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Articles from 1997 In June


Chartting a Course in Medical Device Clinical Trials

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Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI June 1997 Column

CLINICAL TRIALS

Pilot studies can help manufacturers not only make better devices, but also save time, money, and resources. Considerable time and financial resources are spent on clinical research programs intended to demonstrate the safety and effectiveness of medical devices. Careful planning of such programs is essential to meet the manufacturers' goals for their products. The goals of any given clinical research program can vary widely. A sponsor's objective may be to obtain FDA approval for a new Class III product using data from a single pivotal trial that incorporates all the desired indications and label claims critical to success in the marketplace. Or the goal may be to conduct a focused postmarket surveillance and device retrieval program to monitor safety and collect data for use in the design of future products. Whatever the goal, the design of an efficient and successful medical device clinical trials program will almost always involve the use of pilot studies.

MEDICAL DEVICE CLINICAL TRIALS

Medical device clinical trials fall into three categories, distinguished primarily by differences in trial size and research objectives. They are: pilot studies, pivotal trials of safety and effectiveness, and postmarketing studies. Pilot studies, sometimes called feasibility studies, are conducted when additional information is needed on a product or on trial management and logistics before a larger-scale clinical study is begun. Pilot studies are usually single-center trials involving a limited number of subjects and are designed to accomplish any number of objectives within a clinical development program.

Pivotal trials of safety and effectiveness are larger, controlled studies designed most often as hypothesis-testing studies to support the submission of a premarket approval (PMA) application for a new device, a conformity assessment for CE mark registration in Europe, or a 510(k) premarket notification when clinical data are necessary to establish substantial equivalence.

Postmarketing studies, like pilot studies, can vary in size and design, depending on the objective of the research. They can be narrow in scope when designed to gather additional information on a specific safety or performance issue. Other goals of postmarket research include performing comparative studies with alternative or competitive treatments or devices directed at providing support for pharmacoeconomic claims, comparative effectiveness claims, or failure analysis investigations.

MEDICAL DEVICE CLINICAL TRIALS: THE GOALS OF PILOT STUDIES

Pilot studies are typically carried out when there is little or no experience using the device with humans, or if specific information is needed before finishing an investigational plan to demonstrate a device's safety and effectiveness in a pivotal trial. Pilot studies, however, are appropriate at any time in the life cycle of a product when research, marketing, or design objectives cannot be met without data from additional clinical experience.

Unlike pivotal trials, pilot studies are not usually analytical trials designed to test a hypothesis (e.g., that the product performance exceeds that of a competitor). Instead, they usually focus on gathering data for use in optimizing the design of subsequent clinical research or device modifications. Some common objectives of pilot studies for medical devices are summarized below. Although these objectives are discussed separately, multiple objectives can, and should, be combined in a single trial. This can save time, money, and resources.

Preliminary Safety Evaluations. Small pilot studies are used to conduct preliminary evaluations of the safety of new products for which clinical experience is minimal or nonexistent. These are generally open-label studies (i.e., they have no control group) conducted at a single site with fewer than 25 subjects. The design of such trials incorporates measures to minimize risk to the subjects, and their initiation depends upon adequate nonclinical performance and safety testing. Preliminary safety evaluation trials usually focus on the use of the device for a single indication. However, they may include subjects with a range of demographic, risk-factor, and disease-status characteristics, the purpose being to help identify unanticipated adverse events and those characteristics of patients that are most likely to raise safety issues.

Preliminary Performance Evaluations. Preliminary performance evaluations are often paired with preliminary safety evaluations as two primary objectives of a single trial. For the purposes of clinical research studies, performance evaluations of a medical device can be assessed from three perspectives: those of the patient, the user, and the device.

Evaluating patient outcomes provides performance data that help sponsors select the best clinical outcome measure to use in a subsequent pivotal trial to demonstrate effectiveness. This also provides data on the clinical benefit of the device and an estimation of variance on this and other variables, data that are critical for calculating sample sizes in a pivotal trial.

From the perspective of a user, usually a health-care professional, the preliminary performance evaluation will include gathering data on such design features as ease of use, reliability, and control, and on the suitability of the instructions for use.

Finally, the preliminary performance of the device itself indicates how well the product meets its performance specifications in clinical use.

Validation of Outcome Measures. When outcomes are being selected for use as end points in a clinical study, whether for a pivotal trial or for postmarketing research, those outcomes must have clinical significance.1 In some cases, such as the consideration of a reduction in pain as an effectiveness end point for trials of joint replacements, the clinical significance of an outcome measure is well established. But for some devices, sponsors will develop label claims that reflect new or special features of the product. If these an-ticipated claims are critical to establishing the effectiveness of the device, the clinical significance of outcomes and claims must be established, a process that can sometimes be achieved in pilot medical device clinical trials.

For example, consider an injectable product used to treat urinary incontinence. The definition of effectiveness for this product will not hinge on the statistical difference between the subject's condition before and after treatment, or even on a comparison of the subject treated with the new product versus the currently available alternative treatment. Rather, the determination of effectiveness hinges on the clinical significance of the outcome achieved. Is a 25% reduction in the occurrence of urinary incontinence clinically significant? A pilot study can address and justify the subsequent articulation of effectiveness criteria for use in a pivotal medical device clinical trial. Establishing the clinical significance of an outcome measure is a key issue in the design of a pivotal trial, not only because it leads to the definition of effectiveness and the trial success criteria, but also because it will influence the sample size, study rationale, and choice of a control group.

