Devicemakers want home

use guidance to use interna-

tional standards ........Page 3

FDA urges manufacturers

to act before luer connector

standard set ..............Page 3

483 Insider ..............Page 5

Beckman Coulter warning

cites unapproved assay

changes ....................Page 7

FDA sends warning to

Medtronic after company

addresses 483...........Page 7

GMP issues cited in warn-

ing letter to Abbott Dia-

betes Care ................Page 8

FDA sets deadline for CSZ

external consultant quality

audit .........................Page 9

Devicemakers consider

leaving China following la-

bor struggles ..........Page 10

GE relaunches CV diagnos-

tic after manufacturing

problems.................Page 11

Group demands FDA re-

lease UDI regulation imme-

diately ....................Page 12

Issue No. 367

August 2010Warning Letter Quality Is Sliding

Without Prior Legal Review

Ever since FDA Commissioner Margaret Hamburg ended prior

legal review, the quality of warning letters coming out of the agency

has declined, device consultants say, and now the agency is evaluat-

ing that policy change.

“I have noticed what appears to be a diminution in the quality

of warning letters — issues ranging from typographical errors to

lack of legal support for assertions,” Jennifer Bragg, a partner at

Skadden, Arps, Slate, Meagher & Flom, told GMP.

Last summer, Hamburg ended an agency policy requiring prior

legal review of all untitled and warning letters (GMP, August 2009).

To speed up enforcement action, she instructed that the Office of

(See Warning Letters, Page 2)

FDA Sets Two-Year Recall Deadline

For Baxter’s Colleague Pumps

The FDA is giving Baxter two years to recall and destroy more

than 200,000 Colleague infusion pumps as part of a permanent in-

junction the agency imposed earlier this year.

The July 14, 2012, deadline to provide replacements or refunds

to Colleague customers is included in an order the agency released

last month. Baxter also must provide a transition guide, with a list of

FDA-cleared or approved pump alternatives, to help customers af-

fected by the recall.

Analysts see the two-year deadline as good news for Baxter.

During that time, the company can continue to generate disposable

revenues from customers who submit a Certificate of Medical Ne-

cessity to continue using Colleague pumps for the full 24 months,

Rick Wise, an analyst at Leerink Swann, says in an investor note is-

sued last month.

IINNSSIIDDEE TTHHIISS IISSSSUUEE

(See Baxter, Page 4)

Chief Counsel (OCC) would review only warning

letters that have “significant legal issues.”

As a result, the quality of the letters has

dropped, Bragg said. “For years, those within FDA

who were doing the preliminary drafting of warn-

ing letters knew that other eyes would be review-

ing the letters before they were issued,” she said.

“This meant that any errors would likely be

corrected before the final letter was issued,” she

added. “Now that there is not an automatic OCC

review of the letters, this internal check no longer

exists.”

In line with Hamburg’s commitment to en-

sure that the FDA’s work is factually and legally

correct, the agency is evaluating the impact of the

change, spokeswoman Karen Mahoney told

GMP. That evaluation should be completed by

the end of September.

Legal Issues

Following implementation of the new warn-

ing letter policy, Sean Wajert, a partner at

Dechert, co-authored a legal backgrounder for the

Washington Legal Foundation in which he

warned of possible violations of First Amend-

ment rights. Shortly after his paper was released

in January, he was proven right, he told GMP.

That’s when the FDA sent an untitled letter

to Leslie Baumann, a dermatologist and clinical

researcher, for making positive comments to the

media about an injectable anti-wrinkle drug be-

fore the agency had officially approved it.

Wajert argued that Baumann’s comments

were her personal opinion, made in her time off.

“Had that letter been sent through the general

counsel as they were in the past,” a lawyer with a

trained eye would have caught it, and it may not

have been sent, he added.

Lack of prior review may not be the only

contributor to the diminishing quality of warning

letters. Increasing turnover at the FDA also may

be at fault, Bragg said.

“The retirement of a number of senior people,

combined with large increases in hiring, means that

it is increasingly common for people with less expe-

rience to be asked to step in and handle matters that

might previously have been handled by their more

experienced counterparts,” she said.

Edwin Bills, a compliance expert at Bilanx

Consulting, agreed that turnover is a likely factor,

noting that the letters from some FDA districts

are better than those from others.

Turnover

“There is still enough experience in manage-

ment levels to overcome shortage of experience

of investigators,” Bills told GMP. But unless the

agency develops warning letter standards for its

staff, he expects continuing turnover in district

management will result in more widespread prob-

lems with quality and nonenforceable letters.

For devicemakers, a related concern is how

the FDA is interpreting the medical device report

(MDR) requirement, which has come up fre-

quently in recent warning letters.

