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BMEStart Awards Students for Innovative Contact Lens

This year the $10,000 grand prize was awarded to the braniacs at North Carolina State University for their HydrEYE CorneOasis Contact Lens, a hydrating system for patients who have lost control of eyelid function. The product description states that the device is meant for patients with traumatic brain injury.

The other winners are described in the press release:

Coming in second, with a grant of $5,000, went to Columbia University for Procar: A Trocar Worth Trusting. In an effort to decrease malpractice injury claims associated with use of the trocar surgical device in making incisions for laparoscopic procedures, Procar is an advanced trocar designed with a quantitative force-feedback system that will provide tissue layer differentiation and instantaneous notification of intraperitoneal access to prevent over-insertion through abdominal wall—which can inadvertently cause injury to underlying anatomy.

Tied for third place and each awarded a $2,500 grant, NCIIA recognized Purdue University for the Handheld Plasma Isolation Device, which is able to effectively separate plasma from a white blood sample in approximately two minutes without the aid of a power source; and Tulane University for Malaria Retinopathy Automated Detection, which uses a multi-color LED array to more easily detect retina disorders often associated with cerebral malaria.

Scientists Claim Genetically Engineered Spider Silk Breakthrough

Silkworms have been genetically modified to produce silk resembling that of spider silk. (Photo courtesy of ND Newswire)

Scientists have been hard at work attempting to marshal the power of spider silk for a range of medical applications--including wound-care applications; suture materials; and muscle, bone, cartilage, tendon, and ligament repair scaffolds. It makes sense: Spider silk possesses mechanical attributes such as very high tensile strength and elasticity, making it one of the toughest fibers known to man. The problem is that spiders don't produce enough silk to render it marketable for mass human use.

Now, however, a team of researchers at the University of Notre Dame (Notre Dame, IN) the University of Wyoming (Laramie), and Kraig Biocraft Laboratories Inc. (Lansing, MI) has succeeded in producing transgenic silkworms. The advantage of these little animals is that they can spin artificial spider silk with strength and flexibility attributes similar to those of native spider silk.

Until this breakthrough, only very small quantities of artificial spider silk had been produced in laboratories. Kraig Biocraft believed these limitations could be overcome by using recombinant DNA to develop a biotechnological approach to producing silk fibers with a broad range of physical properties or with predetermined properties optimized for specific biomedical or other applications. To put its theories into practice, the company entered into a research agreement with Malcolm J. Fraser Jr., a Notre Dame professor of biological sciences who discovered and patented a genetic engineering tool called PiggyBac, a piece of DNA known as a transposon that can insert itself into the genetic machinery of a cell.

Transgenic silk features strength and flexibility properties similar to those of spider silk. (Photo courtesy of ND Newswire)

With the assistance of Randy Lewis, a University of Wyoming biochemist and an authority on spider silk, and Don Jarvis, a molecular geneticist who specializes in insect protein production, Fraser genetically engineered silkworms incorporating DNA taken from spiders. When these transgenic silkworms spin their cocoons, the silk they produce combines both silkworm and spider silk and displays elasticity and strength approaching that of native spider silk. Since silkworms have long been cultivated to produce silk for commercial purposes, the scientists hope that these genetically engineered creatures can be used for large-scale production of engineered protein fibers with the physical properties required for medical device applications.

"This research represents a significant breakthrough in the development of superior silk fibers for both medical and nonmedical applications," Fraser remarks. "The generation of silk fibers having the properties of spider silks has been one of the important goals in materials science."

For more information on research into spider silk for medical device applications, see the Medical Product Manufacturing News articles "Spider Webs May Mimic Muscles and Serve as Future Medical Device Material," "Buzz Grows Around Insect-Inspired Silk," "Mimicking Mother Nature," and "Scientists Engineer Artificial Silk Using Bacteria."

New AFEs for Ultrasound Applications Improve Noise and Power Performance

TI's AFE5807/8 devices can be used in ultrasound applications.

Two new fully integrated analog front-end (AFE) devices from Texas Instruments (TI; Dallas) extend the company's ultrasound AFE family, promising to enhance noise and power performance in a small package. Featuring a continuous wave (CW) Doppler mixer for mid- to high-end spectral doppler ultrasound equipment, the AFE5807 and AFE5808 address ultrasound designers' need for high performance and image quality with noise performance of 0.75 nV/rtHz. In addition, the integrated CW mode measures and displays blood-flow velocity in ultrasound images. These devices are 25% percent smaller than competing solutions, ensuring a compact system footprint for higher channel count. To view a video about the AFEs, click here.
 
The AFEs achieve low-noise levels better than -155 dBc/Hz at 1 KHz off a 2.5-MHz carrier. Both devices integrate eight channels consisting of several components: a low-noise amplifier with 24/18/12-dB gain settings to enable a 0.25/0.5/1-Vpp linear input range; 50, 100, 200, or 400-? active termination for supporting a range of input amplitudes for different classes of transducers; a voltage-controlled attenuator and a programmable gain amplifier with a total maximum gain of 54 dB for a broad dynamic range; a third-order linear-phase low-pass filter with a selectable bandwidth of 10, 15, 20, and 30 MHz; a 12- and 14-bit analog-to-digital converter with linear variable differential transformer output up to 65 MSPS; and programmable modes for optimizing power and performance for various imaging modes.
 
The new AFEs complement TI's other AFE devices, including the AFE5805 and AFE5804 devices used in portable to midrange ultrasound applications and the AFE5801 and AFE5851 used for handheld, ultraportable ultrasound applications.

For more coverage on ATE technologies used in ultrasound, ECG, and EEG systems, see the Medical Product Manufacturing News articles "Eight-Channel Chipset Offers End-to-End Solution for Portable Ultrasound Systems" and "Little Chip Packs Big Wallop in Portable Devices."

California Law to Require Reporting of Radiation Mishaps

SB 1237 requires that such radiation mishaps, including overdoses during therapeutic treatments, be reported to the patient and their doctor. Federal law currently regulates only the machines, not the technicians or doctors who use them. The bill would also require that the radiation dose be recorded in medical records, making it more likely that troubles can be more easily detected and corrected.

The legislation was introduced by Sen. Alex Padilla (D–Pacoima) and sponsored by the Consumer Attorneys of California. It was triggered last fall when more than 330 patients at Cedars-Sinai Medical Center in Los Angeles and several other California hospitals had suffered radiation overdoses while undergoing CT scans.
 
“This should serve as a foundation for legislation nationwide,” said Michael Heuser, one of the Cedars patients. “Congress needs to step in and use its power to ensure that that these sort of tragic mishaps don’t ever happen again.”
 
Heuser was labeled “Patient 1” after he became the first to report troubles to health care officials, which led to a nationwide warning by FDA. He was bombarded by at least 8 times the allowable radiation dose, a level equivalent to 50,000 chest X-rays. Heuser had to fight with recalcitrant hospital officials to learn that he had been overdosed during the scan.