Validation of Methods for Measuring Outcomes. Distinct from selecting and validating the clinical significance of an outcome is the process of developing a method to reliably measure it. For many clinical outcomes, this does not pose a problem because validated measuring instruments are available for obvious end points, such as a reduction in cholesterol levels. Much more difficult is the reliable assessment of subjective end points, such as cosmetic outcomes, pain, and quality of life. Some end points have not yet been the subject of a controlled study in a clinical setting, making it necessary for sponsors to develop new or improved methods to assess outcome. Such methodologies can be validated in pilot studies.

MEDICAL DEVICE CLINICAL TRIALS: REGULATORY GUIDANCE

There is little formal guidance from FDA on the need for pilot studies, or on methods for their use in medical device clinical trials. However, FDA's Center for Devices and Radiological Health provides some information on the need for such preliminary research in a clinical trial guidance document and a related blue book memorandum.2,3 Although some question the advisability of leading medical device clinical trials into a multiple-phase research program comparable to that for drugs, it is clear that FDA is not advising manufacturers to do so. Certainly the enhanced rigor required by FDA in the design and conduct of pivotal clinical research can require the judicious use of pilot studies, but such studies are not a criterion for approval. Medical devices requiring premarket approval are still subject to only one well-controlled trial to demonstrate safety and effectiveness, whereas for drugs at least two such trials are required.4

MEDICAL DEVICE CLINICAL TRIALS: CONCLUSION

Medical device clinical trials are ultimately designed to gather data to meet FDA product approval requirements and specific marketing objectives. It should also be apparent that valid and credible clinical research can only help in the design of new products to improve health and patient care. The use of pilot studies to clarify the most appropriate indications for use, to identify and validate primary end points, to help choose a control group, to provide data for sample-size calculations, and to define success criteria is becoming an increasingly valuable and requisite step in clinical development programs for Class III products.

REFERENCES

1. "Clinical Utility and Premarket Approval, PMA Memorandum #P91-1," Rockville, MD, FDA, Center for Devices and Radiological Health (CDRH), Office of Device Evaluation, 1991.

2. "Clinical Trial Guidance for Nondiagnostic Medical Devices," Rockville, MD, FDA, CDRH, Division of Biostatistics, 1995.

3. "Guidance on the Review of Investigational Device Exemption Applications for Feasibility Studies," Memorandum #D89-1, Rockville, MD, FDA, CDRH, May 1989.

4. "Statement Regarding the Demonstration of Effectiveness of Human Drug Products and Devices," Federal Register, 60 FR:39180­ 39181.

Karen Becker Witkin is a principal with the Weinberg Group, Inc. (Washington, DC, and Brussels), and manages the firm's worldwide health-care practice. She has written a section of and edited the forthcoming book titled Clinical Studies of Medical Devices: Principles and Case Studies.


Copyright ©1997 Medical Device & Diagnostic Industry

Dispensable Paste Solder Helps Refine a Sticky Procedure

CASEBOOK 2

Dispensable Paste Solder Helps Refine a Sticky Procedure

Increases throughput and eliminates operator error

When a medical equipment refurbisher wanted to improve its procedures and increase productivity, the company decided to first examine its soldering process. Soldering is integral to the work being done at Servicetrends Inc., located in Marietta, GA. The company specializes in refurbishing the electrodes used in lithotriptors, machines that pulverize kidney stones with sound waves.

The electrode's conical upper tip serves as the hub of a "cage" of six insulated copper wires. After the tip has been removed and reground, the ends of the wires must be resoldered into six holes (1.35 mm wide X 12.7 mm deep) in the brass outer conductor.

Soldering the fine wires was a time-consuming operation entrusted to only a few highly skilled workers. Irons were used to force wire solder down inside the small blind holes. The process involved much reworking since excess solder had to be removed and melted, or discolored insulation had to be trimmed away. Electrode department manager Earnest Pringle was certain that if he could find a way to put an identical amount of solder in each hole, the process could be made faster and less operator-dependent, thereby improving productivity.

Pringle contacted EFD Inc. (East Providence, RI) and described his objectives. EFD's product specialists recommended SolderPlus, a paste solder developed as an alternative to flux-core wire. Prepackaged in 10- and 30-cm3 barrels, the material is specially formulated for use with automatic dispensing equipment. Unlike wire solder, SolderPlus can be placed at the bottom of small holes and other areas that are difficult to reach. In addition, using the dispenser's precisely timed air pulse to determine the amount of material applied ensures consistent deposits and makes it easy to cross train any operator on the soldering operation.

Replacing flux-core wire with SolderPlus enabled Servicetrends to make a time-consuming soldering operation faster and less operator-dependent. With the company's previous method, wires had to be soldered one at a time. Now, a dispenser is used to place an identical amount of SolderPlus into each of the holes in advance. A microtorch is used to reflow all six deposits at once. Throughput has increased, and the rework required due to overapplication or scorched insulation has been eliminated.

