inside this issue - fdanews...1.48 cycles in 2003 to 1.78 cycles in 2010, according to the fda....

Fight Against Device Tax Continues One Year After Passage

Devicemakers have gained a new ally in the fight to repeal the device tax as the U.S. Chamber of Commerce throws its support behind a bill introduced by Rep. Erik Paulsen (R-Minn.) earlier this year to repeal the tax.

Paulsen cited the Chamber’s support as evidence that “efforts to repeal the job-crushing medical device tax are gaining steam.”

R. Bruce Josten, executive vice president for government affairs at the Chamber of Commerce, sent a March 22 letter to Paulsen noting, “This new 2.3 percent tax on virtually all medical devices beginning in 2013 will lead to increased healthcare costs, undercut-ting one of the primary goals of healthcare reform.”

Guidance, Standards Failures Behind Deficient 510(k) Filings

As 510(k) submissions continue to decrease in quality according to CDRH, an internal center inquiry has uncovered the top reasons filings are falling short.

Sixty percent of the 510(k) submissions that received two or more requests for additional information from CDRH failed to address guidance documents and/or recognized standards, accord-ing to the FDA analysis. Nearly half had inadequately described the device in the application, and 10 percent of submissions were com-pletely missing clinical data, said Christy Foreman, acting director of the Office of Device Evaluation.

Failure to address guidances or recognized standards should not be the primary reason CDRH has to ask for further information from sponsors, Foreman told an audience at the Association for the

Vol. 38, No. 13March 28, 2011

ReGen looks into ‘legal op-tions’ in FDA dispute over knee implant ............ Page 3

Federal budget delay could prompt excess collection of user fees ................... Page 5

J&J’s Ethicon recalls prod-ucts for package sterility concerns ................... Page 6

FDA releases new guid-ance, final rule for pelvic mass test ...................Page 7

Steris gets FDA ex-tension to switch us-ers to new device under decree ....................... Page 8

Iso-Tex gets FDA warning over sterility, contamination issues........................ Page 9

OIG report highlights concerns about its un-implemented suggestions to FDA ....................Page 10

Nanotherapeutics warning cites lack of vendor qualifi-cation ......................Page 11

Devicemakers ask Japan to make them a priority after quake ......................Page 12

INsIde thIs Issue

(See 510(k), Page 4)

(See Tax, Page 2)

Devices & Diagnostics Letter March 28, 2011Page 2

The tax was passed as part of the Health Care and Education Affordability Reconciliation Act of 2010, signed by President Barack Obama last March.

In January, Paulsen introduced H.R. 436, the Protect Medical Innovation Act, to end the tax. His bill had 41 bipartisan original cosponsors, and as of last week it had 110 supporters in the House. Senator Orrin Hatch (R-Utah) has intro-duced a companion bill in the Senate (D&DL, Jan. 31).

Industry has also pledged to end the tax. “We will continue working with elected offi-cials,” Mark Leahey, CEO of the Medical Device Manufactures Association, said in a March 23 statement. “These efforts have bipar-tisan support, and it is critical that we work together,” he added.

Despite the activity on Capitol Hill, the Obama administration reiterated its position to keep the tax intact to help fund healthcare reform during a Feb. 16 House Committee on Ways and Means hearing on the HHS fiscal 2012 budget.

Benefits of Tax

“The balance is that, as we move for-ward, the medical device companies will also have access to a large pool of new customers who they don’t currently serve, and the addi-tional cost will be balanced by the additional customers in the pool of insured Americans,” HHS Secretary Kathleen Sebelius said at the hearing.

But Paulsen countered that the vast major-ity of device procedures are not elective and are often performed on older patients, the majority of whom have insurance through Medicare.

He also pointed out that after the passage of Massachusetts healthcare laws, upon which the healthcare reform law was modeled, “there

was no increase in device utilization, like you suggested.”

Sebelius remained unmoved and reiterated her earlier point about new customers coming after the reform bill kicks in.

Meanwhile, the comment deadline closed March 28 on the IRS’ docket.

The agency was specifically seeking input on which devices are exempt from the tax, as the statute exempts devices determined by the [Treasury] Secretary to be “generally purchased by the general public at retail for individual use” (D&DL, Dec. 20, 2010).

AdvaMed suggests the IRS use the definition of retail devices under section 4191 of the Federal Food, Drug and Cosmetic Act.