A New Era in FDA Recall Authority

A recall is defined as a “firm’s voluntary removal or correction of a marketed product that FDA considers to be in violation of the FD&C [Federal Food, Drug, and Cosmetic] Act and against which FDA would initiate legal action ex. Seizure. Recall does not include a market withdrawal or a stock recovery.”1


Most product recalls are voluntary, initiated by the manufacturer or distributor of a device. In some instances, a company discovers that one of its products (or its labeling) is defective and recalls it entirely on its own. In others, FDA informs a company of findings that one of its products is defective and suggests or requests a recall. Over the years, this cooperation between FDA and its regulated industries has been demonstrated to be the quickest and most reliable method to remove potentially dangerous products from the market.2


FDA has three categories of recalls: Class I, dangerous or defective products that could cause serious health problems or death; Class II, products that might cause a temporary health problem or pose only a slight threat of a serious nature; and Class III, products that are unlikely to cause any adverse health reaction, but that violate FDA labeling or manufacturing regulations.


FDA develops a strategy for each individual recall that sets forth how extensively it will check on a company’s performance in recalling the product in question. For a Class I recall, for example, FDA would check to make sure that each defective product has been recalled or reconditioned. In contrast, for a Class III recall, the agency may decide that it only needs to spot check to make sure the product is off the market.3


This article explores the changing trend in the FDA’s recall authority through the lens of several cases.


The Colleague

On May 3, 2010, FDA ordered Baxter to

  • Recall and destroy 200,000 Colleague infusion pumps in use.
  • Reimburse its customers.
  • Assist customers in finding a replacement device.

This recall was implemented in the wake of more than 56,000 adverse-event reports received by FDA in the past five years against the infusion pumps. These adverse events included serious injuries and more than 500 deaths. To address identified safety concerns, FDA conducted 87 infusion pump recalls between 2005 and 2009. In 2006, FDA obtained a consent decree against Baxter forbidding further manufacture of the Colleague infusion pumps. The consent decree also required Baxter to submit a corrective action plan within 20 days for correcting the deficiencies with the Colleague pumps already in use. Apparently, Baxter attempted several rounds of upgrades during the past four years, with unsatisfactory results. Baxter’s most recent proposed plan contemplated a new round of corrections beginning in May 2012 that would be complete in 2013. FDA found this proposal unacceptable.


FDA’s Authority

Baxter’s recall is unusual and raises several questions about the scope and course of FDA’s enforcement authority. What is so distinctive about FDA’s actions in Baxter’s recall is that almost all recalls in the past had been voluntary and this is the first time FDA has come so close to exercising its mandatory recall authority. In addition, FDA had never directly required a manufacturer to reimburse its customers for a defective device. In the past, FDA has sought and obtained refunds from defendant companies for the customers as part of the relief sought against the defendant in a permanent injunction action before a district court.4


Under Section 518 of the FD&C Act, FDA has the authority to order mandatory device recalls (S. 518 (a)), repairs, replacements, or refunds (S. 518 (b)). Although FDA’s order to Baxter to recall its Colleague infusion pumps is not technically an exercise of its mandatory recall authority under S. 518, because it is pursuant to the consent decree between FDA and Baxter, it has a stark resemblance to a mandatory recall order by FDA under S. 518 (a). It is further debatable where FDA draws its authority from to order Baxter to refund its customers. Is it the exercise of its authority to order refunds under S. 518 (b), is it pursuant to the consent decree, or is FDA arbitrarily giving itself an equitable remedy of restitution without recourse to the court to decide whether equity justifies restitution? A consent decree is an injunction issued by a federal judge where the parties, the Department of Justice on behalf of FDA, and the defendants (usually the company and one or more of its executives) agree to the terms. Refunds were certainly not negotiated between FDA and Baxter in their 2006 consent decree. FDA can order a defendant company to pay refunds to its customers under S. 518 (b) if the mandatory recall notification under S. 518 (a) would not be sufficient to eliminate the risk. If the recall is FDA’s exercise of its authority under S. 518 (b), doesn’t the recall automatically become a mandatory recall under S. 518 (a)? However, the consent decree permits FDA to take “any other corrective action” to protect the public health or to ensure Baxter’s compliance. FDA perhaps views the refund requirement imposed on Baxter as falling within the catch-all provision in the consent decree.


Not only is the source of FDA’s authority to order refunds ambiguous, but the fact that FDA provided no formula or guidance to calculate the refund to the customers is even more agonizing.  S. 518 defines refund as “the purchase price of the device (less a reasonable allowance for use if such device has been in the possession of the device user for one year or more).” No recourse is available through the implementing regulations (21 CFR 810), which specify the procedure for ordering a mandatory recall but do not speak to the repair, replacement, or refund authority.
Baxter’s silence is strategic. It is certainly not in a position to challenge FDA’s actions. FDA has several enforcement tools available including seizures, injunctive relief, and criminal sanctions. The agency's Office of Criminal Investigations directly refers violations under 21 CFR 331 to U.S. attorneys for criminal prosecution.


Technically, it appears that the most potent tool in FDA's arsenal of enforcement tools is its criminal sanctions. However, criminal sanctions are rarely deployed because most of these violations are committed by businesses in their ordinary course of operations, and in most circumstances, they are willing to cooperate fully with FDA to remedy a violation.


Therefore, civil sanctions remain the most frequently used enforcement tool by FDA, and its authority on civil sanctions is far reaching. However, Congress has not entrusted FDA with the authority to impose compensatory relief or punitive damages. Ironically, FDA’s favorite and most powerful enforcement tools—i.e., disgorgement of profits and restitution—are also not provided to it by Congress. Disgorgement means to deprive the defendant of its “ill-gotten gain.” The difference between restitution and disgorgement is that disgorged funds typically go to the government entity whereas restitution is paid to the victims.


Technically, these remedies are equitable in nature to prevent unjust enrichment and are intended to be deterrent rather than punitive. In practice, FDA has put hundreds of millions of dollars in the U.S. treasury through disgorgement, thereby making the deterrent and nonpunitive nature of these remedies questionable. But disgorgement and restitution are here to stay with FDA having won the legal debate on their justification before three Courts of Appeals.5 The U.S. Court of Appeals for the Third Circuit held that “the inherent equitable powers of the district court that issues an injunction under the [FD&C Act] include the power to order restitution.”6 A regulated company must be increasingly cautious even before defending its products against an action of seizure by FDA in a court proceeding, because FDA will sometimes seek to amend its seizure case into an injunction, which may in turn serve as a stepping stone for disgorgement or restitution.7 Thus far, restitution and disgorgement remain the most practically potent weapons in FDA’s enforcement arsenal, and they remain a massive threat to the defendant companies in challenging FDA’s actions and during negotiations with the agency. 


