Speaking at the Incorporation of New Science into Regulatory Decisionmaking public meeting in February, recentlyappointed CDRH director Jeffrey Shuren said that the goal is to set clearer guidelines on “what situations might justify a change in our decision making and to determine how to communicate those changes to our external constituencies in a timely manner in order to achieve a reasonable level of transparency.” Shuren has been in charge of CDRH in an acting capacity since September, following the departure of Daniel Schultz.

Long-term experience with devices on the market can provide new scientifically significant information that was not previously available to the center, Shuren told the audience. He acknowledged that the center already deals with this evolving science challenge regularly, and that reviewers make adjustments to their work on a case-by-case basis.

“We also recognize that in order to foster innovation, we need to provide industry with reasonably predictable pathways,” Shuren said. “We will not accomplish this if we make our decisions to change course on an ad hoc basis or if we leave our external constituencies in the dark about our decision-making processes and our rationale.”

An internal task force, led by CDRH associate director for postmarket operations Jonathan Sackner-Bernstein, is assessing the way the center currently anticipates using science to support its regulatory decision making. Input from the public meeting will be used to prepare a task force report that will be open for public comment sometime after June. Shuren expects CDRH’s new perspective on scientific regulatory decision making to begin in September.

During the public meeting, the agency received mixed comments on how it should proceed with already approved and cleared devices and those seeking approval and clearance once a signal becomes evident from medical device reports (MDRs). 

Johnson & Johnson emerging technologies vice president Joe Smith raised concerns about the difficulty of understanding MDRs, which he said are often sparsely populated and difficult to understand.

The notion of clustering MDRs and trying to derive from that meaningful and actionable information is something that every company with a marketed device struggles with as an opportunity for continuous improvement...I would hesitate to advise action on sparse and incomplete data at best without a fair bit of process to understand what is the generator behind that...There needs to be a rather substantial process that derives from those MDRs, but then works through trend analysis, root cause, and then a full understanding of what the issue is, and whether there is an issue to start with.

Smith also pointed out that the overall risks and benefits needed to be taken into account. “You can certainly uncover novel attributes of the device postapproval that were unanticipated, but if they don’t change the overall risk profile for the device, then I think that points to more about informing [labeling] than any other [regulatory] action.”

Frequent FDA critic and Cleveland Clinic cardiovascular department chairman Steven Nissen, who sought the FDA leadership position before Margaret Hamburg was chosen, argued against allowing the 510(k) process to be used for high-risk devices. He said that the scenario of dealing with numerous MDR signals should not arise frequently if the approval process is truly rigorous. “The quality of clinical trials in the device world is not very good by contemporary scientific standards. So it is much too common that devices get to market based upon poor-quality trials,” Nissen said.

Another subject that Nissen raised was the need for transparency. “I would like CDRH to be more forthright in communicating when its sees a pattern of MDRs to the public and to practitioners so we are appropriately warned that there are issues,” he said. “If those issues unfavorably affect the risk-benefit equation, we may have alternative devices to use.”

Nissen said that MDRs should be recognized as the tip of the iceberg. “The reason that decisive action is required early is that the size of the problem is almost always substantially larger than it initially appears.” It is important to communicate as soon as there is evidence of a safety issue, he said, “so that others can report cases and we can get a handle on what is really going on.”

If the MDR data suggest a safety pattern, the problem then becomes a denominator issue, argued Hospital for Special Surgery principle scientist Timothy Wright. “You don’t know if it is in certain patient subgroups; you don’t know how it might affect the substantial equivalence of other devices in front of you or already on the market.” Without that information, he continued, it is difficult for manufacturers to determine the scope of the problem.

Addressing another concern, Sackner-Bernstein asked meeting panelists how the center should handle a device under review that uses a predicate device with safety issues.

It depends entirely on the mechanism of action relating to the observations, Smith responded. If the devices have a similar mechanism of action, then the notion of asking questions pointed to the understanding of the cause makes perfect sense, he said.