Exempt Devices

This definition applies to mostly Class I devices, such as bandages, tipped applicators, pregnancy test kits, diabetes testing supplies and denture adhesives.

It also covers devices approved or cleared by the FDA as nonprescription, OTC devices, and to certain home-use devices based on their instructions for use, whether or not they require a prescription.

In its March 22 comments, the association said those device classifications should be flex-ible enough to allow for new industry trends and product innovation.

But the trade group raised concerns about the possibility that multiple taxation of an iden-tical device during the manufacturing process could occur as the IRS definition of manufac-turer remains broad.

AdvaMed recommends the IRS retain the cur-rent definition of manufacturer but clarify that man-ufacturing activities only involve physically trans-formative activities, including the re-processing or re-manufacturing of taxable medical devices. — Virgil Dickson

Tax, from Page 1

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Devices & Diagnostics LetterMarch 28, 2011 Page 3

ReGen Looks Into ‘Legal Options’ In FDA Dispute Over Knee Implant

After years of working with CDRH to get and keep its Menaflex knee implant on the U.S. mar-ket, ReGen Biologics has declined an offer for one last hearing with the FDA, as the agency moves to revoke clearance for the device.

The FDA will now rescind the substantially equivalent determination and the device may not be legally marketed, FDA spokeswoman Karen Riley told D&DL.

But the agency knows it “has no legal authority to rescind its clearance of Menaflex,” ReGen CEO Gerald Bisbee, Jr., contends.

“After six years of unthinkable bias, mis-takes and blunders, we are opting out of the FDA’s administrative process and pursuing other legal options for continuing to market Menaflex,” Bisbee said in a March 22 letter to the FDA.

“There is ample evidence the FDA completely botched its review of our Collagen Scaffold at every stage.”

The FDA’s Riley declined to comment on any possible legal options the company may take.

New Authority

The FDA’s decision to rescind the 510(k) comes at a time when the agency is trying to nail down its authority to do so.

In August, when the FDA released its prelimi-nary suggestions for overhauling the clearance pro-cess, it mentioned that CDRH was considering a regulation to define the scope, grounds, and appro-priate procedures for exercising its authority to fully or partially rescind a 510(k) clearance.

“As part of this process, the center should also consider whether additional authority is needed,” the agency has said (D&DL, Aug. 9, 2010).

The ReGen situation is unprecedented, Janice Hogan, managing partner and co-director of the

FDA/medical device practice at Hogan Lovells, told D&DL.

But a successful legal challenge in the fed-eral courts “is a tough course of action for any company because the courts generally give great deference to administrative agency decisions, particularly in areas of science,” she said.

Meanwhile, ReGen is warning that the FDA’s actions could have a wide impact across the device industry.

“The FDA’s decision that device clearances can be re-reviewed and rescinded long after they have been approved will chill U.S. investors’ enthusiasm for investing in the development and distribution of new devices,” Brisbee said.

Predicate Problem

The decision to rescind the 510(k) was reached after the agency realized that the Menaflex device is intended to be used for dif-ferent purposes than the predicate devices it cited in its submission, and that it is technologi-cally dissimilar from those predicates.

The rescission boils down to the fact that Menaflex is intended to stimulate the growth of new tissue to replace tissue that has been sur-gically removed, whereas its predicate device reinforces damaged tissue.

As a result, the Menaflex device should not have been cleared by the agency, as the differ-ences can affect the safety and effectiveness of the device, CDRH says.

The FDA announced plans to rescind 510(k) clearance for the device last October, but before it could, the agency was required to ask ReGen if it wanted a final regulatory meeting to discuss the rescission and the data that could provide a reasonable assurance of the device’s safety and effectiveness (D&DL, Oct. 18, 2010).

But the company says it adequately addressed the device’s safety and effectiveness at a Nov. 14, 2008, advisory panel meeting. — Virgil Dickson

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Advancement of Medical Instrumentation/FDA Standards conference March 23 in Herndon, Va.

“The whole point of standards and guid-ance is they provide clarity and predictability for industry.”

When an audience member attempted to point out that guidances are not mandatory, Foreman said there is still an expectation that the sugges-tions in guidances will be acknowledged.

Although companies can choose to do some-thing else, they need to address the guidance’s recommendations in some way, she said, adding, “What we’ve found is they are not addressed at all.”

Other leading issues included lack of indica-tion for use, lack of predicate information, and missing performance test or clinical data.

