significantly decrease power consumption—sometimes in half. Such a decrease in power consumption can result in battery requirements being greatly reduced, giving development engineers the flexibility to design an even lighter and more-compact device or elongating battery capacity.

The following technology drivers greatly affect the criteria for selecting miniature air diaphragm pumps and miniature solenoid valves.

Dc Motor Selection

The motor of the miniature diaphragm vacuum pump or compressor is probably the biggest driver affecting the overall performance, efficiency, expected operational life, and cost. Because the motor is the highest-cost component of a diaphragm pump, it significantly affects the overall cost of a fluidic module. Two major motor technology designs, dc brush and dc brushless, can be configured on the pump. Each has respective advantages and disadvantages.

Brush Dc Motors. Dc brush motors are commonly used with many diaphragm pressure and vacuum pump applications when low cost is critical but operational life is not important. Iron core brush motors use carbon brushes to conduct the electrical input from the lead wires to the motor's commutator. The constant rubbing of the brushes on the commutator causes the brushes to wear down much like the lead in a pencil. Brush motors are designed to last from 500 to 5000 hours, depending on the quality of the motor and how it is used.

The motor brushes experience an electrical arcing upon each startup. Frequent arcing heats up the carbon brushes, causing them to wear out more rapidly. Therefore, brush motors that experience frequent on-off cycles wear out more quickly. A top-quality brush motor can be expected to last no more than 3000 hours with frequent on-off cycles. Brush motors used in high-duty applications with more-continuous operation can last longer.

It is important to note that few applications allow a pump to run continuously. Frequent starts and stops are the norm. Occasional cycling may lead to motor stall due to carbon dust buildup between the brush base and commutator. Tapping the outer housing to clear these deposits from the brush tips can usually restart the motor. In addition to limited life, brush motors can introduce unwanted electrical or radio-frequency interference noise into a system's circuitry.

Coreless motor technology differs from a standard brush motor in that the winding is wound onto itself on the rotor. The brushes are made from a highly conductive and efficient precious metal. No iron is on the rotor, making the lighter, coreless (or ironless core) rotor spin at a given performance level with less input energy required. This design results in lower current draw required to power the respective diaphragm pump. Coreless motors come at a premium price because of the precious-metal brushes and the complexity to manufacture the wound rotor. As a result, coreless motors are commonly used in portable, battery-operated systems that require exceptional efficiencies to achieve longer battery operation, but do not require an operational life greater than standard brush motors.

Coreless dc motor-driven pumps for air and gas allow designers to reduce size and weight.
Advances in Brushless Dc Motors. Brushless dc motors eliminate the problems associated with brush motors. In a brushless motor, the magnets are on the rotor, and the windings are wrapped around poles on the stator. Instead of brushes and a commutator bar, the windings are switched on and off sequentially by solid-state electronics. Brushless motors require less maintenance and are smaller, lighter, and more efficient than brush motors with comparable outputs. With motor designs that focus on performance, reliability, and endurance, operational life can be expected to exceed 10,000 hours. A high-precision bearing cage design takes out any play that causes bearing fretting. This precision design can also produce a quieter motor because the mechanical noise common with brush motors is significantly reduced.

One limitation of traditional brushless motors, however, is that they do incorporate slotted stators. The stator consists of slotted iron laminations that are fused to form a solid, uniform stack. The slots form rows that extend the length of the stack, and the windings are inserted into each row. As the rotor turns, the magnets are more attracted to the stator's teeth than to the gaps between them. This uneven magnetic pull, called cogging, reduces the motor's efficiency and makes it difficult to produce smooth motion at low speeds. With typical operating pressure and vacuum loads, current-
technology brushless motors can see efficiencies in the 50–60% range.

A new design variation is a brushless motor that incorporates a slotless stator (one that has no slots to keep the windings in place). The windings are attached to the inside surface of the stator with adhesive. With no teeth to attract the magnets, cogging is eliminated, and the motor produces smooth, quiet rotation. The absence of teeth also provides room for larger magnets in the rotor and more wire in the windings, which means that slotless motors can generate more torque without a corresponding increase in size. Additionally, the slotless design significantly reduces damping losses.

New valves have been designed to provide increased flow and to reduce power consumption.
In both slotted and slotless motors, eddy currents are induced as the magnets pass the stator. However, these currents are weaker in slotless motors, because the distance between the stack and the magnets is greater than in slotted motors. This makes slotless, brushless motors more efficient than slotted motors. Compared with slotted brushless motors, miniature-diaphragm pressure and vacuum pumps can expect to see improved efficiencies of up to 70% coupled with the exceptional life that the brushless design produces.