National Research Center for Women & Families president Diana Zuckerman disagreed that device manufacturers and FDA must have determined a root cause before a regulatory decision is made. “Sometimes it takes a long time to determine the root cause,” she said. “I can’t think of a really good reason why a device that has a pattern of safety issues should be the predicate for another pending device.”

Shuren Wants 510(k) Revamp by June

CDRH director Jeffrey Shuren told his management team that he wants recommendations about how to revamp the 510(k)

review program by May 31.

The recommendations will be made by an internal working group that has solicited public and internal feedback on key challenges related to the 510(k) process. This and other center focus areas are outlined in CDRH’s FY 2010 Strategic Priorities report.

Fixing the 510(k) review program is part of CDRH’s continuing life cycle approach to medical device regulation, according to the report. By July 31, the center expects to have an implementation plan in place with changes beginning by September 30. On the PMA side, CDRH says it will take steps by the year’s end to improve the clinical data quality submitted to the agency. These will include a draft guidance on study designs for clinical trials and an assessment of the clinical study quality submitted in PMAs.

Another goal, according to the center’s priorities report, is to establish “policies and procedures to determine how to optimally use CDRH’s scientific resources to support the center’s programmatic functions.” To enact this, CDRH will hire a deputy center director for science and will develop procedures for using scientific computing resources across the center and agencywide.

The center also plans to improve its guidance and regulation development by creating a centralized team (by September 30) of regulatory and policy specialists dedicated to the strategic development of policies and practices that support the CDRH mission and programmatic functions. To accomplish this, CDRH plans to revise its Good Guidance Practices Manual and existing standard operating procedures for guidance and regulation development. It says it will post updated versions of these documents and other related information on its intranet page by July 31.

Another top priority focuses on improving CDRH’s transparency and communications. “CDRH will provide meaningful and timely information about the products we regulate and the decisions we make, through strategic outreach and systems that support transparency and two-way communication,” according to the report. Goals for this include implementing a strategic communication program and hiring an associate director for external relations.

STERIS Given 18 More Months to Market Unapproved Device

FDA says it is extending by 18 months (from February 2, 2010) the total recommended time period for the transition from STERIS Corp.’s modified System 1 (SS1) processor to legally marketed alternative devices. An updated FDA notice says that the agency has not approved or cleared the device for its labeled claims and the company has chosen not to seek FDA clearance.

The notice says that during a stakeholder call last December, FDA stated its view that healthcare facilities should be able to transition from the STERIS processor to legally marketed alternatives within three to six months. However, since then, the update says, the agency has heard from many healthcare providers and organizations that such a transition timetable may present significant difficulties for some facilities and adversely affect patient care. FDA says it is therefore extending the transition period for 18 months and expects that STERIS Corp. will continue to support existing units throughout the extended transition period.

“FDA does not expect to take regulatory action against healthcare facilities for failing to replace SS1 units within the
18-month transition period,” the notice says. “But these facilities should be aware that the current SS1 is a misbranded and adulterated medical device because it has not been cleared by FDA as safe and effective for its labeled claims. Healthcare facilities should therefore transition to alternative reprocessing devices as soon as practicable.”

Man Jailed for Unapproved Device

A California federal judge has sentenced James Folsom of San Diego to 51 months in jail and ordered him to pay a $250,000 fine. This follows the conviction of Folsom last year on 26 felony counts for selling an unapproved medical device. Prosecutors said that between 1997 and 2008, Folsom sold more than 9000 devices with names such as
NatureTronics and AstroPulse, bringing in more than $8 million.

FDA officials testified at the trial that Folsom never submitted his device for review and approval. Information found on a Web site indicated that the device was a small black box with dials, a digital screen, and wires leading to a pair of stainless-steel cylinders or metal plates. It was intended to be plugged into an electrical outlet while the user holds the cylinders or stands on the plates. The device claims to use electrical frequencies to attack and destroy diseased cells. Reportedly, it is based on the work of inventor Royal Raymond Rife, who claimed in the 1930s that directing radio frequencies at cells could destroy diseased cells. Rife’s work was never proven and experts discredited the theory, reports say.