Contrary to popular belief, Foreman said newly hired reviewers have not contributed to an increase in review cycles. However, an inter-nal inquiry found new staff members might be most likely to ask more questions in an additional information request.

Review Cycle Rise

The study comes as the number of review cycles for 510(k)s has jumped 20 percent, from 1.48 cycles in 2003 to 1.78 cycles in 2010, according to the FDA. Industry, however, claims cycles have jumped 36 percent (D&DL, Sept. 20, 2010).

Currently, 510(k) review times are separated into two tiers — tier 1 submissions, 90 percent of which should be reviewed within 90 days, and tier 2 submissions, 98 percent of which should be reviewed within 150 days, under the Medi-cal Device User Fee and Modernization Act (MDUFMA).

But the agency measures review times in “FDA days,” not calendar days. This means the clock is stopped when the agency asks additional

questions of sponsors. Each time the clock restarts, a new review cycle begins.

Also at the conference, the FDA indicated that soon it may no longer accept abbreviated 510(k) submissions. Unlike standard 510(k)s, the abbreviated route allows a manufacturer to refer-ence an FDA-recognized standard or guidance document instead of providing the data for the FDA to review. Devicemakers must also sign a declaration of conformity for a particular stan-dard or guidance.

Despite the belief that more devicemakers would use this pathway, the program has not devel-oped much interest among industry. The number of abbreviated applications has dropped 15.5 per-cent from 2003 to 2010, from 206 submissions to 174, out of a total of 3,881 510(k) submissions as of Sept. 30.

Abbreviated 510(k)s

Despite the FDA’s intention to create an eas-ier pathway, sponsors find the submissions more burdensome, as companies are sometimes asked for more information than standard submissions, David Osborn, manager of international stan-dards at Philips Healthcare, told Foreman at the conference.

The FDA’s data seem to affirm that assertion, as the number of review cycles for abbreviated applications jumped 32 percent, from 1.43 to 1.89.

An abbreviated submission typically takes lon-ger to prepare due to the required summaries of compliance with the guidance documents, spe-cial controls and industry standards, according to a report by Medical Device Consultants (MDCI).

Further, “many FDA reviewers continue to demand information beyond a summary report to describe the testing performed and to demonstrate how the device fulfills the requirements of stan-dards and/or FDA guidance documents,” MDCI says.

When Foreman asked attendees if losing the program would be “a great loss” to anyone, no one in the audience responded. — Virgil Dickson

510(k), from Page 1

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Appropriations Delay Could Prompt Excess Collection of User Fees

Devicemakers may see lower user fees than expected in fiscal 2012 as a series of continuing resolutions (CR) passed by Congress has resulted in CDRH collecting more money this year than it is authorized to spend.

The current CRs only appropriate the fis-cal 2010 authorized user fee collections limit of $57 million, rather than the fiscal 2011 authorized amount of $61.9 million. If user fee spending con-tinues at the lower 2010 amount for the remain-der of the year, the excess fees could be designated toward user fee reduction in fiscal 2012.

The CR extension, which will keep the gov-ernment running through April 8, was signed into law March 18.

Fee Increase

This could result in an increase in aggre-gate excess collection because FDA set its fiscal 2011 user fees based on the fiscal 2011 authorized collection level, it told industry during a recent MDUFMA reauthorization meeting.

Lack of expected appropriations for fiscal 2011 has also meant delaying plans to bring on more staff, the agency said.

But recent meetings with lawmakers have pointed to “a difficult but possibly not insurmount-able path to preserve the agency’s budget,” says Steven Grossman, deputy executive director of the Alliance for a Stronger FDA.

The FDA may be shielded from some of the larger cuts expected for the final fiscal 2011 appro-priations and the upcoming fiscal 2012 budget. “We were encouraged … even while it was rein-forced to us that FY 11 and FY 12 will be bad budget years for almost all federal agencies and programs,” Grossman said after meeting with more than 50 House and Senate members.

Fortunately, the months of endless continuing resolutions may be coming to an end as many law-makers have said they’re tired of the back-and-forth.

President Barack Obama’s proposed budget, sent to Congress Feb. 14, would increase the FDA’s funding to $4.4 billion for fiscal 2012, a 33 percent increase over 2010. The 2012 budget request is being compared to the fiscal 2010 enacted budget level because Congress never approved an FDA budget for 2011 (D&DL, Feb. 21).— Virgil Dickson

Terumo Cardiovascular Slammed With $35 Million Consent Decree

Terumo Cardiovascular and two of its top executives have signed a consent decree of per-manent injunction for several heart devices after good manufacturing practice (GMP) and report-ing violations.