A Look at Enforcement History

FDA successfully employed its tool of disgorgement of profits in 1999 when it fined Abbott Laboratories $100 million through a consent decree of permanent injunction agreed to by Abbott for its failure to comply with good manufacturing practices (GMP) and the quality system regulation. This was also the beginning of FDA’s declining patience for noncompliance with its GMP regulations and increasing civil penalties. In 2002, Schering-Plough was fined $500 million under a consent decree for its failure to comply with GMP. In imposing these enormous fines on Abbott and Schering, FDA was motivated to ensure that its GMP regulations were taken very seriously by the industry and to warn the industry about the dire consequences of noncompliance. Through Baxter’s recall, is FDA setting a precedent for other device manufacturers to address device deficiencies promptly or face Baxter’s fate—or worse?
Baxter’s recall should not only alert all device manufacturers, but also officers, directors, and managers of such companies, particularly those whose devices have longer life spans. FDA has never in the past resisted naming the individuals as defendants. In fact, personal responsibility is a hallmark of the FD&C Act and reflects a core value of FDA’s compliance and enforcement policy.8


The effects of the permanent injunctions and civil fines go far beyond the fines paid to the government. The costs to the industry are equally expensive in both money and time spent on conversions to new products. According to one of the laboratories that used Abbott’s products, the allocated labor cost per conversion was $698 based on the average time required to complete the work. The conversion of assays required that laboratories take many steps to ensure proper transition, which among others included writing new procedures, performing correlation studies, reestablishing quality control, conducting linearity studies, changing specimen requirements, and establishing new reference ranges. Other steps included training personnel, changing delivery schedules, editing the format of reports, notifying clients, and establishing new relationships with alternative manufacturers. Baxter is taking a pretax charge of $400 million–$600 million for the recall. Given FDA’s high-end estimate of 200,000 units in the field, Baxter’s charge implies an average cost of $2000–$3000 per pump.


Infusion Pump Makers: Proceed with Caution

Infusion pump manufacturers should also in particular be alerted by the more-stringent premarket and postmarket requirements that FDA is implementing by its recently adopted, aggressive, and far-reaching initiative to improve the safety of infusion pumps (see the sidebar). The initiative’s purpose is twofold: to establish additional requirements for infusion pump OEMs and to proactively facilitate device improvements and increase user awareness.9 A central element of this initiative is the Total Product Life Cycle: Infusion Pump—Premarket Notification [510(k)] Submissions (or TPLC Infusion Pump Guidance), a first-of-its-kind guidance document that represents FDA’s current thinking regarding premarket and postmarket requirements for infusion pumps. It also suggests clinical trials for all new and modified devices.

Pump Up the Anxiety

The announcement of the infusion pump initiative was followed by a two-day workshop hosted by FDA on May 25–26, 2010, in Silver Spring, MD. Medical Device News and Insights, whose representatives attended the workshop, commented in its overview that “everyone who spoke wanted to stop the recalls that drain their already strained resources. As far as the existing manufacturers are concerned, it is not clear if every modification will now trigger a 510(k) and clinical trials. Even FDA could not provide satisfactory concrete information as to the design of these clinical investigations, including such critical elements as the numbers of subjects, clinical endpoints, duration, etc.”


FDA’s reluctance to provide specifics may be twofold; first, the requirement is new to the agency as well as to OEMs. Also, the study designs are contigent on technological traits of the individual devices as well as the populations these devices are intended to serve. FDA may evaluate manufacturers on a case-by-case basis.


For more on the infusion pump summit, listen to MD+DI’s podcast.


Baxter could not cure the technical defects with its Colleague infusion pumps for six years in spite of its best efforts. Unfortunately, there is not always a quick fix for certain device deficiencies. It is debatable whether the infusion pumps available for replacement are completely free of defects. Even if it is assumed that the replacement devices are safer, can FDA ignore the reality of errors as part of any conversion process? FDA admitted that infusion pumps are medically indispensable and by their very nature cannot be 100% risk free.10


FDA has given mixed signals to OEMs by its contradicting statements and actions. On one hand, FDA admitted that the problems with infusion pumps are not confined to one manufacturer or one type of device. On the other hand, it is giving reassurance to users by saying that there are many legally marketed infusion pumps that are currently available for sale in the United States. What is it supposed to mean for the Baxter’s competitors who want to capture the lost market share of Baxter? What level of scrutiny does FDA expect to observe with respect to the replacement pumps? Are the competitors likely to face the same fate as Baxter if they fail to comply with the stringent initiative? Considering the immediate medical need for replacement pumps, is FDA going to be more lenient or stricter with the suppliers?
The new initiative further contradicts FDA’s own goal of encouraging device improvement. Any improvement or modification in the device may trigger FDA’s scrutiny under the new initiative and might induce infusion pump manufacturers to hold off on any device improvements. Hospira, which is the market leader in infusion pumps, has 29% of the market, followed by Baxter at 28%, and CareFusion at 24%. Hospira is ready to crank up production of its infusion pumps to replace Colleagues. It seems to have learned an important lesson from Baxter’s experience. It has put a hold on its high-end Symbiq infusion pump until it sorts out technological problems.11


Conclusion

In some ways, Baxter’s recall may be the first of its kind, but it won’t be the last. FDA’s actions in Baxter’s recall and the removal of 200,000 medically necessary, life-sustaining infusion pumps from the market show FDA’s merciless approach toward manufacturers’ failure to provide the defectless devices. Further, FDA is contemplating conversion of these new guidelines for infusion pumps into a force of law. Given the expansive nature of statutes and vague statutory interpretation, the survival in this highly regulated industry will depend upon solid regulatory compliance and strong policy arguments.


References

1.    21 CFR 7.3(g): Enforcement Policy: Definitions.
2.    N Muni, T Gross, A Boam, S Wang, and B Zukerman, “Challenges in Regulating Breakthrough Medical Devices,” Food and Drug Law Journal 60, no. 2 (2005): 137–142.
3.    Guidance for Industry: Product Recalls, Including Removals and Corrections (Rockville, MD: FDA, Center for Devices and Radiological Health, 2003).
4.    U.S. v. Universal Management Services Inc., 191 F.3d 750, 760–62 (6th Cir. 1999).
5.    U.S. v. Universal Management Services Inc.,191 F.3d at 761–63 (6th Cir. 1999); U.S. v. Lane Labbs-USA Inc., 4219 F.3d 27 (3rd Cir. 2005); U.S. v. Rx Depot Inc., 438 F.3d 1052 (10th Cir. 2006).
6.    U.S. v. Lane Labbs-USA Inc., 4219 F.3d 27 (3rd Cir. 2005).
7.    JN Gibbs, “Disgorgement and Restitution,” Regulatory Affairs Focus 11, no. 2 (2006): 34–35.
8.    U.S. v. Dotterwich, 320 U.S. 277 (1943); U.S. v. Park, 421 U.S. 658 (1975).
9.    White Paper: Infusion Pump Improvement Initiative, April 2010; available from Internet: www.fda.gov/medicaldevices/productsandmedicalprocedures/GeneralHospitalDevicesandSupplies/InfusionPumps/ucm205424.htm.
10.    FDA, “Questions and Answers About the Baxter Colleague Recall, Refund, and Replacement Action,” available from Internet: www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm210768.htm.
11.    P Benesh, “Baxter Recall Creates Opening for Hospira,” Investor’s Business Daily (June 4, 2010); available from Internet: www.investors.com/NewsAndAnalysis/Article/536372/201006041738/Baxter-Recall-
Creates-Opening-For-Hospira-.aspx
.