"Our new method is both quicker and more reliable," Pringle says. "The more consistent deposit size results in a better-looking assembly. We also have greater peace of mind knowing that we now have several cross-trained employees who can perform what used to be an operator-dependent procedure."

For more information contact EFD Inc. at 401/434-1680.

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Products featured on the cover

Products featured on the cover

June 1997

Light-curable adhesive meets Class VI requirements

A UV/visible-light-curable adhesive cures in seconds when bonding flexible PVC and polycarbonate substrates in such medical devices as tubing connections, catheters, and oxygen mask assemblies. Tough, flexible Eccobond UV 9115 features a low viscosity, making the adhesive suitable for applications requiring flow around tight-fitting components or cure through UV-stabilized plastic substrates. It withstands gamma sterilization and complies with USP Class VI requirements. Grace Specialty Polymers, 55 Hayden Ave., Lexington, MA 02173. (800/832-4929)

Package tester verifies seal strength and creep resistance

An automated package tester features a new, simplified pneumatic fixure for testing burst seal strength and creep resistance of open-ended pouches. The fixture seals the test probe into porous and nonporous bags, pouches, and header bags for fast, accurate measurements. The BT-1000 package tester provides automatic control of the test cycle and shows a graphic plot of the resulting pressure curve. SQC data are shown on a liquid crystal display and can be printed or downloaded via RS-232 ports. T.M. Electronics Inc., 330 Tacoma St., Worcester, MA 01605. (508/856-0500)

Flexible films and compounds for disposable devices

PVC films and compounds and EVA films are available for such disposable medical devices as blood storage and processing units; drug-delivery and solution systems; and enteral feeding, urological, and drainage bags. Extrusion and injection molding grades are also offered. Products include formulations developed for EtO, steam, and gamma sterilization; compounds are available with DEHP, TOTM, Citrate, and other plasticizers. Ellay Inc., 6900 Elm St., Commerce, CA 90040. (213/725-0050)

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Lubricious Coating Developed for Stainless-Steel Medical Devices

Surface Treatment

Lubricious Coating Developed for Stainless-Steel Medical Devices

Becomes ultraslippery upon contact with body fluids

Easy and safe manipulation of invasive stainless-steel guidewires and other metalbased medical devices is possible with an improved lubricious coating. Developed by STS Biopolymers Inc. (Henrietta, NY), Slip-Coat is thin and flexible and adheres to both wet and dry metal substrates. It is also permanent and nonthrombogenic and has a smooth, nonslip feel when dry. Immediately upon contact with bodily fluids or water, the coating becomes ultraslippery, reducing friction and increasing a physician's ability to control the guidewire during insertion.

Through the use of the Slip-Coat formula, biocompatibility can be achieved at a low cost without changing the materials from which the devices are made. According to STS, earlier formulations have been used successfully on various polymeric, titanium, and nitinol medical devices, including both vascular and urinary catheters, urinary stents, and guidewires. Therefore, the formula is suitable for use in cardiology, radiology, neuroradiology, and urology procedures.

STS specializes in the development, manufacture, and application of medical device surface treatments. Its products include lubricious, antithrombogenic (various heparin complexes), antimicrobial/antibiotic, and nonconductive biocompatible coatings. The coatings can be formulated for short-, intermediate, or long-term effects. Coating services include plasma pretreating, coating application, and development of custom coating technologies. Related services include packaging and sterilization (EtO and steam) and such testing services as biocompatibility, ISO, USP, bioburden, sterility, residuals, shelf life, and package integrity.

For more information, contact STS Biopolymers Inc. at 716/321-1130.


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Inspection

Luminescence Detector Reads Invisible UV Markings

Can be used to confirm bonds in medical assemblies

BALLUFF INC. (Florence, KY) has developed a luminescence detector that reads invisible UV markings on various materials to verify critical processes, provide presence and position sensing, enhance quality control, and perform part counting and product ID. The detector is well suited for maintaining quality control of critical operations such as confirming bonds in medical IV and catheter assemblies. Mixed into adhesives, solvents, and sealants, the invisible UV markers confirm that items have been correctly coated and joined. The device can also be used to inspect packaging lines.

The detector provides high reliability and process control with black or dark objects that do not reflect as well as materials with high reflectivity--such as mirrors, glass, and chromium plating--which present problems for other optical sensors. The unit emits UV light on a 350-nm wavelength. The UV light is converted to visible light upon striking a luminescent object or mark. The reflection is then detected by the unit's receiver through a special filter that sees only visible light in the 450 to 700-nm range, making the detector totally insensitive to other light sources.

The detector can be configured for operating distances from 5 to 80 mm and spot diameters from 3 to 25 mm. A red LED indicates signal output, and DIP switches allow selection between three output logic functions--normal, memory, or one-shot output. Use on high-speed production lines is permitted by a response time of one millisecond and 500-Hz switching frequency. The units operate on 10- to 30-V-dc supply voltage. Average lamp life is 8000 hours, and lamps can be replaced with the unit on-line.

For more information, contact Balluff Inc. at 606/727-2200.

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Sterilization

E-Beam Sterilization System Designed for In-House Use

Can be integrated directly into manufacturing process

TITAN SCAN SYSTEMS (San Diego) has developed an E-beam sterilization system that enables medical device manufacturers to benefit from on-site processing of their products.