Andrew Balo, vice president of clinical/

regulatory affairs at DexCom, told GMP he has

noticed the FDA has become increasingly incon-

sistent in what it considers MDR-reportable.

For instance, DexCom received a warning

letter in May that points out six complaints of

sensor wire fractures that the agency says should

have triggered an MDR. In each case, hair-like

wires broke off underneath a patient’s skin. No

injuries were reported in some cases, while others

involved skin irritations.

The FDA knew about the sensor issue for

two years but didn’t cite DexCom until May.

“They are really coming after the industry

in a more aggressive manner,” Balo said.

— Virgil Dickson

Page 2 THE GMP LETTER August 2010

Warning Letters, from Page 1

August 2010 THE GMP LETTER Page 3

Industry Wants Home Use Guidance

To Use International Standards

Devicemakers are urging the FDA to embrace

international standards as it seeks to create guid-

ance on safety challenges and possible new testing

standards for medical devices used in the home.

“We believe that significant work has al-

ready been done in the standards arena that can

greatly facilitate FDA’s initiative,” AdvaMed says

in one of 11 comments on the FDA’s Home Use

Initiative.

The trade group points to the Association for

the Advancement of Medical Instrumentation’s

“Human Factors Engineering — Design of Med-

ical Devices.” This standard addresses the unique

characteristics of end users in the home environ-

ment that need to be factored into device design.

Other examples include the International

Electrotechnical Commission standard 60601-1-

11, “Collateral Standard for Home Healthcare

Environment,” and the International Organization

for Standardization’s 14971, “Medical Devices —

Application of Risk Management.”

While standards exist to address many of the

agency’s home use issues, AdvaMed acknowl-

edges there are some areas requiring unique FDA

guidance. One of these is the FDA’s expectations

for “summative usability testing” for home de-

vices. Its current guidance, adopted 10 years ago,

suggests 15 as the minimum number of patients

who should be tested.

The agency’s expectations for acceptance

criteria for measuring home use performance in a

usability test are unclear, AdvaMed says.

The agency announced at a May brainstorm-

ing workshop on home use devices that it expect-

ed to release a draft guidance in the next 10 to 12

months. Mary Brady, associate director for Home

Use Initiatives at CDRH, told devicemakers at

the workshop that the guidance likely would in-

clude international standards. — Virgil Dickson

FDA Urges Devicemakers to Act

Before Luer Standard Issued

While manufacturers of devices that use luer

connectors wait for a new international standard,

the FDA is asking them to address the risks of

life-threatening misconnections.

In a July 9 letter to makers of enteral feeding

tubes, the agency encourages them to assess the

risks, consider temporary and long-term options

and then validate the solutions they deem most ap-

propriate. The FDA will assess the validation of

the proposed solution during its premarket review.

The FDA has no standard for the connectors,

but it is working with the International Organiza-

tion for Standardization (ISO) and other groups

to develop an international standard. ISO 80369-

1, “Small-Bore Connectors for Liquids and Gases

in Healthcare Applications,” is expected by the

end of this year or early next year, according to

the Association for the Advancement of Medical

Instrumentation.

The standard will cover incompatible connec-

tors used in intravascular breathing systems and

enteral, urethral, urinary, cuff inflation and neurax-

ial applications, according to the FDA (GMP,

March 2009). The standard also should offer

guidelines for creating a connector that would not

interface with the luer fitting or any other fitting

that is being considered for medical application.

If the FDA adopts the standard, it will pro-

vide guidance on issues such as the time frame

for bringing marketed devices into compliance.

Some manufacturers have implemented de-

sign changes, such as using color coding and la-

beling to flag which feeding tubes must be con-

nected. Others have created proprietary connec-

tions to ensure that devices that should not be con-

nected cannot be connected. Devicemakers also

can follow industry recommendations.

The FDA letter is available at www.fda.gov/

downloads/MedicalDevices/ResourcesforYou/In

dustry/UCM218631.pdf. — Virgil Dickson

The deadline also gives Baxter and its partner

Sigma time to ramp up production of the single-

channel Spectrum pump, Wise says. The recall’s

replacement option allows customers to exchange

Colleague infusion pumps for Sigma’s Spectrum

next-generation smart pumps.

Under an alternative refund option, Col-

league pump owners may receive the pump’s de-

preciated value, which will be no less than

$1,500 per single-channel pump and $3,000 per

triple-channel pump, or the purchase price,

whichever is less.

The FDA’s new order does not necessarily

benefit competitors. The order specifies that “at

no time shall Baxter be required to offer or pro-

vide customers with a replacement pump manu-

factured, sold, or distributed by a competitor,”

Mike Weinstein, a J.P. Morgan analyst, says in an

investor note.

