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FDA Alert on Angioplasty, Stent Experiments

The agency alert says FDA has learned of death, stroke, detachment, and migration of the stents, damage to the treated vein, blood clots, cranial nerve damage, and abdominal bleeding associated with the experimental procedure. Balloon angioplasty devices and stents are not approved by FDA for treating cerebrospinal venous insufficiency, it says.

FDA says it also is reminding doctors or clinical investigators planning or conducting clinical trials using medical devices to treat cerebrospinal venous insufficiency that they must comply with agency regulations for investigational devices. A February Warning Letter was sent to a sponsor/investigator who was conducting a clinical study of such treatment without the necessary approval, the alert says. The sponsor/investigator reportedly voluntarily closed the study.

Device Exec Indicted Over Adulterated Surgical Pencil

A news release says that Zinnanti was president and owner of Zinnanti Surgical Design from 2005–2007. The company, which its Web site says he co-founded, manufactured the Bayonet Electro-Surgical Pencil that was sold primarily to hospitals and used by surgeons to cut and cauterize tissue surrounding a patient’s thoracic vertebrae to allow access to the thoracic back space during back surgery.

The devices were adulterated, the criminal information says, due to current good manufacturing practice violations. The government says that Zinnanti acted with the intent to defraud and mislead FDA about the manufacturing procedures he had in place.

He faces a prison term of up to three years and a fine of $250,000. FDA’s Office of Chief Counsel assisted in the investigation.

Obesity Devices Target of FDA ‘Patients’ Feelings’ Survey

Another potential question to panels and others is, she said, “If we decide that patients don’t value benefits which we think are important, how will we use that information?” Irony noted that sometimes the agency learns that its reviewers like to avoid risk, but they forget about the risk of not approving something that could benefit some patients.

The study, to be done in conjunction with RTI International, was announced for public comment in the Federal Register on April 19. It will recruit 450 people to constitute a national cross section of well-informed subjects and ask them what risk they would tolerate for the benefits of obesity-reducing devices. The survey will include 100–150 people who have already undergone weight reduction procedures such as by-pass surgery or banding so that it can capture attitudes both before and after treatment.

Obesity was chosen as the subject, Irony said, because it has a high prevalence disease and treating it could have a big public health impact. In addition there are several devices that will be coming to the market to reduce weight. However, she noted, obesity treatment also offers a number of difficult risk and benefits trade-offs. “It was a challenging problem to pursue, but I think that it is going to be very rewarding,” she said.

Irony’s talk was at the session sponsored by RTI to showcase its work in the arena of patient feelings on risk-benefit. After the public comment period and approval by the Office of Management and Budget, the survey should take only a few weeks to complete, Irony said. She noted that if sponsors or patient advocacy groups do similar national representative studies, the agency would be interested in those results as well. FDA issued guidance to reviewers and industry on risk and benefits, including patient attitudes, on March 28.

Studying risks and benefits will be complex for the obesity study, as well as for other areas, Irony stressed. Questions will include whether a procedure will be performed once or repeatedly, what uncertainties will remain after the clinical trials, what the variations in outcomes might be among surgeons or medical centers, what the severity of the disease is, whether there is alternative treatments, whether the technology might improve with time, and whether patients tolerate more or less risk for conditions they have had for a longer time.

RTI Health Solutions principal economist Reed Johnson, who does research in this area, said that often when FDA advisory committee meetings have their public comment periods, “Typically a number of patients come in and cry.” They cry, he said, either because a loved one was injured by some therapy or because they believe they can benefit from a treatment which they fear the advisory committee will not recommend for approval. Thus physician advisors on the panels evaluate the evidence often for two days, “And then there is this sort of completely uncontrolled emotional input,” he said.

It’s hard to know how the committees are influenced, Johnson said. But if patients are going to have input, there ought to be a way to interpret whether it is representative, how many patients hold a particular view, and what the characteristics are for the patients who hold particular views, he urged. Calling for moving quickly and decisively toward turning patient input into evidence, Johnson said, “I think we need to think of patients as a source of data and not just a source of emotion.”

Major Changes Urged to FDA’s 510(k) Plans

In a formal comment, AdvaMed notes that the draft guidance would replace and make significant changes to two guidances that it believes have served the agency well for many years. “Given that the statute and relevant regulations in effect today remain consistent with the principles established in these guidance documents, FDA’s goal for revising these documents is unclear,” it writes. “Before proceeding, FDA should disclose the public health concerns associated with the existing guidance documents that the draft is intended to address. Without this information, stakeholders are unable to assess the need for the changes and will not be in a position to determine if the revised guidance document is successful.”