The decree, filed in the U.S. District Court for the Eastern District of Michigan, prohibits the company from manufacturing and distrib-uting two heart-lung bypass systems and other cardiovascular devices to new customers.

It also restricts sales of these systems to existing customers until the company complies with the FDA’s GMP and medical device report-ing (MDR) requirements.

The company has also agreed to pay the fed-eral government $35 million in disgorgement of profits from past sales and additional disgorge-ment amounts if it fails to comply with the con-sent decree in an effective and timely manner.

During an inspection from January through March 2010, FDA investigators observed numer-ous cGMP and MDR violations at the com-pany’s Ann Arbor manufacturing facility. The violations included deficiencies in processes for corrective and preventive actions, nonconform-ing product, complaints, purchasing, process validation, design controls and adverse event reporting.

Under the decree, Terumo will create a work plan to resolve the issues, it says. Terumo CEO

(See Terumo, Page 6)

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Mark Sutter noted the company has already been implementing a “significant quality system initiative.”

The decree also restricts the company from distributing and manufacturing additional devices, such as its perfusion systems, its Cen-trifugal system and its cannulae for cardiopul-monary bypass and cardioplegia delivery.

The consent decree stopped short of requir-ing Terumo to remove the products from the market because of shortage concerns, the FDA says. Terumo will be allowed to continue to provide service, replacement parts and loaner devices to existing customers that submit docu-mentation of medical need.

Other Terumo cardiovascular products that are available without restriction include oxy-genators, perfusion circuits that don’t contain cannulae, and all other products produced at

the company’s other manufacturing facilities in Elkton, Md., and Ashland, Mass. The consent decree does not involve any other Terumo sub-sidiary or corporate entity.

Prior to the 2010 inspection, the FDA had twice pointed out cGMP problems at the com-pany, issuing warning letters in 2004 and in 2006.

The 2004 letter cited a Michigan facility for failing to maintain adequate corrective and pre-ventive action procedures and failing to validate corrective procedures to ensure finished devices were unaffected by manufacturing changes (D&DL, Sept. 13, 2004).

The 2006 letter cites reporting failures. In one instance, Terumo failed to report to the agency within 30 days the results of a review and investigation of 12 malfunctions of the man-ual pump speed-control knob of the APS-1, a life-supporting device (D&DL, Sept. 18, 2006). — Virgil Dickson

J&J’s Ethicon Recalls Products For Package Sterility Concerns

Johnson & Johnson (J&J) subsidiary Ethicon is adding to the growing list of J&J recalls with multiple lots of products that may have compro-mised packaging.

Customer complaints alerted Ethicon to potential sterile barrier breaches in the packaging for several lots of Blake silicone drains, Blake sil-icone drain kits, Blake cardio connectors, J-VAC reservoirs and J-VAC drain adapters, the com-pany said Thursday.

Ethicon has not received any reports of adverse events related to the issue.

Sterility issues were also behind an Ethi-con recall earlier this month involving 585,000 strands or 104 batches of sutures sold under vari-ous names — Ethilon, Ethibond, Mersilene and Mersilk.

Those products’ packages may not have been completely sealed and the contents may not be sterile.

Prior to that recall, Ethicon recalled 700,000 vials of a liquid wound-sealing product, Derma-bond, in February amid reports of discoloration and concerns it may take longer than expected to set.

The last two years have been recall-heavy for J&J and its subsidiaries, with recalls issued for products such as hip implants, OTC allergy medication Sudafed, autoimmune treatment Sim-poni and antipsychotic treatment Invega Sustenna (D&DL, Aug. 30, 2010).

The company is also dealing with a recent warning letter for Cordis over stent issues (D&DL, March 14).

On top of those issues, as subsidiary DePuy Orthopedics faces numerous lawsuits, recalls and an FDA investigation, its CEO David Floyd recently called it quits (D&DL, March 14). — April Hollis

Terumo, from Page 5

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FDA Releases New Guidance, Rule for Pelvic Mass Test

The FDA is down-classifying ovar-ian adnexal mass assessment score test sys-tems from Class III into Class II with special controls.