Officials said Folsom escaped FDA detection by conducting business under false names. He marketed his device “for investigative purposes,” creating the impression that FDA was considering it for approval. Folsom is a former business associate of Kimberly Bailey, who sold similar devices and has been serving a life sentence since 2002 for plotting to kidnap, torture, and murder her business partner.

Amalgam Rule Spurs State Gags on Dentists

FDA’s historic position on the safety of mercury-based dental amalgams, and its controversial final rule last August affirming this, are fueling a battery of state-level cases against dentists who try to warn their patients about the devices. According to Tulsa, OK, attorney Jim Love, who represents many of the dentists, the cases attack the dentists’ First Amendment right to free speech. “This is a pervasive problem in many, perhaps a majority of states,” Love told me in February.

He cited the example of a 2007 North Carolina State Board of Dental Examiners declaratory ruling, which involved 30 statements that dentist W. Carl McMillan planned to make to patients and to local newspaper readers. The board, which bans claims by dentists that they practice mercury-free or metal-free dentistry, prohibited 11 of the statements concerning harmful effects of mercury in amalgam.

McMillan’s statements, the board ruled, “appear to be intended as advice to patients or prospective patients, yet there is no indication that the dentist has gathered any information about the patient’s health history, esthetic concerns, finances, or treatment goals before making the statements.” Additionally, it said, the statements did not comply with the standard of care because they omitted informed-consent discussions and could subject him to discipline for neglect and incompetence.

Finally, the board said, “the statements improperly portray the alleged dangers of dental amalgam as established fact.” It said FDA, the WHO, and the American Dental Association “have rejected similar assertions as unsupported by peer-reviewed, controlled research. To avoid misleading patients and potential patients, petitioner must disclose that the FDA, WHO, and ADA have approved dental amalgam for use in nonallergic individuals.”

Other state dental licensing and disciplining authorities have taken similar cues from FDA’s position, Love says. He is currently defending Shelby, MI, dentist Heather Stratton. A fellow dentist complained that she had made seven statements in a magazine interview about the dangers of mercury, including mercury in dental amalgam.Stratton’s statements, as reported by the magazine, were as follows:

? Most medical and scientific researchers have called for a ban on the use of mercury in all products.

? Mercury (amalgam) causes adverse effects on the immune, urinary, cardiac, respiratory, and digestive systems.

? Mercury (amalgam) produces kidney toxicity, neurobehavioral changes, autism, and multiple sclerosis.

? “Low” levels of mercury (amalgam) affect memory, attention, motor coordination, and steadiness.

? The WHO has concluded that dental fillings contribute more mercury to a person’s body than all other sources of mercury combined.

? No amount of exposure to mercury vapor can be considered harmless, especially considering its cumulative effects.

? 50% of dentists in the United States no longer use mercury amalgam fillings.

The complainant dentist, Vincent Benivegna of East Lansing, MI, called these statements false and misleading, citing “ADA and FDA research [that] has proven that dental amalgam fillings do not contribute to systemic mercury levels significantly and do not cause these detrimental effects.” He gave no documentation and asserted that Stratton “should be required to author another article to retract these inflammatory claims.”

The Michigan Dental Association elected not to refer Benivegna’s complaint to the state’s licensing and regulatory authority. Instead it sent the complaint to the Macomb District Dental Society for a professional ethics review.

In his response to the society on behalf of Stratton, attorney Love said the challenged statements are “verifiably true,” providing a 22-citation bibliography for them. He also cited judicial precedents, which established the constitutional right of physicians and dentists to communicate factually with their patients. “Being a member of a regulated profession does not result in a surrender of First Amendment rights,” Love wrote. He said that Stratton "has a legal obligation to advise patients of the adverse effects identified by manufacturer warnings. Michigan dentists have a legal duty to pass along manufacturer warnings to their patients.…Given the tenor of Dr. Benivenga’s complaint, we seriously doubt that he is upholding his legal obligation to warn his patients of the potential health risks associated with the use of dental amalgam."