Bethany J. Hills and Monika Bhatt are attorneys in Hodgson Russ LLP’s Life Sciences Practice Group. Bethany can be reached at [email protected] and Monika at [email protected]

Unlocking the Power of Coronary CT Angiography

iSTOCKPHOTO

There may be an opportunity for CT angiography to be used as an inexpensive screening tool to bring a large unidentified population with coronary artery disease (CAD) under medical surveillance—a population that would otherwise be susceptible to unexpected heart attack deaths. To harness this diagnostic tool, several other things need to happen: CT scanner speeds need to be increased to render the coronary artery blockages and calcifications conspicuous, radiation exposure needs to be further reduced, and the software behind this tool needs to be made more user-friendly and intuitive, i.e., capable of shutting the system down if radiation levels reach unsafe levels. Computer-aided diagnostic software, which uses pattern-recognition algorithms, could help improve the accuracy and specificity of identifying early coronary vessel calcifications and soft plaques similar to how they have improved the accuracy of mammography in detecting breast cancers. Predictive algorithms and simulation software could also help predict the course of medical events and help develop a strategy for medical management or intervention. Finally, reimbursement barriers have to be overcome, by way of clinical data, to make this procedure more clinician- and prescription-friendly.


In 2010, more than 10 million Americans will experience chest pain.1,2 Of this population, about 950,000 will die from CAD—and of that number, 335,000 will die from heart attacks (also referred to as myocardial infarction (MI)) without being hospitalized.3,4 The estimated direct and indirect costs of treating patients with coronary heart disease is $177 billion in 2010.2

Figure 1. The progression of plaque in CAD.

CAD is a condition in which there is an obstruction to the coronary blood vessel flow into the pumping heart muscle due to the formation of plaques. Plaques (fatty deposits within the walls of the coronary) are either vulnerable (soft) or nonvulnerable. The vulnerable plaques can be ripped during unaccustomed exertion (e.g., vigorous exercise without training), leading to platelet activation and blood clot formation. These factors increase the likelihood of obstruction, which can lead to a heart attack (see Figure 1).


When investigating a patient with CAD, cardiologists need to know the anatomy of the arteries and blockage, the ischemia caused by the blockage, and the state of viability of the heart tissue (see Figure 2). Cardiologists use several tests to discover these traits: stress test electrocardiogram (ECG), thallium scan or perfusion studies, invasive catheter coronary angiography, coronary CT angiography (CCTA), and magnetic resonance (MR) angiography.5 This article focuses on CCTA.


CCTA is a noninvasive procedure performed by injecting a radiopaque dye into the patient and capturing the images of the heart from different angles using a CT scanner. This method provides anatomical information about the coronary arteries including the presence of blockages, plaques, and calcifications. Calcification is the deposit of calcium within the plaques inside the walls of coronary arteries and denotes advanced CAD. As per literature, calcium scoring, i.e., the measurement of total calcification in the coronary vessels, has a direct relationship with the longevity of the patient.6 A CT scan of the heart without a radiopaque dye can be used to determine the calcium score.

Figure 2. When investigating a patient with CAD, the cardiologist would like to know three important characteristics of the heart: the anatomy of coronary arteries and blockage, the ischemia caused by the coronary blockage, and the state of viability of the heart tissue.


The recent integration of positron emission tomography (PET) and CT, although very expensive, meets the dream objective—an imaging technique that provides information about the anatomy, ischemia, and viability, in a single test. However, screening a large population with this type of expensive imaging is not feasible.7 To be effective in detecting undiagnosed CAD, the screening tool should not only have a high degree of reliability, high yield, and good validity, but it should also be cost-effective with a high degree of acceptance among physicians and patients.8


The authors designed a questionnaire and interviewed several interventional cardiologists across the United States to determine the feasibility of using CCTA as an early tool for the detection of CAD. Based on interview responses, CCTA is mainly useful in the following settings.


Emergency Settings. In the emergency room (ER), CCTA can quickly perform a “triple rule out” among MI or unstable angina, aortic dissection, and pulmonary embolism—all of which have acute chest pain as a primary symptom. CCTA is a simple procedure that can be performed in the ER as opposed to a nuclear stress test, MR angiography, or ECG stress test, primarily due to time constraints in the ER setting and the fact that a patient with acute chest pain may not be in a position to undergo some of these tests. Because more than 50% of ER visitors in the United States come in with chest pain, CCTA has clear applicability in the ER setting.9


Coronary Anomaly. CCTA is a niche diagnostic tool in cases in which interventional coronary catheterization cannot detect coronary artery anomalies (anatomical arterial abnormality).


High-Risk Patients with Abnormal Stress Test. Some high-risk patients with abnormal stress test results may not be able to undergo a coronary artery bypass graft, and CCTA is a good tool to help identify coronary artery plaques.
Symptomatic Patients with Stable Angina. CCTA is a noninvasive screening tool that can locate and measure coronary plaque. It is relatively cost-effective when compared with other cardiac imaging techniques (see Table I).


Asymptomatic Patients.
CCTA can help in risk stratification and help manage patients to prevent major consequences of CAD. It is useful for patients who have no coronary symptoms but are at high risk of CAD due to a strong family history or other risk factors.


CCTA is a user-friendly outpatient procedure that can be conducted in about 30 minutes, and it is relatively cost-effective compared with other procedures.10 Although CCTA is not propagated as a standard screening tool for CAD in the United States, the negative predictive value of this procedure has made it a popular addition in routine physicals of corporate executives in some South Asian countries.


Economic dynamics and American Hospital Association (AHA) guidelines play an important role in limiting the wide use of CCTA for screening purposes. Most insurance companies in the United States do not reimburse for this procedure except for those indications currently listed in the AHA guidelines, such as for the detection of coronary anomalies. If the indications are further expanded in the guidelines to include screening for early detection of CAD and preventive management of impending MI, then CCTA may reduce heart attack deaths by bringing this asymptomatic population under preventive care. At present, health-conscious asymptomatic patients may have to pay out of their own pocket to take this test.


In addition, many interventional cardiologists interviewed said that cardiologists have a vested interest in not selecting CCTA because

  • They lose control of the patients as the case gets transferred to the imaging facility and to the radiologist.
  • If a large blockage is seen on a CCTA, they still have to proceed with therapeutic interventional catheterization anyway.
  • The reimbursement for interventional cardiac catheterization is far more than CCTA for the physician (see Table I).
  • The setup cost for CT scanners is high, unlike gamma cameras in thallium studies, and CCTAs' reimbursement coverage is relatively low in the United States.


One of the operational limitations for CCTA’s acceptance as a screening tool for CAD is the injection of a contrast agent and its nephrotoxic side effects. Additionally, the radiation dosage for a 64-slice scanner is anywhere from 4 to 16.3 mSv (millisievert) depending on gender and the physician performing it. According to FDA, “For a person without symptoms, CT screening is unlikely to discover serious disease, and the potential harm to the individual may be greater than the presumed benefit.”11 However, the response from some of the cardiologist interviewees was that the radiation effects caused by interventional coronary catheterization under fluoroscopy (the current gold standard for CAD diagnosis) is much higher than the radiation dosage delivered by CCTA. For symptomatic patients, radiation is not a problem; for asymptomatic patients, however, it is a concern because there could be false positives with CCTA, where the blockages might never progress to a symptomatic stage.