Also, the similarities between the Colleague

and Spectrum pumps should make for a smooth

transition and nurse retraining, which Baxter is

obligated to provide.

However, neither Weinstein nor Wise ex-

pects 100 percent retention. “Triple-channel

pumps make up roughly 25 percent of Baxter’s

installed base,” Weinstein says. “With no triple-

channel option in the Sigma lineup, we see this

segment of the company’s business as being most

vulnerable to competitive erosion.”

Baxter expects the U.S. recall to cost up to

$588 million. But it should have no impact on the

company’s international sales of Colleague

pumps, Baxter says. The company has pledged to

continue to update the pump, giving the device a

new battery management system and upgrading

software and mechanical systems to improve the

pump’s user interface and performance.

The FDA’s order ends more than a decade of

discussions between Baxter and the agency on

correcting flaws with the pumps. The devices

have been subject to several Class I recalls over

the years due to battery swelling, inadvertent

power shutdowns and service data errors, the

FDA says.

The agency imposed the permanent injunction

April 30 after Baxter submitted a proposed correc-

tion schedule, under a 2006 consent decree, indicat-

ing it did not plan to begin a new round of correc-

tions to the pumps until May 2012 and would not

complete the repairs until the following year.

That plan was unacceptable, the FDA said,

as it would allow devices with known safety con-

cerns to remain in use until 2013 (GMP, June).

In signing the consent decree, Baxter com-

mitted to ensure compliance with the FDA’s

good manufacturing practices and quality sys-

tem requirements at all of its facilities that man-

ufacture, process, pack, label, hold or distribute

the Colleague pumps (GMP, August 2006).

— Virgil Dickson

Page 4 THE GMP LETTER August 2010

Baxter, from Page 1

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August 2010 THE GMP LETTER Page 5

Lack of Internal, Supplier Audits

Is Cited in Sgarlato Form 483

Sgarlato Med has received a Form 483 after

an inspector found the company does not perform

incoming inspections or internal quality audits.

The San Jose, Calif., company has no estab-

lished procedure to ensure receiving inspections

are performed, the April 5 form says. Sgarlato’s

purchasing control procedures do not address

steps for qualifying suppliers, contract manufac-

turers or service providers. Although Sgarlato

maintains an approved supplier list, no proce-

dures were available to address how the suppliers

were evaluated or approved.

At least two critical suppliers, the contract

manufacturer of the company’s foot and ankle

implants and the contract packager, had not been

audited by Sgarlato at the time of the inspection,

and the company has no documentation of evalu-

ation or qualification, the form says. The compa-

ny also has not conducted internal audits of its

quality system.

Sgarlato could not be reached for comment

by press time. The Form 483 is available at www.

fdanews.com/ext/files/Sgarlato.pdf.

Micrus Receives a Form 483

For Late MDR Submission

An FDA inspector cited Micrus Endovascu-

lar for failing to submit a medical device report

(MDR) within 30 days.

The company received a complaint March 8

detailing a physician’s difficulty in passing a coil

through a microcatheter, which moved suddenly

and ruptured a patient’s aneurysm, an April 12

Form 483 says. The rupture was clotted by the

completed deployment of the device.

The San Jose, Calif., company did not sub-

mit an MDR until the inspection even though it

had filed an MDR for a similar incident, in which

a patient died following a ruptured aneurysm, ac-

cording to the form.

Micrus also failed to document corrective

and preventive actions (CAPAs), including inves-

tigations of causes of nonconformities, imple-

mentation of CAPAs and the verification or vali-

dation of corrective actions, the form says.

The company did not respond to a request for

comment by press time. The Form 483 is available

at www.fdanews.com/ext/files/Micrus.pdf.

Averaging OOS Results for IVDs

Leads to 483 for MP Biomedicals

MP Biomedicals Diagnostics Division aver-

ages three values for controls, including out-of-

specification (OOS) results, as part of the final

release for its in vitro diagnostic (IVD) test kits,

according to a recent Form 483.

The Solon, Ohio, company usually runs low,

middle and high values of controls, running the

tests in triplicate and averaging the results.

A review of 30 release records of phenylala-

nine showed that in 17 of the records, one of the

three values was OOS.

MP did not investigate the failure or docu-

ment a clear reason for acceptance, the April 22

form says.

Averaging the three values resulted in a final

value within specification, it notes.

When MP establishes values for its calibra-

tors, it subjectively removes data points it deems

to be outliers without performing an investigation

or seeking an explanation.

The company could not be reached for com-

ment by press time. The Form 483 is available at

www.fdanews.com/ext/files/MPBiomedicals.pdf.