The test system measures one or more pro-teins in serum or plasma to determine the like-lihood that an adnexal pelvic mass in the fallo-pian tubes or ovaries is malignant.

The tests are used to identify women who should be referred to a gynecological oncologist for surgery, despite negative results from other clinical and radiographic tests for ovarian can-cer. It is used in conjunction with a clinical and radiological evaluation.

Off-Label Use

In addition to the special controls, the FDA also suggests a boxed warning in the label to reduce the risk of off-label use.

The FDA is concerned about potential off-label use of the tests in patients not already iden-tified as surgery candidates for pelvic masses, or who haven’t had an independent clinical or radio-logical evaluation.

An ovarian adnexal mass assessment score test system is not indicated for use as a screen-ing or diagnostic test for ovarian cancer, the FDA notes.

Using the test in this way could lead to unnecessary further testing and surgery due to false positive results, or could delay tumor diag-noses because of false negative results, the FDA says.

The agency also released a special controls guidance for the devices, providing recommen-dations on premarket notifications and labeling for the tests.

Manufacturers preparing 510(k) submissions for this type of device should address whether the test includes analytes that have never been

incorporated into an in vitro lab test before, the guidance says.

If that is the case, the sponsor should indicate whether specific instructions for blood collection and blood collection tube handling are required due to the unstable nature of such analytes, it adds.

Sponsors should also demonstrate the sta-bility of the specimens across extremes of low temperature, time to freezing, freeze-thaw and shipping. Specimen stability claims for the test should represent the least stable analyte in its score test system, the guidance says.

Sponsors should also describe how they selected the acceptance criteria for each analyte.

Finally, companies should justify inclu-sion of each individual analyte. One option is to demonstrate that the analytes included in the calculation of the score are informative for ovar-ian malignancy using data from the clinical study.

Petition for Reclassification

The device was originally placed in Class III because there was no predicate device to which it could be found substantially equivalent. How-ever, devicemaker Vermillion submitted a peti-tion in July 2009 requesting reclassification of its ovarian adnexal test into Class II.

After reviewing the company’s petition, the FDA determined the tests can be classi-fied into Class II with special controls, which will provide reasonable assurance of safety and effectiveness.

The move could save Vermillion and other manufacturers with similar devices in develop-ment a significant amount of money as the costs associated with the submission of a PMA poten-tially reach $1 million, the FDA says.

The special controls guidance can be found at www.fda.gov/MedicalDevices/DeviceRegulation andGuidance/GuidanceDocuments/ucm237299.htm. — Virgil Dickson

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Steris Gets FDA Extension to Switch Users to New Device

Steris has an additional six months to tran-sition facilities that use its SYSTEM 1 for ster-ile reprocessing to an alternative reprocessing method, a switch required by an FDA consent decree.

The company requested the extension, to Feb. 2, 2012, in light of the agency’s ongoing review of a biological indicator accessory for its new sterilizer, the SYSTEM 1E. However, there is no assurance the FDA will clear the indicator, Steris said in a March 21 SEC filing.

The extension will also allow healthcare pro-viders additional time to assess alternatives, make any necessary changes to internal protocols, install replacement devices and conduct operator training.

Under the consent decree, Steris was origi-nally required to develop a transition plan to support existing SYSTEM 1 customers through Aug. 2.

Steris’ regulatory issues with SYSTEM 1 go back several years. After issuing a warning let-ter for the device in 2008, the FDA sent out a MedWatch notice in December 2009 following reports that providers had been burned by the solution used in the SYSTEM 1 (D&DL, Dec. 7, 2009).

Replacement Sterilizer

In April 2010, after more than a year of waiting, Steris received clearance for the SYS-TEM 1E, a liquid chemical sterilizer marketed as a successor to the SYSTEM 1.

After receiving the clearance, the company submitted 510(k)s for several accessories for the new system, including the biological indicator, which indicates the presence of biological materi-als on equipment to be sterilized.

The new indicator is not necessary to operate SYSTEM 1E, Steris says. — Virgil Dickson

Data Shortfalls for Imports Are Worrying CDRH

CDRH is growing increasingly concerned with the number of imported devices that lack sufficient U.S. entry data.

Importers will need to work closely with their import personnel to verify that information submit-ted is correct, CDRH Office of Compliance Director Steven Silverman said in a March 24 letter to indus-try. Timely review of entries requires consistent and accurate identifiers for companies and correct prod-uct codes.