Designed for in-line or end-of-line sterilization, the SureBeam system can be integrated directly into the device manufacturing process. Unlike other sterilization technologies that use gamma or EtO, the E-beam technology eliminates the handling, transportation, and storage of radioactive isotopes and materials.

In-house sterilization can eliminate costs associated with handling, inventory, labor, and transportation to and from off-site sterilization ontractors. In-house sterilization also supports just-in-time manufacturing and other supply-management goals.

The SureBeam can sterilize individual devices at high volumes or process bulk products in their final packing cartons. Small enough to fit into existing production facilities, the system can also be relocated to support changing production needs.

The SureBeam requires less than 600 sq ft of space and is delivered fully operational. Titan provides total support for its use, including installation, regulatory validation, operational procedures, and ongoing service. Preengineered modules in the system include an E-beam accelerator, material-handling equipment, a self-contained shielding and safety system, and a SureTrack control system.

For more information, contact Titan Scan Systems at 800/438-1423.

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Industry News

Industry News

Hundreds of Products and Services
Displayed at MD&M Orlando

Held March 15-17, 1997

The second MD&M Orlando Conference and Exposition, held recently in Orlando, FL, gave area device manufacturers a chance to see a variety of materials, components, equipment, and services available to the industry.

Among the more than 150 companies exhibiting was Miltronics Inc. (Painesville, OH), a contract manufacturer specializing in precision machining custom devices for medical OEMs that design and market implants, instruments, and disposables. Among the services provided are multiaxis machining, micromachining, CNC milling and turning, EDM, grinding and honing, laser marking, electropolishing, passivating, finishing, and inspection. Virtually all materials can be machined, including stainless steels, Monel, Hastelloy, titanium, Inconel, aluminum, and exotic alloys. Tolerances to 0.0001 in. can be provided. For more information, contact Miltronics at 800/942-3011.

One of the many new products introduced at the show was Solid Edge Version 3, a Windows-based mechanical-assembly design and drafting software product from Intergraph Software Solutions (Huntsville, AL). The software provides ease-of-use and productivity for mechanical design engineers. Its latest version features advances in assembly design and feature-based modeling to broaden the range of parts design. Version 3 also adds a stand-alone 2-D drafting package to the Solid Edge family, as well as Web-ready technology and development tools that enhance the product development process. The software now combines the advantages of high-performance 3-D solid modeling with production-ready 2-D drafting capabilities. For more information, contact Intergraph at 800/807-2200 or visit the company's Web site at http://www.intergraph.com/solidedge.

Logicon Inc. (Colorado Springs, CO) provided attendees with a description of the training workshops and consulting services it offers. The company offers scientific, managerial, quality, regulatory affairs, information management, and engineering consulting services that can be applied at all levels throughout an organization.

Its workshops and services can be customized for on-site delivery. Some of the workshops offered include Introduction to Design of Experiments, Product Reliability, Design Control, Software Verification and Validation, and New Quality System Regulations (GMP) for Medical Devices. For more information, contact Logicon Inc. at 800/732-0037.

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3D Systems Opens Colorado Facility

$5-million facility operating in Grand Junction

3D Systems Corp. (Valencia, CA) recently opened a $5-million manufacturing facility in Grand Junction, CO. "Opening this new facility marks an important step forward in our plans to meet anticipated demand for our products," said Charles W. Hull, the company's president.

The first machine to ship from the facility is an SLA-250 Series 50, one of the latest variants in 3D's product line of rapid prototyping equipment. A number of advanced SLA-350s and larger SLA-500s are in final testing and being prepared for shipment to customers. In addition to manufacturing, the company relocated a number of departments to Grand Junction, including quality assurance, manufacturing engineering, and customer service. Corporate headquarters remain in Valencia, CA.

The 66,000-sq-ft manufacturing site represents the first phase of a planned expansion that could eventually total 188,000 sq ft. Site preparation and the building shell plan have already been completed for the next phase of construction.

For more information, contact 3D Systems at 805/295-5600 or visit the company's Web site at http:// www.3d.com.

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Parts Competition Won by Pressure-Formed X-Ray Unit Covers

Award presented by Society of Plastics Engineers

Profile Plastics Corp.'s (Lake Bluff, IL) pressure-formed x-ray unit covers have won the Society of Plastics Engineers Thermoformed Heavy Gauge Parts Competition. The competition was held in Ft. Mitchell, KY. The pressure-formed covers are part of an x-ray unit that Profile Plastics redesigned for GE Medical Systems. The new cover design was developed because the original structural-foam covers were expensive, heavy, and cumbersome for operators to handle.

The award recognizes OEM components using the thermoforming process. Entries in this national competition are evaluated on the basis of design, uniqueness, aesthetics, and degree of manufacturing complexity.

Profile Plastics specializes in custom-molded, highly engineered plastic parts manufactured through the thermoforming processes of pressure, vacuum, and twin-sheet forming. For more information, contact Profile Plastics Corp. at 847/604-5100.

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Perfecseal Expands Operations in Puerto Rico

New facility to make thermoformed trays

Philadelphia-based Perfecseal is expanding its thermoformed-tray manufacturing capabilities to its facility in Carolina, Puerto Rico. Under the guidance of Perfecseal Mankato (formerly Mankato Corp.; Mankato, MN), the thermoforming machinery and technology will be located in a new facility adjacent to the existing plant.