The association also notes the current uncertainty about the 510(k) program and says that issuance of the guidance will profoundly affect industry’s ability to introduce new devices into the marketplace. “Before altering FDA reviewer expectations and the regulatory burden associated with navigating the main route by which most devices enter the U.S. marketplace, FDA should commission the conduct of a thorough economic impact analysis,” it states. The comment raises seven areas of concern as well as offering specific line-by-line comments.

In its comments, Johnson & Johnson expresses a concern that some of FDA’s proposed changes may result in an increase in 510(k) review times and an increase in the number of “not substantially equivalent” decisions. It also offers both general and specific comments.

Companies that are part of Cook Group Inc. say they appreciate that FDA stated clearly that principles of safety and effectiveness underlie the substantial equivalence determination in every 510(k) review. “Questions have been raised recently about the ability of the 510(k) program to provide a reasonable assurance of safety and effectiveness to physicians and patients,” Cook says. “When FDA uses the concept of substantial equivalence in its review and clearance of 510(k) applications, it does, in fact, provide a reasonable assurance that the device is as safe and effective as other legally marketed devices for the same intended use, based on the information in the application and historical information about the precedents.

The comment lists six areas in the draft guidance needing substantial improvement: recommendations concerning the Special 510(k) Program, the order and types of questions in the flowchart included in the guidance, the use of multiple devices as predicates, the amount of information recommended for 510(k) summaries, the relation of this guidance to a 1998 guidance on general/specific intended use, and statements concerning changes in labeling for MRI compatibility.

Finally, Public Citizen says that, in general, it opposes the draft guidance because it would “perpetuate FDA’s long-standing overly permissive interpretation of the regulatory provisions for ‘same intended use’ and ‘different technological characteristics.’” It says that such permissive interpretations have allowed FDA to clear many moderate- to high-risk devices that differ significantly from their already marketed predicate devices without the new devices undergoing appropriate clinical testing to ensure that they are safe and effective, resulting in significant harm to patients.

Linda Kahan, Former FDA Executive, Dies at 64

A 1968 graduate of Vassar College who obtained her law degree from Georgetown University in 1985, Kahan joined FDA’s Office of Chief Counsel in 1989 after obtaining two master’s degrees in history from Columbia University, the Post reported. In OCC, she oversaw medical device cases and helped draft FDA’s mammography regulations.

In 1999, she was promoted to CDRH deputy director, and that year became an early advocate of device user fees. In an FDA presentation touting their implementation, she said they would provide “more rapid generation of income for companies” as well as quicker access to devices for patients. After reviewing reasons why industry had opposed user fees in the past, Kahan said the Center had streamlined and reengineered, leading to an improvement in review times and elimination of 510(k) backlogs. But, she wrote, an increasingly complex workload had exceeded allocated resources and it no longer was possible to shift additional resources without undermining other public health responsibilities.

Positioning the Clinton administration’s legislative proposal for device user fees, Kahan said the FDA Review Fee Act of 1999 would allow imposition of fees relating to medical devices, including $40,000 for a PMA, $4500 for a PMA supplement, and $1000 for a periodic PMA report. There would be no fee for a 510(k) application, her presentation said.

Since then, the fees have been enacted and currently stand at well over four times those amounts. In addition, 510(k) submissions have become subject to user fees of between $2359 and $4717.

Five Common Mistakes to Avoid When Designing with Bioresorbable Materials

Bioresorbable resins, such as those offered by Teleflex Medical OEM, can be advantageous because of their potential impact on patient health and safety.

Bioresorbable polymers can be very advantageous to the medical device designer owing to their unique properties and potential impact on patient health and safety. But they do present some unique challenges. While most issues can be overcome with forethought and experience, here are five tips to help engineers avoid the most common issues encountered when working with bioresorbable materials.

It is critical to not only establish how long the bioresorbable device should last in situ, but also to define what it means "to last." If the design calls for the device to degrade after six months of use, for example, does that mean that the mechanical or physical properties are gone after six months, or that all remnants of the polymer are gone? For the majority of bioresorbable materials--the bulk erosion class of polymers--water permeates the entire device. And while the mechanical properties of the material may deteriorate in six months, it may take another year for all of the material to completely resorb in the body. As a corollary to this issue, the other class of bioresorbable polymers, surface erosion polymers, do not permit water to completely permeate the device; only the surface layer is affected by the degradation mechanisms at any time. So, the mechanical and physical properties of the device erode as a function of the dimensional characteristics of the medical device.