Additionally, the agency is encouraging submis-sions of voluntary affirmation of compliance (AofC) codes along with the appropriate qualifier. Including these data and codes will increase a shipment’s like-lihood of being processed based on import system screening, rather than being held for further FDA entry review, Silverman says.

The full letter can be found at www.fda.gov/MedicalDevices/ResourcesforYou/Industry/ucm248321.htm. — Virgil Dickson

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Iso-Tex Gets FDA Warning Over Sterility, Contamination Issues

Friendswood, Texas-based Iso-Tex Diagnos-tics has been handed an FDA warning letter for good manufacturing practice violations related to radiopharmaceutical diagnostic agents.

During a May 4, 2010, to June 2, 2010, inspec-tion of the company’s plant, the FDA’s Dallas dis-trict office found a number of issues related to product and facility sterility.

After receiving positive sterility test results for its injectable agent Glofil I-125, Iso-Tex con-cluded that the samples were contaminated envi-ronmentally. The FDA chided Iso-Tex for fail-ing to consider that the drug itself might be contaminated.

Additionally, after a sample of the company’s Jeanotope-125 diagnostic agent tested positive for contamination, Iso-Tex concluded the results were a false positive due to a defective test kit filter.

The company conducted follow-up testing on additional samples and found a single case of con-tamination. The FDA rebuked Iso-Tex for failing to determine the root cause of the positive test.

Manufacturing sterility issues are raised in the letter, which cites Iso-Tex for failing to establish writ-ten procedures to prevent contamination of sterile products.

Additionally, Iso-Tex “does not have adequate control systems to prevent contamination of … floors, walls and ceilings of smooth, hard surfaces that are easily cleanable,” the letter says. It also failed to provide exhaust systems adequate to control contaminants.

Iso-Tex Diagnostics manufactures sterile, non-pyrogenic radiopharmaceuticals. The company did not respond to a request for comment as of press time.

The warning letter is available at www.fdanews.com/ext/files/UCM247412.pdf.— Kevin O’Rourke

Covidien Device Gets OK From FDA Neuro Panel

An FDA advisory panel has unanimously backed a new device that blocks off large intra-cranial aneurysms in patients unlikely to respond to other available treatments.

The Neurological Devices Panel voted 8-0 that the benefits of Covidien’s Pipeline Emboliza-tion device outweigh its risks, and that the device was both safe and effective.

Even if the FDA approves the device, the Pipeline is expected to have limited impact on Covidien’s bottom line, Rick Wise, an analyst at Leerink Swann, says in an investor note. Accord-ing to panel briefing documents, large and giant aneurysms are relatively uncommon in the U.S., with an estimated annual incidence of 2,000 patients.

Covidien estimates Pipeline’s overall market opportunity at $100 million to $150 million, Wise said. In light of Covidien’s $11 billion annual

sales, it will likely not be considered a significant source of revenue, he added.

Despite that, Covidien considers the panel vote an important achievement, as safe and effec-tive treatment of large and giant, wide-neck or non-saccular aneurysms remains a significant unmet clinical need, Aaron Berez, general man-ager of the Neurovascular unit at Covidien, said.

During the meeting, panel members praised the company’s data, noting that panel delibera-tions are often a struggle as experts attempt to make concrete decisions on weak or vague clini-cal data — “something that didn’t happen this time,” Scott Evans, a senior research scientist at the Harvard School of Public Health, said.

Covidien’s PMA application is based on the results of the Pipeline for Uncoilable or Failed Aneurysms (PUFS) clinical study, which included data from 108 patients. PUFS is a single-arm study of large and giant, wide-neck or fusiform aneu-rysms, typically not coilable, with six-month safety and effectiveness endpoints. — Virgil Dickson

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OIG: FDA’s AE Protocol Still Needs Improvement

Nearly two years ago, the HHS Office of Inspector General (OIG) recommended that CDRH develop a clear protocol for documenting follow-up on adverse events. But the center has failed to act on several of those recommendations, according to a new OIG report.

OIG made this and other suggestions to CDRH after it found the division was not using the reports in a systematic manner to address safety concerns about devices (D&DL, Nov. 2, 2009).

To improve its adverse event tracking, the FDA had planned to transition devicemakers to the FDA Adverse Event Reporting System (FAERS) last year but missed that deadline.

Drugmakers will transition to FAERS by this fall, but CDRH has decided to develop its own system.