Diaphragm Pumps: Innovative Materials and Shapes

The diaphragms in miniature diaphragm pumps and microcompressors are stretching and flexing under load, and sometimes at elevated-temperature conditions. Ethylene propylene diene monomer (EPDM) elastomers have limited elastic properties to withstand the cyclic stretching required for high-flow-output applications. Therefore, many current- technology miniature diaphragm pumps and compressors are only rated up to 40°C and are unable to endure the rigorous cyclic stretching required for higher-output applications. Pumps configured with EPDM and operating at higher ambient environments typically endure ripped diaphragms before they achieve 3000 hours. To extend diaphragm life past 10,000 hours under operating conditions that the latest portable medical devices require, an advanced-performance elastomer with improved mechanical capabilities has been developed that can withstand 70°C. Extensive research was conducted that resulted in the development of this advanced EPDM, or AEPDM. This elastomer material configuration has been tested to last 10 times longer than standard EPDM. Depending on the fluidic loads and ambient operating temperatures at which the miniature diaphragm pump is operating, AEPDM diaphragms have been found to exceed 20,000 hours of operational life.

Pumps can now be easily configured to accommodate specific vacuum and pressure requirements.
The shape of the diaphragm itself has been evaluated and optimized to improve vacuum, pressure, and flow performance efficiencies. The performance of typical flat diaphragms is limited by the amount that the diaphragm can be stretched. High-performance air and gas pumps require increased pump stroke beyond the stretch limits of the flat diaphragm. Higher vacuum or higher flow performance for these flat diaphragms requires that either a larger flat diaphragm be used (which would require a larger pump head design) or that a shaped diaphragm be used to provide an increased surface area. Shaped diaphragms allow the pump stroke to increase by as much as 80%. By optimizing the pump's diaphragm shape, significantly increased output performance can be achieved in a much smaller, compact envelope size.

Higher Flow: Larger Valve Orifice, Not Larger Pump

Miniature solenoid valves are required to direct and control the flow in many portable medical devices that require miniature diaphragm pumps or microcompressors. The valves typically cannot exceed a 10-mm package size because of the enclosures being used today. The latest design trends have challenged component manufacturers to produce smaller, lighter components, specifically miniature solenoid valves, to accommodate ever-smaller products. As valves decrease in size, they have smaller orifices and restricted throughput, effectively giving up higher performance for a smaller package. The typical 10-mm solenoid valve has up to 1⁄6th the throughput area compared with the pump output capacity.

The restrictions of these small, ineffective valve orifices, therefore, require the pumps in a fluidic system to overcome significantly large pressure differentials. To compensate for this reduction in throughput, fluidic systems engineers commonly use a pump with up to 200% more capacity than necessary. Even with the pumps that provide higher output, minimal performance gains are achieved while adding unnecessary weight, and increased power consumption, as well as increased heat, noise, and size. Additionally, as portable medical device designers develop smaller instruments with more functions, more solenoid valves are required, which compounds the increased heat, noise, and power-
consumption problems.

Recent advances in solenoid valve technology have focused on decreasing the overall size of the valve but increasing the size of the orifice. Finite-element analysis can be used to study the fluid flow throughput and the flux efficiency of the magnetic field created by the solenoid. Such analysis should enable the development of new designs that provide flow of up to two times the current capabilities. In addition, improved efficiency in the solenoid design significantly reduces power consumption and heat generation.

Advanced manufacturing processes can lock in exact, optimized orifices that enable fluidic tailoring to achieve application-specific flow. The new miniature solenoid valves can be mounted individually, mounted on a manifold, or soldered directly onto a printed circuit board.

Conclusion

Typically, the weak link in a fluidic circuit has been the small valve with its small, restrictive orifice. Instead of specifying larger, higher-output pumps, fluidic designers are working with providers to explore tailored options that optimize the solenoid valve orifice to a diaphragm pump to best meet their system criteria. Advantages include smaller, lighter pumps that produce less noise. Differential load pressures, overall size, and weight are decreased.

Portable medical devices increasingly seek to achieve higher flow, longer battery operation, and longer device life. Smaller but more-cost-effective fluidic modules can provide tailored configurations of advanced miniature diaphragm pumps and valves. Properly ranking the overall system criteria and the respective component requirements is essential to ensuring project success and quick time to market.

Dan Schimelman is director of business development at Hargraves Technology Corp. (Mooresville, NC). He can be reached at dschimelman@hargravesfluidics.com.


Reference

1. “Consumer Medical Devices Market to be Worth $5 billion by 2011, says InMedica” (Belmont, CA: Tekrati, February 4, 2008) [online] cited 22 February 2008; available from Internet: http://industry.tekrati.com/research/10003/.