Determination of the degradation time must be based on the final device after all processing steps have been completed. The processing method--such as extrusion, compression molding, or solvent casting--along with such factors as the number of drying cycles for the polymers and storage time, can all affect molecular weight, molecular weight distribution, and crystallinity of the polymers. In turn, molecular weight properties and crystallinity can dramatically impact degradation time. This fact may be obvious, especially for people experienced with other polymers that are sensitive to water content, such as polyurethanes. But what may be less obvious is the impact of sterilization as a final processing step. Whether the method involves water or irradiation, sterilization can reduce the molecular weight of bioresorbable polymers by as much as 50%.

The exclusion of water during all phases of handling bioresorbable materials is critical. A defining characteristic of bioresorbable materials is that they are sensitive to aqueous degradation in situ. But designers and manufacturers sometimes forget that this characteristic is also a factor when handling the material prior to actual device use. It is imperative that companies take extra care in the storage, and therefore, the exclusion of water, throughout the lifetime of these polymers. This may include storage of the raw polymers; preparation of the polymers for processing; the processing environment; storage of the work in progress; and packaging/storage of the finished goods.

Consistency is key to reproducibility. To achieve reproducible performance of the finished medical device, the properties of the bioresorbable polymer must be consistent throughout the device. As noted, these polymers are susceptible to degradation--or at the very least, changes--during processing. With this in mind, it is critical to have uniform conditions throughout the processing steps. For example, if molding is employed, temperatures should be consistent and there should not be differences in residence time in various parts of the mold.

Consider the cost factor. Bioresorbable polymers are far more expensive than most conventional elastomers or engineering plastic. So, waste minimization is a very practical concern. We strongly recommend that designers partner with experienced micromolders that are specifically experienced in this area to ensure cost-effectiveness.

Steve Coulter is the senior research associate at Fallbrook Engineering Inc. (Escondido, CA).

Making Sense of Smart Orthopedic Implants

Sensors developed at Rensselaer Polytechnic Institute can be integrated into orthopedic implants with little, or no, implant modifications.

Smart orthopedic implants--those incorporating sensors capable of providing information about conditions inside the body--have been created in the research world for decades. But because they incorporate large, expensive, and complex electronic and sensing components, many smart implants have never made the leap from the laboratory to the operating room. Now, however, engineers at Rensselaer Polytechnic Institute (Troy, NY) have developed a sensor technology for use in orthopedic implants with one primary virtue: simplicity.

"The reason why smart orthopedic technology has never made it into daily clinical practice is that in all previous research applications, my own included, the electronics and sensors were very expensive and generally large and cumbersome," remarks Eric Ledet, assistant professor of biomedical engineering at Rensselaer. "More importantly, however, they could only be incorporated into custom implants--be they fracture plates or knee or hip prostheses." Thus, even if the cost of such sensors were not prohibitive, the need to custom modify each implant would render the technology unsuitable for daily clinical practice, Ledet adds.

Historically, strain gauges--tiny sensors used for measuring very small amounts of deformation--have been employed in the lab to make smart orthopedic implants. However, such sensors can only be mounted on implants that have undergone extensive surface preparation. "Strain gauges actually have to be glued on, creating a permanent bond," Ledet says. "Thus, you have to modify the implant pretty substantially just to get the old type of sensors on."

In contrast, the Rensselaer researchers' sensors can be integrated with little, or no, modifications to the implants. Tiny disks measuring as little as 4 mm in diameter by 500 µm thick, they can be attached to the implant by means of mechanical attachments or simple adhesives. Moreover, their implantable surfaces do not have electrical connections. Consequently, in polyethylene-metal knee implants, for example, the sensors can be placed in between the polyethylene component and the metal tibial component. "Their small size affords us many opportunities for slipping them into nooks and crannies," Ledet comments.

Intended to serve as smart components in future orthopedic implants, the new sensors measure a range of parameters at the surgery site, including force, pressure, and temperature, Ledet explains. Transmitted wirelessly, information about the condition of the implant is detected using an external antenna and then sent to a reader.

"The parameters measured by the sensor have one thing in common," Ledet says. "They all indicate a deformation of the sensor." For example, a sensor placed on a tibial tray in a total knee replacement can be used to measure the forces operating on the implant, enabling clinicians to gather crucial postsurgical information, Ledet adds. "Is the prosthesis being loaded appropriately? Is it going to wear properly? Is there micromotion in the femoral component that could lead to osteolysis? Our sensors can measure these and other conditions."

While the engineers acknowledge that their technology is not yet ready for prime time, they believe that it does not face any insurmountable hurdles. "Because there is pent-up demand for smart-implant technology, we are confident that
we can move forward rapidly with our concept because it is a simple system with few ways to fail."