Interviewed cardiologists said that calcium scoring, i.e., plain CT heart scans without the injection of radiopaque dye to evaluate the calcium deposits in the coronary arteries, could be recommended every 10 years after age 40. This method could be alternated with a stress test every (other) five years. At present, CCTA is not considered a standard of care for detecting CAD by U.S. regulatory and reimbursing bodies, whereas stress tests, thallium scans, and ECGs are.

Figure 3. Opportunity area for a new or modified device as a screening tool for cost-effective and early detection of CAD.

Despite the epidemic proportion of CAD, there is really no effective screening tool in place today to pinpoint coronary artery blockage as represented in Figure 3. CCTA can provide the objective evidence to bring a larger asymptomatic population with undetected CAD under medical management—to stabilize soft plaques and advocate lifestyle changes that delay the progression of the disease and the occurrence of heart attacks.


The Role of OEMs

There have been rapid advances with CT technology with the advent of multislice scanners. These high-resolution and high-speed systems obtain excellent images of the coronary arteries. With prospective ECG gating (heart being imaged while an ECG trace is recorded), the effective dosage of radiation could be reduced from 10–15 mSv to as little as 1.2 mSv. Currently, 64-slice scanners are widely available; however, 128-slice scanners have entered the market and are very good at identifying soft vulnerable plaques while keeping the artifacts low.


The software used in CCTA can be further improved to make it more intuitive, user-friendly, and especially to improve synchronization with regards to the ECG and diastolic heart images. To reduce the radiation exposure to the patient, there is an urgent need for the software to be able to self-check and measure the radiation exposure. The software should be able to create an alarm or shut the system down if the levels reach inappropriate ranges. This feature should be incorporated into the design of the CT system itself. Manufacturers can help by providing more outreach and educational training for technicians.


For CCTA to emerge as a viable screening procedure for the early detection of CAD, device manufacturers need to overcome certain barriers, including the lack of clinical evidence of efficacy or accuracy of predicting CAD. Clinical evidence–based amendments to AHA guidelines would eventually lead to improved reimbursement coverage from insurance companies. Finally, a drop in the setup cost of CT systems thanks to improved reimbursement coverage would facilitate greater acceptance by the medical fraternity.


Conclusion

There is an overwhelming need for a noninvasive, economical tool that can safely screen for significant coronary artery stenosis. CCTA, due to its low cost (almost 10 times less expensive than invasive catheterization) and high negative predictive value, is uniquely suited to address this need. The incorporation of new pattern recognition and predictive software tools into current high-resolution, high-speed CT systems might help increase the sensitivity of CCTA, allowing the method to be useful for ruling out soft plaques, a harbinger for impending heart attacks. Also, more clinical data are needed to convince the reimbursement bodies to expand the reimbursability of CCTA as a screening procedure.


References

1.    S Boyles, “Cardiac Catheterizations: Too Many Performed?” Heart Disease Health Center, WebMD, March 2010; available from Internet: www.webmd.com/heart-disease/news/20100310/cardiac-catherizations-too-many-performed?src=RSS_PUBLIC.
2.    “Heart Disease and Stroke Statistics—2009 Update, A Report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee,” Circulation 119, no. 3; available from Internet: http://circ.ahajournals.org/content/vol119/issue3/.
3.    G Thorgeirsson, G Thorgeirsson, H Sigvaldason, and J Witteman, “Risk Factors for Out-of-Hospital Cardiac Arrest: The Reykjavik Study,” European Heart Journal 26, no. 15 (2005): 1499–1505.
4.    “Sudden Deaths from Cardiac Arrest—Statistics, American Heart Association”; available from Internet: www.steeltonfire.com/ems/cardiacarrest.pdf.
5.    MJ Shirani, “Advanced Cardiovascular Imaging: The American Experience,” Current Cardiovascular Imaging Reports 1, no. 1 (2008): 2–3.
6.    P Greenland et al., “ACCF/AHA 2007 Clinical Expert Consensus Document on Coronary Artery Calcium Scoring By Computed Tomography in Global Cardiovascular Risk Assessment and in Evaluation of Patients With Chest Pain,” Journal of the American College of Cardiology 49, no. 3 (2007): 378–402.
7.    M Vasken Dilsizian, “Keeping Current with the Latest Advances in Cardiovascular Imaging,” Current Cardiovascular Imaging Reports 1, no. 1 (2008): 1.
8.    JMG Wilson and G Jungner, “Principles and Practice of Screening for Disease,” Public Health Papers No. 34, WHO 1968; available from Internet (pdf): http://whqlibdoc.who.int/php/WHO_PHP_34.pdf.
9.    WE Cayley Jr., “Diagnosing the Cause of Chest Pain,” American Family Physician 72, no. 10 (2005): 2012–2021.
10.    MJ Budoff et al., “Cost-Effectiveness of Multidetector Computed Tomography Compared with Myocardial Perfusion Imaging as Gatekeeper to Invasive Coronary Angiography in Asymptomatic Firefighters with Positive Treadmill Tests,” Journal of Cardiovascular Computed Tomography 3, no. 5 (2009): 323–330.
11.    “FDA Unveils Initiative to Reduce Unnecessary Radiation Exposure from Medical Imaging,” FDA News Release; available from Internet: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm200085.htm.


Sudhi Gautam heads the Medical Solutions Group at Patni Americas Inc. (Milpitas, CA). Arathi Asthi is an intern at the company.

A Logical Choice for Medical Device Software

The goal of medical device software development should be to select a process and architecture that ensure a safe and effective product. The methods utilized to achieve this goal differ among medical device manufacturers, but the result must be a safe and effective product that delivers value. FDA provides guidance on medical device software development processes to assist developers in achieving a verifiable safe and effective medical device. This guidance addresses important topics with which a manufacturer’s software development team should be very familiar: adherence to organizational software development policies, accurate and understandable documentation, efficient test plans, validation and verification, and a framework for the entire software life cycle.1


For embedded real-time systems, one of the main decisions to be made at the start of the medical device project is whether a commercial multitasking real-time operating system (RTOS) will guarantee predictable and reliable behavior of the system software. Often, the decision to use an RTOS is based on anticipated programmer convenience, rather than expected simplicity of verification and expected reliable real-time performance of the medical device software. Most multitasking RTOSs have complex methods of scheduling task execution similar to a desktop operating system’s method of switching among applications. The operation of a multitasking RTOS is difficult to verify completely, and incorrect assumptions about its dynamic operation and side effects could have serious implications.


If the requirement is sufficiently well defined, a finite state machine–based architecture can provide an attractive alternative to conventional RTOSs.