Copyright ©2008 Medical Device & Diagnostic Industry

The Organizational Challenge to Outsourcing

GUIDE TO OUTSOURCING EDITOR'S PAGE

Under pressure to stay ahead of the competition and to innovate with ever-decreasing budgets, you may very well see outsourcing as the key to the future. In a recent survey, manufacturers and other industry experts cited reduced margin pressures, increased return on investment, and faster time to market as three key drivers of outsourcing. The online survey was conducted by the Wharton Business School in Philadelphia and HCL Technologies in October 2007, and a report was issued in February 2008. HCL is an outsourcing firm based in India.

The respondents indicated that they see strong potential in outsourcing or collaborating with outside partners to meet today's manufacturing challenges. “The picture that emerges from the survey is of an industry struggling with profound changes . . . from the way it is organized, to the way it operates, to whom it serves,” the report says.

Most of the individuals surveyed were optimistic about the capabilities of outsourcing partners. Interestingly, 84% agreed that “an outsourcing partner can appreciate the complexity of your varied supply chain and support you through the consulting and execution alike.”

The challenge is no longer just keeping up with quality levels or finding a vendor with sufficient expertise, though. It is also addressing organizational issues. “You have to treat [outsourcing] much more like an alliance,” notes Saikat Chaudhuri, a professor of management at Wharton. He says the structure of such alliances varies from putting staff on the vendor's site to using an offshore subsidiary that can work with the vendor.

Regardless of the structure, the report emphasizes that outsourcing partnerships require careful thought about what you hope to accomplish with the relationship. Strong lines of communication are essential in any outsourcing arrangement, and if your outsourcing partner is offshore, it is an even greater challenge that must be addressed at the outset.

The report recommends that device companies set specific goals for the outsourcing initiative, maintain realistic expectations, and align the goals of vendor and client. No matter what your reason for outsourcing, always make sure that you and your vendor have the same expectations. Develop clear specifications, articulate team structures and roles, and most of all, plan ahead.

Sherrie Conroy for The Editors

California Company Expands Operations into Mexico

OUTSOURCING NEWS

Tijuana, Mexico, will serve as a second home to device contract manufacturer Medegen (Ontario, CA). The company, which creates components for IV therapy and other devices, has opened a 42,000-sq-ft facility to house its manufacturing operations.

“Expansion of our manufacturing facilities will provide medical companies with high-quality and cost-effective outsourcing,” says Jeff Goble, president of Medegen.

The company expanded to meet anticipated demands of the growing device industry. With the expansion, Medegen can offer customers services from initial product design to delivery of sterile devices. The FDA-registered manufacturing plant has ISO 13485 certification as well as FDA quality system regulation compliance.

Proximity played a role in selection of the site, according to the company. The plant is located less than a mile from the California-Mexico border.

In addition to contract manufacturing, the facility will handle finishedgoods assembly for Medegen's Maximus IV therapy products.

Copyright ©2008 Medical Device & Diagnostic Industry

An Uncertain Path

INDUSTRY ASSOCIATIONS

(click to enlarge)
Bradley Merrill Thompson is a member in the healthcare and life sciences practice of Epstein Becker & Green PC (Washington, DC). Leah R. Kendall is a senior associate with the firm.
Over the past few years, the realm of combination products has undergone dramatic growth and change. Many start-up companies have ventured into the converging world of medical devices, pharmaceuticals, and biologics, and several of industry's largest players are also grappling with the challenges posed when two or more FDA-regulated articles are joined together.

In 2007, FDA's Office of Combination Products (OCP) underwent several leadership changes. Meanwhile, the much-anticipated good manufacturing practices (GMPs) and adverse-event reporting regulations for combination products continued to wind their way through the agency's internal review processes. Now, with Thinh Nguyen in place as the new permanent director, OCP seems poised to make new and exciting headway in its quest to further develop and refine the regulatory landscape for combination products.

Against this backdrop, in late 2007, the Combination Products Coalition (CPC; Washington, DC) began to plan its 2008 advocacy agenda. As it did, the organization's diverse group of member companies identified a need to step back and take the industry's pulse on existing combination product policies and guidance. The organization's goal in doing so was to ensure that it remained focused on its mission of developing and advocating improved policy positions on regulatory issues affecting combination products, which necessarily cut across multiple diverse industries.

With that goal in mind, the CPC members developed and sponsored an online survey designed to gauge industry priorities for guidance and rulemaking activities in the realm of combination products. The results of the survey—which was conducted in December 2007 with the assistance of survey software from the Regulatory Affairs Professionals Society—are being used to develop CPC's 2008 policy agenda and offer input on policy development priorities to OCP. This article summarizes the results of the survey.