What Happens After Global Harmonization Goes Kaput?

Taking over many of its roles, Trautman said, will be the new International Medical Device Regulators Forum, which held its first meeting in Singapore, at the end of February 2012. It is a voluntary group of regulators meant to “accelerate international medical regulatory harmonization and convergence.”

One of the key differences is that the membership will be regulators only, unlike GHTF, which included regulators and industry. A goal of the new group is for regulatory requirements and approaches across countries and regions to become more similar, “as a result of the adoption of the same technical documents, standards and scientific principles (harmonization) and similar regulatory practices and procedures.”

The GHTF was successful, Trautman said, in establishing one set of good manufacturing practices so that various nations’ GMPs were close to identical, although FDA and other nations’ agencies did have additional requirements. Asserting that it is time for some fundamental changes, however, Trautman said sometimes there are issues that are written into law and that was an area “where some of the issues were starting to get stuck in GHTF.”

Many of the regulators in the founding GHTF countries believe that “We have basically developed a regulatory framework through GHTF guidance documents for emerging regulators, but we need to start stepping up to the plate and really start converging on some of our practices,” Trautman said.

A model for the new group, she said, is the Pharmaceutical International Conference on Harmonization (ICH), where regulators agree on the work items at the highest level of the respective agencies. Although the topics might not be as big as some tackled in GHTF, she said, the convergence may be vital. In the ICH, “They said they really needed and valued the time that regulators had to sit down and talk regulator to regulator, and not have to worry about sensitive information, private information, and so forth.”

Trautman stressed that, although FDA is one of the largest regulatory agencies, it can’t regulate the world, performing inspections of the 9000 medical device manufacturers registered with the agency. “So we have to find ways not to duplicate” and find ways regulators can leverage off of each other,” she said. In addition, there was a complaint over the years in GHTF as to how industry representatives were chosen, because sometimes it was the larger associations that had the money for the travel involved in participating.

She did add, however, that under the new IMDRF, working groups will be set up to involve other stakeholders including industry, physicians, and other institutions. Various work efforts may include regulators-only, industry-only, or a mixture.
Nations at the first meeting were Australia, Brazil, Canada, Europe, Japan and the United States, with observers from China, the Russian Federation and the World Health Organization. China, she said, is working actively on getting approval from its government to become a full member at the management committee level. It was also a positive sign that Russia came to the table, she said, and the World Health Organization is playing a big role.

The Asian Harmonization Working Party is invited as an affiliate, she noted. Its chairperson, who is always a regulator or a government representative from AHWP, can observe at the management committee meetings. That’s important, she indicated, because AHWP is a strong consortium of countries that have less mature systems and that are actually in various areas beyond Asia. The Asian-Pacific Economic Cooperation also is an observer.

One goal the group has in the near future is reviewing the GHTF National Competent Authority Report Exchange Program which was set up to exchange postmarketing safety information on medical devices with global distribution. Trautman said the system had been helpful in Europe. For the United States, however, one difficulty is this country must have formal confidentiality arrangements with the prospective governments in order to share confidential information. The GHTF documents will be maintained through the IMDRF.

Trautman also told the group it is likely to hear more about product registries in light of problems with metal-on-metal hip implants and breast implants. But, she added tha, for the most part, “globally, the governments do not have the authority to go ahead and go full force with registries.”

But also in terms of registries, she said, “We really need, as an industry, to look at who can we partner with, because the regulators, the industry, we can’t fund everything. The doctors, the hospitals and the institutions, they need to step up and play in this game, too, from a global perspective.”

Background and other documents on the new group are at:

Flexible Vinyl Compounds with Biobased Plasticizers Promote Safety, Sustainability

BioVinyl compounds with Dow Ecolibrium biobased plasticizers offer a safe and environmentally friendly alternative to phthalate-containing PVC for medical applications.

Rising safety and environmental concerns have prompted many hospitals to consider phasing out the use of PVC medical products because of their incorporation of DEHP and other phthalates. But this PVC-free policy is a misguided approach that prohibits the use of an often-optimal medical material, according to Michael Roberts, business development manager at Teknor Apex Co. (Pawtucket, RI). Looking to overcome the stigma of PVC while eliminating the use of phthalates, Teknor Apex has developed BioVinyl flexible vinyl compounds made with biobased plasticizers that promote patient safety while offering a reduced carbon footprint.

"A lot of hospitals are evaluating whether to [phase out] PVC, but they're doing so without really looking at sustainability or the scientific data around the product," Roberts comments. "If you get out of PVC, you are moving into a product that is less optimal for the application and not necessarily better for the environment. In reality, you're just adding cost, increased design energy, and increased inefficiency into the product line."