Exposing Structure and Organization in Reactive Systems

All software performs as an integrated system of one or more finite state machines (FSMs), whether the software is explicitly designed from that perspective or not. This is especially true for complex reactive real-time embedded software systems. Disregarding this fact often results in poorly structured software whose unnecessary
complexity breeds mysterious bugs and anomalous behavior. Because finite state logic is the foundation of the digital hardware that executes software, it follows naturally that FSMs should be used in reactive embedded software applications. FSMs scale easily from microcontroller-based through multiprocessor platforms, simple through complex. In fact, an entire software application can be constructed and executed as one or more FSM tasks, altogether eliminating the need for a multitasking RTOS. FSMs do not have to be small, but they do have to be unambiguously defined.


A major benefit of using finite state logic to design software is that it clearly communicates system logic, structure, and
organization—both in human-accessible and machine-readable forms. It is easy to review the design and to validate and verify its operation.


Software developers see this characteristic of finite state logic as soon as they partition an application into logical resource objects, each to be implemented as an FSM task. In an infusion pump, for example, tasks such as air bubble detection, pump motor speed control, user interface switching, dial processing, and battery power management are easily implemented as FSMs. Conversely, partitioning an application for an RTOS is more arbitrary and is usually based on application processes. The logical partitioning into resource objects is easily justified as the architecture of medical device software because each task can be efficiently and verifiably implemented as an FSM.


Finite state logic is a method for describing the dynamic behavior of a system as it reacts to external events and internal conditions, resulting in specific actions and optional outputs. The system, or task, has a finite number of predefined states and is said to be in a specific state at any instant of time. In a particular state, the task responds in a state-specific way to any of the events that may occur while the task is in that particular state; it is possible to define different states in the same task that focus on events in their own distinctive ways. The task will enter a new state in response to an event, as part of the defined reactive behavior of the previous state. Such systems are sometimes called Mealy-Moore state machines.


Every state diagram maps directly to a simple state table. The state diagram and its corresponding state table constitute the language of finite state logic. The state diagram depicts the set of states as circles, which are the source of directed arrows, each labeled with text indicating the defined events and conditions in which a transition from the current state to the next state will occur. The corresponding state table provides the same information in a list, or tabular form. Creating a state diagram of a system or task is an analytical process that usually requires some iteration to precisely define the required behavior. A task state diagram can be directly coded into a source code module, and together, they can be easily reviewed by a design team. State diagrams, along with supplementary text descriptions, then become an important part of a company’s premarket submission’s design documentation.

Figure 1. Basic infusion pump state diagram.


Figure 1 is an example of a state diagram for operation of a hypothetical generic infusion pump. An actual design of an infusion pump would involve more task state machines, but this example conveys how state logic can be used to describe the general operation of a system.


The validation process requires that designs be traceable to requirements, so let’s establish the basic requirements that this state diagram must fulfill.

  • After system initialization, the infusion pump shall be idle (pump not infusing).
  • Infusion shall begin upon pressing the [START] button.
  • Infusion shall stop when either the volume has been delivered or the [STOP] button has been pressed.
  • Volume and infusion rate may be set while idle or infusing.
  • While idle, air bubble detection shall cause a visual alert and prevent the start of infusion. When the air bubble is removed, the visual alert will be removed, allowing infusion to be started.
  • While infusing, air bubble detection shall be indicated by audible and visual alerts, and shall cause the pump to stop. If the [STOP] button is pressed while the air bubble is detected, the audible alert shall be removed, and subsequent removal of the air bubble shall not restart infusion. If the air bubble is no longer detected, and the [STOP] button has not been pressed, the audible and visual alerts shall be removed, and the pump shall resume infusing.

Notice the five defined states in the Figure 1 state diagram. Each state is named, and directed arrows indicate the allowable state transitions. Notice also that each transition is labeled with the event and action to occur. It is common to label state transitions with an “input/output” or “event/action” as is shown in the diagram. Some events may stimulate an action (or output) but leave the FSM in the current state to process further events as they occur—for instance, in this diagram, changing the rate or volume in the ready-idle and pump infusing states.


As Figure 1 shows, a lot of detail can be captured within a state diagram. A state table can always be generated directly from any state diagram; people generally prefer to create and inspect state machines in the visual context of state diagrams.


Imagine the benefits of constructing an entire medical device software system in which each task is defined in this manner. This method highlights the ease of translating the state logic of each task directly into source code. Using finite state logic and state diagrams, the software design review process is intuitive and meaningful, because it is easy to exhaust the possible reactions of the system at any particular state. This powerful technique makes it easy to trace software back to requirements and generate test plans. Every medical device software developer should be conversant with this technique.


Choosing a Level of Finite State Logic

Finite state logic can be deployed at various levels of software design: from the entire software architecture to the graphic pushbutton used to toggle a device. State logic can be used with an RTOS and simplifies the design and implementation of required features and processes. However, the performance benefit of direct execution of task state machines is reduced when running under an RTOS scheduler that executes the processes, even if the processes contain explicit state logic.


Conventional RTOSs are not designed to execute finite state logic efficiently; they force the processor to regard each task as a separate application, requiring a full context switch before they can resume execution of a task from where it previously was suspended. Additionally, event processing and intertask messaging managed by a typical RTOS are valuable services to many applications, but they can be more efficiently integrated within an FSM-based architecture, where these services are processed directly by the tasks themselves.


The performance benefit achievable by continuous, concurrent, and direct execution of task state machines is derived from the inherent nature of finite state logic—given a specific state of a system, no action or output processing is required until a specific defined event has occurred. In other words, tasks are performed at high execution rates. This setup translates into very efficient processor usage and acceptable performance at processor clock speeds lower than those required when using a conventional RTOS (with its attendant overhead). This characteristic of finite state logic architecture has potential power savings for portable medical devices.


Many designers choose not to use a commercial or in-house–designed RTOS for their medical device software for justifiable reasons. They instead opt to build the software specifically for the device. This method is perfectly acceptable, as long as the resulting design exhibits good organization and structure, can be reasonably maintained, and is well documented. This is the ideal case for the use of FSMs to improve accuracy, inspection, debugging, reliability, and overall performance.


Develop a Strategy

If finite state logic methods seem worthy of consideration for your next medical device software system, begin developing a deployment strategy now. This strategy should address the following:

  • Training staff in using finite state logic effectively.
  • Enhancing the organization’s software development policy.
  • Methods of improving documentation for the product.
  • A plan for FDA premarket approval.

Training members of the software development team to use finite state logic effectively should be central to a successful strategy. There are resources for IEEE-CEU certified training on FSMs for embedded software systems, such as Staccato (www.mapletechproductions.com). If the use of an RTOS is still a consideration for the medical device software architecture, the training strategy should include UML Statecharts–based products.


The organization’s software development policy should be reviewed and modified to incorporate the use of finite state logic. Source code style, including file and function headers, can be enhanced to reflect the finite state logic structure. Improvements to the software design review process should reflect the shift from source code verification to the review and validation of system state diagrams.


The versatility of finite state logic should also be applied to the requisite software documentation process identified in the software development policy. Using state diagrams with supplementary text  ensures an unambiguous description of product specification, software requirements, and detailed design documents. Medical device software documented in this manner improves the traceability of operational requirements from product specifications through software implementation.