Survey Scope and Methodology

The CPC survey was designed to evaluate participating manufacturers' demographics, their satisfaction with existing combination product regulatory guidance, and their opinions as to topics on which more or better guidance is needed. Participants ranked potential regulatory guidance topics according to perceived importance and then answered questions related to the type of guidance they would like to see and why they thought such guidance was needed. Throughout the survey, respondents were encouraged to elaborate on their answers in free-form comment boxes.

The survey was distributed widely among pharmaceutical, medical device, and biologics manufacturers with the help of several trade groups and industry publications, including MX magazine. Respondents completing the online survey were allowed to remain anonymous, although they could submit optional identifying information. In order to avoid having a single company or industry segment disproportionately represented, respondents were asked to complete only one survey per organization. However, due to the anonymity provided by the survey software, companies' adherence to this request could not be confirmed. Individuals completing the survey were asked to collaborate with colleagues at their company to provide a comprehensive view of their organizations' activities.

Demographics

The first section of the CPC survey revealed the following respondent characteristics and experiences.

Primary Product Focus. The medtech sector was particularly well represented among survey respondents, with 78% of the survey's 32 participants indicating that their primary product focus was medical devices. Five of the 32 companies (16%) indicated that their primary product focus was pharmaceuticals, while only two companies (6%) said that biological products were their primary product focus.

Annual Sales. Survey respondents represented a wide range of sizes—from start-up companies to manufacturers with more than $1 billion in annual domestic combination product sales. However, the majority of respondents indicated they were either start-up companies or had less than $100 million in annual U.S. sales of combination products—which is not surprising given the relatively recent advent of combination products.

Combination Product Experience. In order to stratify responses by experience level, the survey asked respondents about their familiarity with developing and commercializing combination products. Participants were asked to rate their experience on a scale from no experience to extremely experienced. Nearly half (47%) said they had a moderate level of experience with combination products, which was defined as having commercialized, developed, or licensed and marketed at least one combination product. Slightly less than a quarter of respondents (22%) said they had low experience, and another 22% described themselves as extremely experienced. Low experience was defined as having one or more combination products in the beginning stages of development. Extremely experienced was defined as having commercialized, developed, or licensed and marketed several combination products. Only three survey participants (9%) said they had no experience at all with developing or commercializing combination products.

The survey asked respondents to indicate the stage of their most-developed combination product. The majority of respondents had at least one product in the postmarket stage. However, every stage of development was represented among respondents. Also, the survey gauged companies in regard to the total number of combination products that they had developed and brought to market. The majority of respondents had produced between zero and three products, although five companies indicated that they had more than 10 combination products on the market.

Figure 1. (click to enlarge)
Categorization of combination products produced by survey respondents, compared with categorization of all combination products reviewed by FDA's Office of Combination Products in 2006. Sources: CPC survey, OCP FY 2006 performance report to Congress.
The survey also required companies to categorize their combination products in the same way that OCP categorizes them. Respondents were allowed to select as many categories as needed (see Figure 1).1 The types of products represented in the survey were generally proportionate to the number and type of combination products that undergo FDA review.

Satisfaction with Existing Guidance

The second major section of the survey inquired about respondents' satisfaction with existing guidance sources, including both FDA and non-FDA sources, such as trade associations, consultants, and legal counsel. The latter sources were included as means of assessing the totality of existing guidance. More than half of the respondents (56%) indicated some level of dissatisfaction with existing guidance, saying they were either not satisfied or very dissatisfied. Although 12 of the 32 participants said they were somewhat satisfied with existing guidance, no company indicated that it was very satisfied with existing guidance on combination products.

All three participants who said they had no experience with combination products indicated they were dissatisfied with existing guidance. Further, only one of the six respondents at the premarket submission level of product development indicated any level of satisfaction. In addition, only one of the five pharmaceutical companies said they were satisfied with existing guidance.

On a more granular level, some respondents offered additional comments about their satisfaction with existing guidance. For example, one respondent commented on the need for additional detail in FDA guidance, noting that “part of the problem with existing guidance documents is that they are at the 40,000-foot level, and there needs to be more guidance at the 10,000-foot level.” Other respondents commented on specific areas where they were dissatisfied with existing guidance, such as device change control issues and the lack of detail on how pharmaceutical requirements apply to combination products.

Topics for FDA Guidance

In gauging the need for regulatory guidance on specific topics, the survey offered participants a list of 17 distinct regulatory topics and asked them to select the five topics on which they believe combination product guidance is needed most.