According to Alan McClure, president and CEO of Perfecseal, and John Rottunda, president of Perfecseal Mankato, this expansion will enable Perfecseal Puerto Rico to offer its customers there and in parts of South America a complete medical packaging product line of trays, lids, pouches, labels, and rollstock.

Perfecseal Mankato will continue to be responsible for product development and tooling for new thermoformed packaging. Perfecseal is a division of the Curwood Group, a wholly owned subsidiary of the Bemis Company, Inc., and is one of the largest manufacturers and marketers of packaging materials for the health-care industry, with additional facilities in North America, Northern Ireland, and the Asia-Pacific region. For more information, contact Perfecseal at 800/999-7626.

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Griffith Micro Science Announces New Division

Will offer analytical and laboratory services

Griffith Micro Science International Inc. (GMS; Oak Brook, IL) has created a new division, Griffith Analytical, to take on all GMS analytical and laboratory services. Certified to ISO 9001 and EN 45001, the new division represents a significant expansion of GMS's worldwide capabilities.

Locations in the United States, United Kingdom, Belgium, France, and the Netherlands provide a variety of services including product and package design, technical and regulatory review, system cost-reduction studies, GMP/ISO auditing, bioburden programs, validation-related testing, and environmental monitoring. For more information, contact Griffith Analytical at 630/472-4511.

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Nd:YAG Laser Systems

Products featured at MD&M, Orlando

Held March 15-17, 1997

Nd:YAG Laser Systems

Pulsed Nd:YAG lasers and beam-delivery systems are available for cutting, welding, drilling, and micromachining surgical instruments, battery casings, and related components. The four-axis ProLas systems are compact workstations designed for prototype and midsize production runs. They come equipped with an SLS laser that is available in the range of 10, 20, or 100 W with up to three fibers for welding parts of various shapes and configurations. A PC controls the operating parameters of the laser and the four-axis motion system. Lasag Corp. (847/593-3021)



Motion-Control Devices

A company specializes in stepping-motor drives and systems. Products include miniature full- and half-step bipolar drives from 2 to 9 A at 12 to 80 V dc, microstepping drives from 1 to 7 A RMS at 12 to 80 V dc and complete microstepping systems with integrated power supplies. Encoders, stepping motors (size 17 to 42), power supplies, handheld terminals, software, and accessories are also available. The firm can provide technical assistance, even with the most complex applications. Intelligent Motion Systems Inc. (860/295-6102)



Machining Services

A contract manufacturer uses laser and water-jet equipment to cut, drill, weld, mark, and heat-treat custom components. Facilities house 12 laser systems and 16 CNC water-jet stations, all governed by sophisticated process controls. A wide range of materials can be processed, including titanium, stainless steel, plastics, stone, and composites. The company can maintain high precision and quality while minimizing cost. LAI Laser Applications Inc. (410/857-0770)



Optical Measuring System

Suitable for inspecting electronic, plastic, and metal working parts, an optical measuring system features a programmable ring illuminator. The SmartRing's multiple-ring design gives the user complete control of illumination direction and incidence angle, useful for imaging surface details. The working distance remains a constant 4 in., and no mechanical motion of the illuminator is necessary to vary the incidence angle. The improved SmartScope measuring system also features the new AccuCentric zoom lens that provides larger working clearance, sharper images, and better illumination. A digital color camera with a third-generation DSP chip set is included. The system is available with a Windows-based software package, offering 24 Mbyte of memory. Optical Gaging Products Inc. (716/544-0400)



Specialty Compounds

Suitable for manufacturing a variety of medical devices, specialty compounds have been formulated to meet extrusion or molding requirements for flexible, semirigid, and rigid applications. Materials are engineered to achieve features such as gel-free clarity, color stability after sterilization, radiopacity, migration resistance, and slipperiness with DEHP, phthalate-free, and halogen-free alternatives. Recent product introductions include a line of compounds that use vegetable-derived stabilizers and lubricants rather than bovine derivatives for increased clarity and gamma stability. AlphaGary Corp. (800/221-6599)

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For more information on engineering resins from Dow Plastics, call 800/441-4369.

PROFILE

Engineering Plastics Help
Bypass Design Troubles

Minimally invasive surgical procedures are popular with physicians, patients, and insurance providers alike, since they all reap the benefits of decreased tissue trauma, lower infection risk, and shorter hospital stays. Device manufacturers, encouraged by the success of existing less-invasive techniques, are eager to expand the applications of these technologies. Some suppliers, in fact, are even researching ways to use less-invasive therapies to support critical procedures that still require full surgical intervention.

One such manufacturer, Ethicon Endo-Surgery Inc. (Cincinnati), recently began investigating how to apply less-invasive techniques to coronary-artery bypass surgery, focusing not on the actual bypass but on the removal from the patient's leg of the great saphenous vein, which is commonly used to reroute blood from the aorta to the coronary artery. In conventional procedures, the vein is removed through an open incision, which sometimes extends from the ankle to the groin. The result is a long scar, often accompanied by prolonged pain and a worrisome risk of infection. With roughly half a million such procedures being performed every year, the market seemed ready for a safer and gentler alternative.