The center plans to introduce a prototype this year for the new adverse event database to replace its Manufacturer and User Facility Device Experi-ence Database (MAUDE).

By the end of June, the FDA will determine system requirements and select the platform for the new database (D&DL, Feb. 28).

Since OIG first brought up its concerns, CDRH has reaffirmed plans for the new database and developed a tracking system that facilitates referrals to its Office of Compliance and prompts follow-ups, OIG notes.

OIG also continues to push the FDA as a whole to improve monitoring of foreign clinical trials.

As more sponsors seek benefits from conduct-ing research abroad, such as lower costs or the abil-ity to conduct larger trials in less time, medical ethi-cists have raised concerns about the ability of local regulatory bodies and institutional review boards to adequately monitor the trials.

The OIG has found the FDA rarely conducts clinical investigations at foreign sites.

If a sponsor has not consulted with the FDA about its foreign clinical trials prior to seeking mar-keting approval, “the agency has no way of know-ing whether and where foreign clinical trials are taking place and therefore cannot conduct inspec-tions while the trials are in progress,” OIG says.

Further, sponsors often submit inconsistent data, making it difficult to locate clinical trial information, particularly site locations and subject enrollment information, OIG says.

To address this issue, OIG has suggested the FDA require standardized electronic clinical trial data, create an internal database and explore ways to expand its oversight.

The FDA has indicated it is piloting a site selec-tion tool to standardize clinical trial data and may expand use of the tool within the agency.

The OIG report, “Compendium of Unimplemented Recommendations,” can be found at oig.hhs.gov/publications/docs/compendium/2011/CMP-March2011-Final.pdf. — Virgil Dickson

Excellent change forms are notenough to keep medical devicemanufacturers out of trouble withthe FDA. That’s because inspec-tors are looking at more thanwhether your forms pass muster.They’re also trained to scrutinizehow well your change control pro-cedures support those forms —and how well you follow thoseprocedures. How do you justifyand document changes? Are youdoing enough with training tocommunicate both requirementsand changes? Get the rightanswers — before change control issuessabotage your next inspection.

Drawing guidance from both the FDA and industry, this new reportarms medical device manufacturers with proven tips for buildingchange control forms that can sail through inspections. Step-by-step, this report helps you master the many aspects of change con-trol and the many regulations that must be factored into emergencydecision-making and routine company procedures.

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Nanotherapeutics Warning Cites Lack of Vendor Qualification

As the FDA continues hammering the importance of supplier qualification, it has handed Nanotherapeutics a warning letter cit-ing failure to complete the vendor qualification required by the company’s procedures.

The Alachua, Fla., company’s standard oper-ating procedure (SOP) requires on-site audits of all critical suppliers.

However, at least five had not been audited at the time of the FDA’s inspection, according to the Feb. 22 letter posted online last week.

Nanotherapeutics’ contract packager per-forms incoming material inspections of certain products, and those results are not used in the supplier qualification process, the letter says.

The company also failed to perform qual-ity audits at defined intervals. Specifically, there was no documentation showing audits were con-ducted in 2008.

Nanotherapeutics told the FDA it has revised its internal audit SOP and provided dates that demonstrate compliance with the SOP and sat-isfy federal regulations, the letter says.

Management Review

The company’s quality manual also calls for semi-annual management review meetings to review the quality system, but documentation indicated there were no meetings in late 2007 or in 2008.

The Form 483 response stated that two man-agement review meetings were held in 2007, and indicated Nanotherapeutics has conducted the meetings on schedule since March 2009.

However, the company did not provide evi-dence to support the management review meet-ing requirement and to satisfy federal regula-tions. Therefore, the FDA cannot determine the adequacy of the response, the letter says.

Nanotherapeutics also modified its Origen DBM/NanoFUSE DBM with bioactive glass — a bone void filler — to increase the melt temper-ature of gelatin in the Origen paste.

This modification represents a change that could significantly affect the safety or effective-ness of the device and requires submission of a new 510(k), the FDA says.

The letter adds that neither the design con-trol SOP nor the change control system SOP address design changes.

It also points out corrective and preventive action (CAPA) violations, noting that verifica-tion activities are not routinely conducted nor required by the company’s CAPA SOP.

CAPA Failure

One CAPA, created due to nonconform-ing packaging, involved 100 percent in-house inspection of a packaged product.

But the continuing nonconformances seen in those inspections were not fed back into the CAPA system to determine if additional actions are needed, the letter says.