Weighted rankings were determined by assigning selected topics a point value from 1 to 5; a topic ranked first received a point value of 5, a topic ranked second received a value of 4, and so on. When weighted, the number one topic was clinical studies (see Table I). In second place was GMPs—a subject on which a draft proposed rule and a well-known written guidance document do exist.2

Weighted Rank
Regulatory Guidance Topic
1
Clinical studies
2
Good manufacturing practices (GMPs)
3
Premarket approval submissions
4
Cross-labeled combination products
5
Adverse-event reporting
6
Combination product definition; postapproval modification issues (tie)
7
Preapproval inspections
8
Preclinical research
9
Labeling
10
Primary mode of action
11
Advertising and promotional issues; request for designation (RFD) and product jurisdiction (tie)
12
User fees
13
Recall requirements
14
Postapproval inspections 
Table I. Respondents' ranking of 17 regulatory guidance topics related to combination products. Each respondent selected five topics on which they believe combination product guidance is needed most. Weighted rankings were determined by assigning selected topics a point value from 1 to 5; a topic ranked first received a point value of 5, a topic ranked second received a value of 4, and so on.

When ranked by the raw number of responses, clinical studies and GMPs switched places as the top two topics, with GMPs slightly edging out clinical studies in terms of the number of respondents ranking those subjects in their top three priorities.

All companies ranking GMPs as their top priority were self-described as moderately experienced combination product companies with less than $100 million in annual domestic combination product revenue. Nearly 80% of companies that ranked GMPs as either their first or second priority were moderately experienced.

Slightly more than a third of companies (37.5%) ranked clinical studies as one of their top-three priorities. Nearly 60% of respondents placed the topics of clinical studies or preclinical research among their top-three priorities. Research (either clinical studies or preclinical research) seemed to be important for device companies in particular. Of the participants who put a research topic among their top three priorities, only two were not device companies.

A number of additional topics were cited as being important to many survey participants. These included adverse-event reporting, cross-labeling, postapproval modifications, the definition of a combination product, and premarket submissions.

Type and Reason for Guidance

After respondents ranked their priorities for guidance topics, the survey requested additional information about the type of guidance they thought was needed on those topics, and why. Participants could select more than one type of guidance for each subject.

For all ranked guidance topics, the majority of respondents indicated that they would prefer a traditional, written guidance document as a resource. Several respondents also indicated that, in addition to a traditional guidance document, they would like to have either a question-and-answer or frequently asked questions document, documented case studies and examples, or both types of resources. Further, in some cases, respondents would also like FDA to conduct a public meeting or workshop on a particular topic. However, most respondents preferred guidance in a written format instead of guidance given orally, such as at a meeting.

The survey also asked participants to indicate why they thought guidance was needed for their top five topic priorities. Again, respondents could select as many reasons as they thought applied. The reasons from which they could choose were as follows.

  • Guidance doesn't exist but should be developed.
  • Existing guidance is inadequate (unclear, too general).
  • Existing guidance is inappropriately burdensome.
  • Existing guidance is needlessly complex.
  • Existing guidance conflicts with another.
  • Other (specify).
Figure 2. (click to enlarge)
Respondent reasons as to why guidance is needed for the top-10 regulatory guidance topics (weighted). Each topic is ranked by the percentage of affirmative responses among respondents who listed that topic as one of their top-five priorities.
Results were peppered across all choices. However, the first two choices—guidance doesn't exist or guidance is inadequate—were by far the most frequently selected reasons (see Figure 2). Overall, the results suggest that industry wants more guidance related to combination products.

Conclusion

A few key takeaway messages were evident in the results of the CPC survey. Overall, industry members would like additional guidance—and in more detail—on combination product issues. Among the survey's limited sample size of manufacturers, clinical studies and GMPs represent top priorities for combination product guidance. Several other topics were ranked as second-tier priorities. For many of these issues, FDA and OCP have issued some preliminary guidance, either written or oral.

CPC has presented the survey results to OCP so the agency can consider the data when establishing its priorities. CPC will also continue its role in generating policy ideas for the agency to consider.




References

1. “FY 2006 Performance Report to Congress for the Office of Combination Products as Required by the Medical Device User Fee and Modernization Act of 2002,” (Rockville, MD: OCP, FDA, 2007); available from Internet: www.fda.gov/oc/combination/report2006/OCP%20Performance%20FY2006%20Final%20HHS%20Clearance.pdf.

2. “Guidance for Industry and FDA: Current Good Manufacturing Practice for Combination Products, Draft Guidance,” (Rockville, MD: OCP, FDA, 2004); available from Internet: www.fda.gov/oc/combination/OCLove1dft.html.

Copyright ©2008 MX