Love told me that FDA’s final rule on amalgam has provoked an upsurge in such gag-the-antiamalgam-dentist campaigns throughout the country—a consequence he says he warned the agency about during the rulemaking. However, the agency made no reference to these campaigns in its preamble, which reviewed comments received from stakeholders. “They just didn’t address it—they couldn’t. There’s nothing they can say,” Love says.

Thus FDA, which generally has a dismal record of its own in the First Amendment arena, knowingly facilitates inhibition of dentists’ free speech at the state level, according to Love. This impedes public awareness of amalgam risks. He says he has letters from dentists declaring that the state-level actions, bolstered by FDA’s position, have effectively inhibited them in their interactions with patients regarding dental amalgam.

Meanwhile, there is a new effort to persuade the Philadelphia Board of Health to require patient-informed consent prior to use of dental amalgams. Mercury expert Boyd Haley, University of Kentucky chemistry professor emeritus, has submitted a detailed affidavit on the toxic heavy metal’s risks. In it he faults FDA and others for not scientifically researching the levels of mercury vapor released from dental amalgams. He asserts that the reason is not the difficulty of doing so, but rather the liability and loss of business that would result if it were done. Haley has called FDA’s amalgam safety science “absurd.”

FDA Preemption Cases Still Cause Confusion 

When the U.S. Supreme Court ruled in Riegel v. Medtronic that many state tort claims against manufacturers of premarket-
approved medical devices are preempted by federal law, it didn’t give clear guidance on which types of cases may still proceed in litigation. As a result, lower federal courts are struggling with the issue and have reached varying conclusions, according to an analysis by attorneys Steven Ellison, Peter Goss, and Joe Wearmouth (all of Faegre and Benson).

The attorneys say that, in theory, Riegel provided that state law claims may proceed so long as they don’t interfere with federal regulations. But the courts have had difficulty determining which cases are parallel and thus don’t interfere with federal requirements.

A decision in Hofts v. Howmedica took a broad view, finding that the Medical Device Amendments don’t prevent a state from providing a damages remedy for claims premised on violation of the Federal Food, Drug, and Cosmetic (FD+C) Act. The court’s reasoning was that a medical device manufacturer could be liable under state tort law for any departure from its approved PMA submission.

Decisions in two other cases— Riley v. Cordis and a litigation involving Medtronic’s Sprint Fidelis —agreed with Hofts that if a medical device manufacturer’s alleged conduct is prohibited by the FD+C Act, then a state law claim premised on that conduct is not expressly preempted by the Medical Device Amendments. However, those decisions also held that state law claims may be impliedly preempted. Those decisions, based on two other cases, appear to say that for a state claim to proceed, a plaintiff must argue that the device manufacturer’s conduct violates the FD+ C Act but doesn’t interfere with FDA’s enforcement of it.

Determining what types of claims are not preempted under Riley and the case involving the Sprint Fidelis likely will depend on future decisions in similar cases, the attorneys say. They find some guidance from the Sprint Fidelis case that a state statute providing a remedy for violation of the FD+C Act may escape preemption. But generalized common law theories, such as strict liability negligence and breach of implied warranties, do not—as long as the product at issue has been approved through the PMA process.

Also still to be determined, they lawyers say, is how courts will rule on express warranties. Most courts agree that express warranties made by a manufacturer that exceed the scope of the PMA process are not preempted. But they remain divided on preemption of express warranty claims stemming from a label approved during the PMA process.

Finally, the attorneys write, all of these issues may become moot if Congress follows through on intentions that some politicians have voiced to legislatively overturn Riegel. The Medical Device and Safety Act of 2009 was introduced in the House to amend the Medical Device Amendments to say that “nothing in this section shall be construed to modify or otherwise affect any action for damages or the liability of any person under the law of any state.” So far, they say, only one subcommittee has held hearings and no further action is pending. But with a number of prominent politicians promising to roll back Riegel, they conclude, a battle in Congress over the scope of device preemption seems likely to occur in the near future.