In an effort to retain the desirable properties of PVC without the use of phthalates, Teknor Apex partnered with Dow Chemical Co. to incorporate Dow Ecolibrium biobased plasticizers into its BioVinyl family of flexible vinyl compounds. Derived from vegetable substances, the phthalate-free plasticizers serve as a direct replacement for DEHP in PVC. They are suitable for use in IV lines, endotracheal tubes, oxygen and anesthesia masks, drainage bags, and other medical applications in which PVC has traditionally been employed.

While ensuring that patient safety is a key goal, BioVinyl compounds featuring Dow Ecolibrium plasticizers offer the additional advantage of being environmentally friendly. Life cycle analysis tests performed by Dow and supported by a third party revealed that the flexible vinyl compound equipped with the biobased plasticizer reduces carbon dioxide-equivalent emissions by 41% compared with conventional vinyl. "It's one of the lowest carbon footprints of any plastic," Roberts adds.

BioVinyl compounds with Dow Ecolibrium are processed using conventional methods and at a price comparable to other nonphthalate vinyl compounds, according to the company. "Almost all green plastics either compromise cost or performance. Or, if you get cost or performance, they're derived from oil," Roberts says. "In our case, you really don't pay a premium above a nonphthalate and it performs as well as, if not better than, traditional products and plasticizers."


The People Have Spoken: FDA's OK, Medtech Innovation is a Priority

As the nation awaits the Supreme Court's ruling on the fate of President Obama's healthcare reform law—on which everyone seems to have an opinion—NEHI, formerly the New England Healthcare Institute, recently conducted a national survey to gauge the understanding of and receptivity toward issues pertaining to healthcare innovation. Yet despite the broad focus, the survey revealed some interesting insight into the views of the general populace on such issues as the role of FDA and medtech innovation.

While the effort may not have quite targeted the average 'man on the street,' NEHI's 2012 Innovation Barometer did survey 500 'opinion leaders,' defined as voting members of the general public that regularly read newspapers and follow current events in the healthcare sector. These respondents were asked their opinions on a range of topics related to healthcare innovation, many of which centered on reducing healthcare costs and increasing efficiency. However, several questions encompassed innovation in the medical device realm, revealing that the area has substantial support from many people.

For example, when asked what the priorities of government should be during the next five years in order to control healthcare costs, 83% of respondents felt that a high priority should be to support research to discover new medicines, medical devices, and other healthcare technologies. And 51% went so far as to deem it a "very high priority." When next asked which option should be the government's highest priority for controlling costs, 15% of survey takers thought that it should make support of medtech research the primary priority. This option came in third after making the healthcare system more efficient and taking stronger action to improve public health by reducing the rate of chronic conditions.

Among the most interesting medical device-related morsels of the survey, however, were the results to the following question. "FDA is responsible for approving new drugs and medical devices in the U.S. so that they are safe and effective for use.  Please indicate which one statement you agree with most.

  •  If the FDA approves a product that later turns out to be harmful, but still helps some patients, it should still approve the product but disclose the risk to patients and doctors: 36%
  • The FDA should approve a product, even if it has evidence to suggest it may harm some patients, provided the product helps other patients and the FDA discloses the risk: 22%
  • If the FDA approves a product that later turns out to be harmful, it should leave it to physicians and healthcare providers to determine the best course of action for patients: 16%
  • The FDA should not approve a product if it has any evidence that it will harm any patient: 14%
  • If the FDA approves a product that later turns out to be harmful to some patients, it should withdraw its approval even if the product still helps some patients: 8%
  • Not sure (Not read): 4%"

Ultimately, 58% of respondents felt that FDA should approve a product that may be harmful to some patients as long as the risk is disclosed and it is proven to be effective for other patients. Furthermore, a follow-up question revealed that 68% of respondents supported an upgrade to FDA's scientific capabilities to review and approve new products on a more timely basis, even if it increases deficit spending.

While these responses represent only a small sampling of the American public, they are especially interesting and surprising in light of escalating criticism of FDA from attorneys and various patient-advocacy groups. So, are these vocal critics of FDA and the medical device industry accurately representing the "voice of the people?" It's hard to tell, but NEHI's survey certainly provides a welcome peek into the views of 'regular people' affected by the controversial U.S. healthcare system and provides a bit of an unbiased perspective. And, additionally, it's refreshing to see that medtech innovation is something that the American public seems to support as claims that the medical device tax could be an innovation killer continue to abound. --Shana Leonard