Dissecting the Problem

Ethicon engineers set out to develop a new technique and disposable instrument to remove the saphenous vein endoscopically. The procedure would involve from one to four 1-in. incisions in the leg, through which endoscopic instruments and fiber-optic scopes could be inserted to locate, dissect, and extract the healthy vein. "We had various ergonomic issues to keep in mind when considering the structure of the instruments," says Gary Knight, Ethicon senior design engineer. For example, the procedure would require the simultaneous use of several components, which therefore had to be relatively simple to manipulate. The instruments also had to be long and thin enough to fit through the small incisions, but strong enough to withstand the force applied by the surgeon. In addition, all components had to be smooth, with no sharp edges that could damage the vein. Obviously, such a demanding design placed severe restrictions on the types of materials that could be used. Performance and reliability would be critical, although cost had to be considered too. Knight also wanted materials that would accommodate future refinements to the device design.

Faced with a difficult task of materials selection, Knight turned to Dow Plastics (Midland, MI) for some professional advice. "We had plastics in mind from the outset of this project," says Knight. "And because Dow Plastics is part of our Supplier Alliance program, we felt confident turning to representatives from Dow for their materials expertise and technical guidance." Discussions focused on how Ethicon could incorporate standard engineering plastics into products that must compete in a high-end, value-driven business. "Ethicon presented the design ideas and goals for each component, and from there we were able to discuss materials options," says Karen Winkler, senior applications development engineer for Dow Plastics.

The Heart of the Device

The team began with what Ethicon calls the Subcu-Dissector and Subcu-Retractor, ancillary instruments inserted through incisions in the leg to create and maintain operative space in the subcutaneous tissue. Knight was particularly concerned with the instruments' operating tips and manipulating handles. To be effective, the handles had to be strong and comfortable to hold while accommodating a variety of optical scopes, which would be inserted through them. "The internal portion of the handles contained a good deal of intricate structural ribbing," says Winkler; they therefore required a strong, easily molded material.

Winkler suggested Calibre polycarbonate resins with a glass filler, citing the materials' rigidity, strength, and good flow characteristics. Calibre MegaRad polycarbonate resins were evaluated for use in the transparent, spoonlike tips because of their strength, their resistance to gamma sterilization, and, most important, their good optical properties, which would allow the surgeon to see the position of the vein clearly at all times. Winkler also recommended Pellethane polyurethane elastomers for the scope-holding clip inside each of the handles "because they provide the flexibility necessary to hold the different scopes in place throughout the procedure."

Having specified the materials for the enabling instruments, the team turned its attention to the primary device, the Vessel Dissector, which dissects the saphenous vein from connective tissues. Because of the component's 20-in. length, initial discussions involved a design made from both metal and plastic. "Many complicated issues arose as a result of the initial design," says Knight. "How would the instrument be assembled? How would it be disposed?"

Understanding these concerns, Dow representatives suggested using glass-filled Isoplast thermoplastic polyurethanes. Isoplast resins combine the toughness and dimensional stability of amorphous resins with the high performance and chemical resistance normally associated with semicrystalline resins. According to Winkler, the metal-like stiffness of these resins yielded a dimensionally tolerant and accurate device, while good melt-flow characteristics allowed the material to fill the long, one-piece mold easily and evenly. "Isoplast resins offered Ethicon the chance to change the design to a one-piece instrument, eliminating assembly concerns," adds Winkler.

The final component in Ethicon's device--the Allport Clip Applier--would perform the delicate task of clipping the branches of the saphenous vein to permit its removal. The unit releases spring-loaded titanium clips that remain in place permanently. The handle is similar in design to the handles of the Subcu-Retractor and Subcu-Dissector, and contains intricate internal ribbing; therefore, Calibre resins were an obvious choice for this handle as well. The rotation knob, which is attached to the handle, was also made with Calibre polycarbonate.

A Leg Up on the Competition

Only 18 months elapsed from the initial meeting about the procedure and instruments to product commercialization. "Timing was definitely an important factor for us," remembers Knight. "We wanted to get the initial designs into the marketplace quickly so we could get feedback from the surgeons and optimize the instruments as they were actually being used. Disposability was another key element," he continues. "Because the procedure is so new, we will most likely be making improvements to the instruments over the next several years. We can make those changes much more easily and cost-effectively with a disposable plastic design. In fact, we determined that a reusable metal design would cost up to 10 times more to produce and maintain."

Knight adds that surgeons feel confident using the plastic instruments thanks to their light weight and reliability under limited use. In fact, Ethicon hopes that within a few years, the endoscopic procedure will replace the traditional vein-harvesting method altogether.

Knight attributes the success of the instruments to the effective teamwork between Ethicon and Dow Plastics. "Dow representatives were with us from the start," he says, "discussing materials and providing the support we needed to develop and introduce the innovative components into the market quickly and competitively. This project is a direct result of the valuable professional relationship we share."

For more information on engineering resins from Dow Plastics, call 800/441-4369.