FDA Cautions on Device Radiation Exposure

FDA says it is taking steps to reduce unnecessary radiation exposure from CT scans, nuclear medicine studies, and fluoroscopy. An agency news release says it is urging adoption of two principles of radiation protection—appropriate justification of the radiation procedure and optimization of the radiation dose in each procedure. The three targeted procedures are the greatest contributors to total radiation exposure in the U.S. population and use much higher radiation doses than other procedures such as standard x-rays, dental x-rays, and mammography, the release says.

The agency intends to issue targeted requirements for CT and fluoroscopic device manufacturers to incorporate safeguards into machine design, to develop safer technologies, and to support safe practitioner use. FDA held a public meeting March 30–31 to solicit input on the subject.

Potential requirements for improving safety include: the devices must display, record, and report equipment settings and radiation dose; the devices must be able to capture and transmit radiation dose information to a patient’s electronic medical record and to national dose registries; and users must be alerted if the dose exceeds a diagnostic reference level set at the optimal dose for most patients. Additionally, users could be required to undergo training.

FDA is also working with the HHS Centers for Medicare and Medicaid Services to incorporate key quality assurance practices into the mandatory accreditation and conditions of participation survey processes for imaging facilities and hospitals. It says that such practices will improve oversight and promote safe use of advanced imaging technologies in those facilities.

GMP Violations Found at OST Medical

An FDA inspection last November and December at OST Medical’s Sentinel enteral feeding pump manufacturing facility in Warwick, RI, found violations of the agency’s CGMP requirements, according to a recent warning letter from FDA’s New England district office. Specific deviations from regulations included:

? Failure to establish and maintain procedures to ensure that all received product conforms to specified requirements.

? Failure to maintain a device history record including acceptance records that demonstrate that the device is manufactured in accordance with the device history record.

? Failure to review, evaluate, and investigate any complaint involving possible failure of a device, labeling, or packaging to meet any of its specifications.

? Failure to establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit.

? Failure to establish and maintain procedures for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device.

OST was told to take prompt action to correct the violations. The letter asks the company to submit certification by an outside expert consultant that the establishment’s manufacturing and quality assurance systems have been audited according to quality system requirements. Certifications are due July 27, 2010, and again on January 27, 2011, as well as one year later.

The letter directs the company to submit within 15 days a listing of the specific steps it plans to take to eliminate the violations and prevent them from recurring. The company also needs to submit documentation of corrective actions taken and a timetable for completion.

The agency reminded OST of its obligation to report in writing any correction or removal of a device it initiates to reduce a health risk posed by the device. “During our inspection, we observed you contact a number of customers with updates regarding your devices,” the letter says. “Please be aware that if any future corrections are conducted to reduce a risk to health, then you will need to report these to FDA as corrections or removals.”

FDA Seizes Applied Ozone Generators

At the request of FDA, U.S. marshals have seized 77 ozone generators from Applied Ozone Systems (Auburn, CA.) An agency news release says the device, valued at $75,900, has not been determined to be safe and effective in treating cancer, AIDS, hepatitis, herpes, and a number of other diseases and conditions that the company claims it can.

The company never responded to an FDA request last December for a voluntary recall, the release says. The agency is concerned that patients who use the devices as directed by the manufacturer may believe that ozone therapy is an appropriate treatment, and thus may delay or stop conventional or prescribed effective treatment. There also is an infection risk from potential contamination of the applicator or catheter, according to the agency.

FDA inspected the company last October under an inspection warrant obtained after the owner refused to allow agency staff to inspect the facility. FDA says the inspection revealed significant deviations from CGMP requirements for medical devices and confirmed that the company does not have FDA marketing approval or clearance for the device.