Another citation notes the company had no procedure or work instruction for the 100 per-cent packaging and labeling inspection of pre- sterilized product.

Acceptance criteria are not defined and instructions on documenting packaging failures are not addressed, the letter says.

Nanotherapeutics’ Form 483 response indi-cated that it will write more detailed instruc-tions for the inspection of final product and will train personnel with those instructions prior to any product release.

Nanotherapeutics did not respond to a request for comment by press time. The warning letter is available at www.fdanews.com/ext/files/ucm247031.pdf. — April Hollis

http://www.fdanews.com/ext/files/ucm247031.pdfhttp://www.fdanews.com/ext/files/ucm247031.pdf


Devicemakers Request Priority For Japan’s Electricity

As rolling blackouts continue to hit Japan fol-lowing the recent earthquake, devicemakers are asking the Japanese government to prioritize the allocation of power supplies to medical device fac-tories that manufacture mechanical ventilators, oxy-gen devices, defibrillators and other products vital for human life.

The Japan Federation of Medical Device Asso-ciations (JFMDA) sent the request to the country’s health and economy ministers via a March 17 letter. It notes that as the blackouts have intensified, manu-facturers are growing more concerned that the out-ages could prevent them from ensuring a stable sup-ply of life-supporting medical devices.

“Power outages of three hours have seriously damaged the production capacity of these [facili-ties],” JFMDA chairman Kazuo Ogino says. Ogino requests the country give devicemakers special con-sideration and secure the necessary power for them.

Scheduled blackouts are also making it diffi-cult to maintain normal operations, devicemaker JEOL says. The impact on JEOL’s immediate abil-ity to ship equipment and parts will depend, in part, on how quickly Japan’s electrical and transportation services can be restored.

The letter also outlines concerns that acute shortages of gasoline have hampered member com-panies from dispatching medical devices to affected areas. Ogino asks that adequate gasoline be secured for emergency vehicles.

Public transportation has also been disrupted, and many of JEOL’s employees are having difficul-ties commuting to the factory, the company adds.

On top of the gasoline and public transit issues, severely damaged roadways have been cited by Japan’s Pharmaceuticals and Medical Devices Agency as the reason for several canceled or post-poned facility inspections. The agency has also delayed planned meetings with industry. It has not provided updates on the issue since March 16 (D&DL, March 21).

In related news, FDA officials are enhanc-ing the screening of products coming from Japan to ensure they don’t contain excessive radiation. The 9.0 earthquake that hit Japan earlier this month damaged several nuclear facilities causing excessive radiation from the plants.

The FDA’s import tracking system has been programmed to automatically flag all shipments of FDA-regulated products from Japan, and the agency will pay special attention to shipments from compa-nies in the affected areas.

While the initiative has primarily focused on food, the FDA is working with U.S. Customs and Border Protection to see if its automated targeting system can identify shipments of other FDA- regulated products before they arrive so they can be targeted for examination.

The agency’s import staff will review each shipment of regulated goods originating from Japan and determine if it should be examined and sampled or released. — Virgil Dickson

Reporters: Wilson Peden, Molly Cohen, Kevin O’Rourke, David Pittman

President: Cynthia Carter; Editorial Director: Pamela Taulbee; Executive Editor: April Hollis

Copyright © 2011 by Washington Business Information Inc. All rights reserved. Devices & Diagnostics Letter (ISSN 0098-7573) is published weekly, 50 issues, for $1,197. Photocopying or reproducing in any form, including electronic or facsimile transmission, scanning or electronic storage is a violation of federal copyright law and is strictly prohibited without the publisher’s express written permission. Sub-scribers registered with the Copyright Clearance Center (CCC) may reproduce articles for internal use only. For more information, contact CCC at www.copyright.com or call (978) 750-8400. For site licenses for multiple users or to purchase multiple copies, contact Andrew McSherry at (703) 538-7642.

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Excellent change forms are not enough to keep medical device manufactur-ers out of trouble with the FDA. That’s because inspectors are looking atmore than whether your forms pass muster. They’re also trained to scruti-nize how well your change control procedures support those forms — andhow well you follow those procedures.

Drawing guidance from both the FDA and industry, this management reportarms medical device manufacturers with proven tips for building change

control forms that can sail through inspections. Step-by-step, this report helps you master the manyaspects of change control and the many regulations that must be factored into emergency decision-making and routine company procedures.

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