A strategy that incorporates the use of finite state logic in device software can result in a comprehensive process. The set of documents submitted for FDA approval is a valuable company asset. The documents reflect an organized process that can benefit from state diagrams (or equivalently, state tables) at major parts of the life cycle, appearing in design outputs, implementation plans, test plans, and maintenance plans. They are helpful source documents for user documentation and for designing training courses.


Conclusion

The medical device manufacturer, caregiver, FDA, and the consumer all have a stake in safe and effective medical devices. The FDA guidance stresses the expectation that there will be a process that is documented and under control. Software developers, in considering the architecture for the medical device, have a few options to consider: a commercial or in-house–designed RTOS, a device-specific architecture, or a system of FSMs. Finite state logic, based on the Mealy-Moore paradigm, may be deployed on various levels within the software system.


Using finite state logic benefits not only the designers, but also those involved in testing, debugging, documenting, validating, and verifying. State diagrams and corresponding state tables capture the behavior of FSMs and convey to the reviewer the overall organization, partitioning, and structure of the medical device software system. A strategy to deploy finite state logic in medical device software should include training personnel and adopting improved documentation methods to reflect the organization and structure afforded by this powerful technique.


Reference

1. General Principles of Software Validation; Final Guidance for Industry and FDA Staff (Rockville, MD: FDA, CDRH, 2002); available from Internet: www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/ucm085371.pdf
.


William Spees is a forensic software engineer at CDRH (Silver Spring, MD). Don Berndt is owner of Mapletech Productions LLC (Maple Glen, PA).

A Secretive Agency Makes a Secretive Safety Appointment


The appointee, William Maisel, “is no figurehead,” an anxious-on-industry’s-behalf Med City News writer, Thomas Lee, reported in August.


“He will oversee auditing of CDRH procedures to ensure consistency and accuracy across the center. More importantly, however, Dr. Maisel will chair the new Center Science Council (CSC), a new body responsible for setting scientific standards for approving devices and issuing recalls.”


Opining on the face value of Shuren’s various public remarks that industry “will see much more transparency and certainty” from CDRH as it reforms its 510(k) program, Lee went on to fan the flames of anxiety that he knows are mounting out there.


Maisel’s new charge, CSC, “is still a little vague,” Lee reported, citing an FDA report that said part of its work should be to meet regularly and “be available, as needed, to discuss and vet potential changes in the center’s regulatory expectations on which staff at lower organizational levels wish to seek additional advice from a wider range of experts, or whose impact could be cross-cutting enough to warrant broad or center-level attention. Another role for the CSC relates to increasing the consistency of 510(k) decision making.”


What was missing from the FDA report was CSC’s potential role in resolving disputes between medical device companies and staff examiners. Maisel’s appointment will bring no comfort to medical device makers. As director of the Medical Device Safety Institute at Beth Israel Deaconess Medical Center in Massachusetts, Maisel has been “an outspoken safety expert,” Lee said, citing a trade newsletter.


This is disturbing to industry, Lee suggested. For example, Maisel criticized Medtronic Inc. for its handling of the massive recall of its Sprint Fidelis leads. “Manufacturers have repeatedly and knowingly sold potentially defective devices without public disclosure,” Maisel wrote in a 2008 article published in the New England Journal of Medicine. “For example, after identifying and correcting a design flaw that could cause premature depletion of ICD batteries, Medtronic continued to sell its inventory of potentially defective ICDs without public disclosure. Similarly, the two other major ICD manufacturers, Guidant (now part of Boston Scientific) and St. Jude Medical, have knowingly marketed potentially defective arrhythmia devices unbeknownst to the public.”


Lee ominously reminded readers that in the same article, Maisel concluded: “The welfare of medical device recipients must become a higher priority for FDA and manufacturers, and it is increasingly apparent that such a change will require congressional action. Essential consumer protections are currently lacking.”


Maisel is hardly the kind of man manufacturers would like to see being secretly added to a key position in FDA’s embattled—and formerly most industry-courting—program center. Under Shuren and his furtive appointee Maisel, CDRH is clearly slipping out of the industry bed it has been in for so long, and raising the focus on safety for a constituency that holds no financial stake in device approvals—the largely voiceless American public.


The cloistered nature of FDA’s personnel system has deepened under the Obama administration. Previously, personnel appointments were routinely announced and shared with interested media through open e-mail messages from the appointing manager, describing the individual’s background and closing with, “Please join me in welcoming…”


That openness faded away in the closing months of the Bush administration, and when I asked commissioner Margaret Hamburg and deputy commissioner Joshua Sharfstein during a private meeting for its restoration, they seemed disinterested but said they’d “look into it.” The curtain has not been lifted since.


Of course, there are theoretical detriments from a management point of view to outsiders knowing who at FDA is or might be looking at their stuff—inappropriate contacts might result, interfering with management’s control of a matter.
Under both Bush and Obama, no information may reach inquiring reporters about CDRH appointments except through designated CDRH press officer Dick Thompson. Asked to respond to Lee’s article, and to provide Maisel’s bio and date of appointment, Thompson did not respond.


More FDA Secrecy on LASIK Outcomes Study

FDA is maintaining stoic silence on persistent questions about the protocol and the principal researchers for a long-term LASIK eye surgery patient-experience study it asked the Department of Defense (DoD) and the National Eye Institute to conduct in October 2009.


The study, which is due to report in 2012, has been called “conflicted” by LASIK critics because the DoD component, the U.S. Navy Refractive Surgery Program in San Diego, has publicly testified in favor of the surgery and performs it for all DoD service arms. The challenged study involves military service personnel who have undergone the procedure.


At a CDRH advisory committee public hearing on LASIK in April 2008, U.S. Navy Refractive Surgery Program director David Tanzer presented data indicating that more than 98% of naval aviators who had undergone LASIK surgery said they were either “extremely satisfied” (90.9%) or “moderately satisfied” (7.2%) with their results.


Based on these data, plus a 95.4% satisfaction rate reported to FDA in preapproval IDE clinical data, DoD has been encouraging vision-impaired service personnel to undergo the procedure at government expense, eliminating their need for glasses and contact lenses and thereby improving their performance on the battlefield. However, the data source for this high satisfaction rate remains secret, and this rate is considerably higher than publicly available data.
In the LASIK procedure, a U-shaped flap is cut in the surface of the cornea and a laser is used to reshape the cornea to enhance vision. The flap is then put back in place, but according to critics, it never heals and remains susceptible to accidental dislodgement and infection. In some cases, these conditions may lead to deferred, later-life permanent vision impairment, blindness, depression, loss of employment, and suicide.


An estimated 4 million LASIK surgeries—quadruple the rate nine years ago—are performed in the United States each year at vividly advertised prices as low as $299 per eye. According to a premarket clinical data analysis by former CDRH ophthalmic surgery devices branch chief Morris Waxler, who led the 1998 review and approval of lasers used in these surgeries, there had been an overall long-term success rate for LASIK of less than 50%. Long-term postmarketing data, he says, confirm the premarket incidence (15% or higher) of adverse events leading to permanent vision problems including (but not limited to) dry eye, haze, night driving problems, blindness and suicidality caused by these FDA-approved devices in the commercially exploited civilian population.