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Custom IV assemblies

Spotlight on IV Components Custom IV assemblies

A company designs and manufactures custom bag assemblies, IV assemblies, and precision injection-molded components to exact specifications. It uses the latest materials and technologies and emphasizes a team concept of manufacturing from initial design to the finished product. Also available is a sterilizable medical film with good barrier properties and no leaching plasticizers. Advanced Scientifics, 163 Research Ln., Millersburg, PA 17061. (717/692-2104)



Disposable needleless valves

Needleless valves limit the risk of infection to health-care providers by replacing the hypodermic needle ports. A company's needleless line consists of a variety of low-priming-volume disposable parts including slip luer valves, Y ports, T ports, 1/4-in. tubing valves, and ANSI standard valves. These components are available in a variety of gamma-, EtO-, or autoclave-sterilizable materials. Halkey-Roberts Corp., 11600 9th St. N., St. Petersburg, FL 33716. (800/303-4384)



Luer-activated valves

Designed for needleless access systems where fluid delivery is vital, luer-activated valves feature an enhanced design that is compatible with most drugs, including lipids, and provides for the safe inspiration, aspiration, and complete flushing of blood and other viscous fluids. The LAV+ valves feature a preloaded nonlatex diaphragm that checks flow until mechanically opened with a luer. This provides dependable fluid-flow control to protect both patient and clinician. The valves are composed of an elastomeric diaphragm and a sonically bonded thermoplastic body that is pressure tested to 45 psig. Materials meet USP Class VI requirements and can be gamma or EtO sterilized. NP Medical Inc., 101 Union St., Clinton, MA 01510. (508/365-2500)



Latex-free injection sites

With good reseal, a family of latex-free injection-site components offers all the properties of natural rubber without the contaminants, thereby eliminating the possibility of natural rubber latex sensitivity reactions. Components include Y injection sites, T connectors, and sampling ports. Made of 100% synthetic polyisoprene and available in a standard gold color, they are sterilizable by EtO or gamma irradiation. Harmac Medical Products Inc., 2201 Bailey Ave., Buffalo, NY 14211. (716/897-4500)



IV components and tubing

A company offers a variety of IV components including injection sites, spikes, chambers, clamps, and connectors. A spike-and-chamber assembly with ball check valve protects the line if the setup is tilted. Pinch, slide, and roller clamps are available for flow control applications. The company also carries tubing in more than 100 stock sizes as well as various other components. Samples and a catalog are available. Qosina, 150-Q Executive Dr., Edgewood, NY 11717. (516/242-3000)



Custom IV components

A manufacturer of disposable medical devices offers a variety of IV components. Its product line includes male and female luer adapters, stopcocks, check valves, single- and dual-flow piercing devices, barbed connectors, clamps, caps, Y fittings, T fittings, and tri-connectors. Custom designs are available. Burron OEM Div., B. Braun Medical Inc., 824 Twelfth Ave., P.O. Box 4027, Bethlehem, PA 18018. (800/359-2439)



Fluid-system connectors

Quick-disconnect couplings for use in low-pressure fluid-management systems are available in a wide range of sizes and styles. Connectors from more than 20 product families find applications in devices and systems for vascular compression, body-temperature control, noninvasive blood pressure monitoring, thoracic surgery drainage, laparoscopy irrigation and insufflation, blood assays, stomach pumping, urine collection, autotransfusion, vital-signs monitoring, and cardiopulmonary procedures. Products are manufactured in controlled environments with specialized protocols for material handling, packaging, and assembly. Custom designs are a specialty. The company is ISO 9001 certified. Colder Products Co., 1001 Westgate Dr., St. Paul, MN 55114. (800/492-0091)



IV components

Standard sleeve stoppers, flashback bulbs, and metal seals for IV systems are available for a variety of needs and can be provided quickly and in large volumes. The manufacturer frequently provides custom designs that meet the requirements of various infusion dispensing systems. Analytical support is offered for unique formulation requirements including evaluation of coatings and laminates. Latex-free formulations are available. The West Co., 101 Gordon Dr., Lionville, PA 10341. (800/231-3000)



One-way check valve

A one-way, normally closed, minimal-cracking-pressure check valve uses a patented sealing mechanism that eliminates backflow without sacrificing forward-flow performance. Drug use is maximized through a unique internal housing design that allows for complete solution recovery. The valve is available with male/male and male/female connections for compatibility with all IV products using ANSI standard connectors. Composed of medical-grade materials, the valve can be gamma or EtO sterilized. Filtertek Inc., P.O. Box 310, Hebron, IL 60034. (815/648-2461)



Large-bore shielded connectors

Large-bore tubing connectors are joined together by a luer-type tapered fit to provide secure, leak-free connections. A protective sleeve around the tapered sealing surface eliminates the risk of touch contamination. The connectors protect health-care personnel from exposure to bodily fluids and also protect the patient by guarding the system's sterility during disconnects. Made of clear, medical-grade acrylic, the connectors can be gamma or EtO sterilized. Resenex Corp., 9614-F Cozycroft Ave., Chatsworth, CA 91311. (818/882-7518)



Rubber components

A supplier of molded rubber components offers a product line that includes stock and custom-designed components. Latex-free and silicone-free compounds are available. Latex-free formulations have been used to produce injection sites and septa that do not produce protein reactions in patients. Other developments include halobutyl stoppers that require minimum amounts of silicone, yet are extremely low in extractables. Tompkins Rubber Co., P.O. Box 160, 550 Township Line Rd., Blue Bell, PA 19422. (610/825-3400)

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Surface Modification Improves Performance of Microcatheter

CASEBOOK 1

Surface Modification Improves Performance of Microcatheter

Helps reduce friction caused by tortuosity of brain vessels

When Target Therapeutics (Fremont, CA) introduced its Tracker microcatheter, which permits examination of the distal portions of the brain, the new product was quickly accepted by radiologists. The next step for the manufacturer was to improve the microcatheter using a coating that would reduce the friction created by the tortuosity of the brain vessels. Such a coating--with high lubricity and tenacity--could provide enhancements such as more accurate placement of the catheter, greater insertion speed, increased patient comfort, and expanded access.