FDA has agreed to study this issue, but details of the study have been kept secret. Innumerable requests since March for the names and affiliations of its principal researchers and for a copy of its protocol have gone unanswered by FDA’s press office, now the sole portal for news media access to internal agency information. The office’s former head, George A. Strait, once said he saw its function as “telling the good news about FDA,” and the office consequently is not known for releasing negative news about the agency’s activities—which agency complicity in an allegedly biased LASIK safety study would seem to be.


It could be argued that maintaining military confidence in the LASIK procedure is a national security issue, justifying FDA’s suppression of the 15%-plus long-term real-world failure rate through agency adherence to the preferred 4.6% rate submitted in premarket data that supported LASIK device approvals 12 years ago.


FDA’s acceptance of the smaller number has recently been publicly recanted by Waxler, who is now retired and working with injured LASIK patients campaigning for beefed-up FDA warnings and marketplace enforcement. Earlier tis year on ABC’s Good Morning America, Waxler criticized the data on which he says his team erroneously approved the LASIK lasers in 1998. Since that television appearance, FDA has asserted that the data were not flawed, but have not provided substantiation for that claim.


In retrospect, it may seem important for FDA to conceal the shortcomings of that approval and the newer data showing a much higher failure rate for LASIK than was seen in the data supporting the device approvals. After all, if military service personnel elected not to undergo the procedure because of a reputed threefold higher risk of postservice and long-term vision impairment, battlefield consequences could feasibly endanger military objectives and even national security.


Asked to comment, FDA’s press office and senior agency management did not respond.


AdvaMed Calls Infusion Pump Guidance “Premature”

AdvaMed says FDA’s announced intention to convert its draft infusion pump guidance into a special control is premature at this time. In recent comments on the guidance, AdvaMed says deferment would allow FDA and manufacturers some flexibility to meet FDA’s objectives.


“Although FDA has given thought to the draft guidance and to the new requirements it will impose on infusion pumps in order to improve the safety profile of infusion pumps,” the comment letter says, “manufacturers may develop more effective mechanisms to meet FDA’s objectives and requirements than can be predicted now at this early stage.

Additionally, as manufacturers strive to meet FDA’s new objectives and as infusion pumps change over time, there will inevitably be new issues and questions that arise. Guidance enables FDA and manufacturers to pivot more quickly to address those questions and issues than does a special control regulation.”


If FDA proceeds to convert the guidance to a special control, AdvaMed says it recommends that the agency allow sufficient time for implementation of the new, final guidance to ensure that there are no unforeseen issues that are then transferred to the special control regulation.


The letter also raises concerns and makes comments on assurance case reports, clinical evaluations, preclearance inspections, different technological characteristics, different pump types, legacy devices, and changes to marketed pumps.


Meanwhile, in submitted comments, the Medical Device Manufacturers Association (MDMA) challenged many aspects of the draft guidance, saying that while some of its elements are warranted, others are overly broad and opaque. “Failure to address the points raised [...] will create more uncertainty for companies developing these important products and as a result, patients suffering from severe pain, cancer, and other ailments may not have access to the most effective therapies,” it said.


MDMA also raises serious concerns about FDA’s process in developing and implementing the guidance. It says the agency’s announcement that it is treating the draft guidance as being immediately effective before stakeholders have an opportunity to comment and for those comments to be incorporated is inconsistent with Good Guidance Practices regulations and with agency efforts to enhance transparency and communication with various stakeholders.


The group encourages FDA “to wait until the public comment period is concluded, review, and incorporate the comments provided by stakeholders, and issue a final guidance based upon this feedback,” the comments say. MDMA wants the final guidance to “recognize the unique characteristics of various infusion pumps, provide data in support of new recommendations, and afford medical device manufacturers a reasonable timeline in which to comply with the new policy so that patient access to these important products is not impacted.”


In its comments on the document, the Combination Products Coalition praised FDA on its stakeholder outreach and discussions and said it agrees with the guidance’s general principles concerning information and data that should be submitted in a premarket notification submission for an infusion pump.


But the coalition called on FDA to clarify that the guidance document relates only to noncombination products. It said that some of the guidance’s concepts could be misinterpreted as applying to drug-device or biological-device combination products. The long-standing regulatory position of FDA and industry is that infusion pumps and the drugs or biological products they dispense are not considered combination products.


FDA and FCC Coordinate on Wireless Medical Devices

FDA and the Federal Communications Commission recently spent a day and a half listening to industry and others on how to keep up with and not hinder the wireless medical devices revolution. FDA commissioner Margaret Hamburg, who was at FCC for the first time, told the session that “To harness the full power of the devices’ benefits, we must improve the efficiency of the regulatory processes where the two agencies’ jurisdictions’ overlap and jointly understand the challenges.”


She said the range of wireless devices could “reduce costs, bolster quality, and benefit both patients and providers by making health data and information immediately accessible for patient care,” possibly changing the face of medicine forever. Noting that the first national broadband plan, released by FCC in March, “commits the agencies to clarifying and streamlining the regulation of converged communications and healthcare devices,” she asked attendees to speak freely about concerns over regulatory requirements and potential barriers.


In the coming months, FDA will issue a draft guidance, informed by the meeting, on “how to approach mobile apps that are truly medical devices,” and facilitate innovation, Hamburg said.


She and FCC chairman Julius Genachowski signed a memorandum of understanding at the meeting committing their agencies to coordination on medical devices. Genachowski said the “enormous benefit” of FCC and FDA working together became clear during his agency’s outreach for the healthcare chapter in the broadband plan.


Hamburg also noted that as she walked around the displays of medical devices at the meeting, she also realized they “would make an enormous difference to families [and] caregivers in homes and communities.”


Among the current or expected devices described during the meeting were a “smart Band-Aid” that continuously reads an individual’s vital signs and sends them to a monitor; remote diagnostic devices; technology to allow patients to get care from a specialist thousands of miles away; and devices that track patients’ glucose level or cardiovascular data.
A number of speakers indicated that the innovations are outpacing best practices standards as well as regulation.

MedApps CEO Kent Dicks said that when his company got its first FDA clearance a few years ago for a smart phone application, the agency had not previously dealt with that kind of innovation. He said both the company and the agency had learning to do. MedApps had to train a new reviewer in a different FDA department each time as it added capabilities, such as in vitro testing and cardiology. He did say he thought that situation is improving.


Tom Watlington, head of Sotera Wireless, asked the agencies not to be perfectionists. For instance, he said there are times when wireless connections with devices will be lost, but those issues can be ameliorated through patient education and through devices that can tell the patient they are outside the network’s range and can thus store data to forward it later. That’s where FDA will play a major role “with its expertise in risk management and human factors
 design,” he said.


Dexcom chief technology officer Jorge Valdes urged the agencies to stay flexible in what they allow, noting for instance that consumers already expect the excellent color and graphics available on smart phones. He asked the agencies to clarify where the regulatory authority sits between them. Valdes also asserted that “plenty of technology” already exists in financial and consumer applications to deal with devices’ reliability and security, so the agencies should not reinvent the wheel in that arena.