That goal was realized when BSI Corp. (Eden Prairie, MN) used its PhotoLink technology to specially tailor a surface modification for Target's catheter. Trademarked Hydrolene, the surface technology allowed for a 2-µm-thick chemically bonded hydrophilic polymer to coat the FasTracker catheter. Application of the low-friction coating is a two-step process, requiring coating of the exterior surface of the catheter with preformed polymers which are then activated with UV light.


Tests show that the Hydrolene coating reduced push/pull force within a guiding catheter by more than 50%. And after 20 pulls through the guide, the FasTracker maintained its lubricious characteristics. This improved adherence is produced by the covalent bond inherent in the PhotoLink technology. In addition, studies show that platelet aggregation and creation of clots through adherence of blood components to the surface of a catheter coated with Hydrolene is less than with an uncoated catheter or a catheter coated by other methods.

Robert Hergenrother, manager of applied research at Target, helped develop the FasTracker and was instrumental in specifying BSI's coating. "Their coating was fairly easy to apply," he says. "The chemistry was relatively benign, soluble in water and alcohol rather than some other solvents. And it worked without much modification to our base product."

BSI's technology also helped reduce Target's manufacturing costs. The silicone-based coating previously used required batch processing. Hydrolene, on the other hand, permits nearly continuous product manufacturing, allowing faster turnover and shorter cycle times. Replacing batch manufacturing with a continuous-stream processing system helped lower Target's production costs.

Target reports that physicians are enthusiastic about the performance of the Hydrolene-coated microcatheter. Target's original goals--more accurate placement of the catheter, greater speed, better patient comfort, and the ability to reach previously inaccessible areas of the brain--were all met.

"We needed Hydrolene in order to stay competitive," says Hergenrother. "It allowed us to improve our product line and to protect our market share. In addition, this technology has probably allowed us to think more aggressively about modifications and optimization of our devices."

For more information contact BSI Corp. at 510/440-7700.

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REGULATORY REFORM

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI June 1997 Column

EDITOR'S PAGE

Cooperation between industry and government will be the key to meaningful transformation of the regulatory process.

Sitting in the audience at the annual meeting of the Medical Device Manufacturers Association in Washington, DC, last month, I experienced a sensation not usually associated with such events. I felt, somehow, excited.

This is not to say that this meeting was dramatically better or more dynamic than others I've attended. What I felt, rather, was a growing sense, after each speaker had finished, that this year may well prove to be an epochal one for the U.S. medical device industry.

To judge from what I heard, there is a growing consensus for change among both industry and government. Whether significant legislation will pass this year is still uncertain, but surely at no time since 1976 has there been greater interest on both sides in redrawing the way medical devices are regulated.

Unlike the ill-considered medical device amendments of 1990, the bills that are now taking shape in Congress are largely the product of negotiation and consultation among industry, FDA, and legislators. The result should be a streamlined regulatory process that will protect public health while speeding the introduction of new products.

Even without a new law, the kinds of changes in both procedures and attitudes already under way at FDA are substantial. As device center director Bruce Burlington acknowledged at the meeting, there is a limit to how much change he can introduce without new legislation. But combined with the changes that have already been instituted--such as preannounced inspections and real-time product reviews--the center's reengineering initiatives will constitute a memorable watershed in themselves.

Cynical onlookers might argue that the true intent of FDA in introducing these changes is to avoid meaningful, and permanent, legislative reform. But the evidence is strong that attitudes at the agency are truly changing. I was particularly struck at the meeting by the frankness of FDA deputy commissioner William Schultz in acknowledging "how out of touch" with industry the agency has been until recently. Citing several examples of how the agency had misinterpreted or
ignored industry, Schultz seemed to be at pains to emphasize that FDA is now listening much more closely and responsively to industry.

For its part, industry has shown itself to be an active partner in the conversation. The grassroots regional meetings that resulted in many of the positive changes Schultz discussed are continuing this summer with three new industry-FDA committees addressing ways to improve internal agency communications, the product approval process, and warning letters.

Such cooperation will be the key to meaningful transformation of the regulatory process. Although this kind of relationship between industry and government seems perfectly natural now, just five years ago it was almost unimaginable. Looking back to an editorial on this topic I wrote in May 1992, I found the following conclusion: "Few would disagree that the relationship as it is now structured is disastrous. For both industry and government, forging a new and productive relationship will be the challenge of the decade."

The developing consensus for regulatory reform may yet break down. But if present trends continue, it seems likely that this challenge will be met.

John Bethune

[email protected]


Copyright ©1997 Medical Device & Diagnostic Industry