FFOORRMM 448833 IINNSSIIDDEERR

Page 6 THE GMP LETTER August 2010

August 2010 THE GMP LETTER Page 7

Beckman Coulter Warning Cites

Unapproved Assay Changes

Beckman Coulter received a warning letter

citing it for making unapproved changes to a car-

diac diagnostic.

The company made significant modifica-

tions that may affect the performance of the

AccuTnI, according to the June 21 warning

letter posted last month. The assay measures

cardiac troponin to determine if patients have

suffered a heart attack.

The letter addresses the use of the AccuTnI

with Beckman’s Access immunoassay system.

The company initiated a Class I recall in March

of the AccuTn1 used with its Unicel DxI im-

munoassay system because of the unapproved

changes. That recall will be completed in Au-

gust when the assay will have been removed

from all of the DxI systems used in the U.S.,

Mary Luthy, Beckman Coulter spokeswoman,

told GMP.

In response to the warning letter, the compa-

ny is conducting a clinical trial of the AccuTnI.

Once the trial is completed, the company

will submit two new 510(k)s for the assay — one

for use with the DxI and one for the Access sys-

tem, Luthy added. She expects those to be sub-

mitted in the first half of next year.

Meanwhile, Beckman plans to continue pro-

viding the AccuTn1 to customers currently using

the Access system for troponin testing. However,

it will not provide the assay to new U.S. cus-

tomers until the 510(k)s are cleared, Luthy said.

Beckman first alerted labs about concerns

with the AccuTn1 test kits when it found the tests

were more likely to return a positive result when

used on the DxI test system as compared with the

Access system.

The warning letter is available at www.fda.

gov/ICECI/EnforcementActions/WarningLetters/

ucm217576.htm. — Mari Serebrov

FDA Sends Warning to Medtronic

After Company Addresses 483

In what some devicemakers are referring to

as the “new FDA way,” Medtronic has received a

warning letter even though the company has ade-

quately addressed the agency’s concerns.

The FDA acknowledges receiving several

responses from Medtronic to a Feb. 4 Form 483.

“You appear to be addressing our concerns,” the

agency says in the warning letter.

The May 7 letter, posted last month to the

FDA’s website, stems from a month-long inspec-

tion of Medtronic Navigation’s Louisville, Colo.,

facility, which makes Class II image-guided sur-

gical systems (GMP, July).

Although the Form 483 included nine obser-

vations, the warning letter cites only four:

● A complaint — involving a surgical incident

in which a bur hole was not aligned with a

tumor because the accuracy of the image

was off — was not submitted as a medical

device report. Also, two cases noted in a re-

view of the customer tracking system per-

tained to device failures but were not con-

sidered complaints;

● Some software defects were not documented

in accordance with the company’s standard

operating procedure;

● An internal risk analysis report for the Treon

StealthStation failed to establish or define

the acceptable risk level; and

● A StealthStation was released before all the

required activities were completed.

Medtronic provided responses to all the obser-

vations, company spokesman Brian Henry told

GMP. He declined to speculate on why the agency

chose to cite the four included in the letter. No date

has been set for a follow-up inspection, he added.

The letter is available at www.fda.gov/ICE

CI/EnforcementActions/WarningLetters/ucm2180

93.htm. — Mari Serebrov

GMP Issues Cited in Warning

To Abbott Diabetes Care

Abbott Diabetes Care received a warning

letter about GMP violations at its Alameda,

Calif., facility, which makes FreeStyle and Navi-

gator blood glucose monitoring products.

FDA investigators noted that the sampling of

three lots for quality control testing and inspec-

tion was out of compliance, according to the July

2 warning letter. The company also failed to ade-

quately address problems with empty blister

packs and scratches on its FreeStyle Lite strips.

The letter stems from an FDA inspection that

ended March 5. Although Abbott responded to the

Form 483 from that inspection, the agency says it

can’t determine the adequacy of the response to

these two observations because the company did

not provide documentation of the corrective action

and some of the action is ongoing.

The agency deemed Abbott’s responses to

two other observations inadequate. One dealt

with four revisions of the Navigator shelf life en-

vironmental design verification protocol.

“The first revision was never used,” the let-

ter says, “the second revision was used at the

start of the validation and the third revision was

used at the completion of the real time aging of

the units and the verification/validation of the

tests.” The final revision requires that real-life

units be tested at set intervals. The testing was

done — but not at the specified times.

In response, Abbott updated its design con-

trol procedure to improve the level of change to

protocols, but it did not address the failure to fol-

low company procedures, according to the letter.

The final observation notes that some em-

ployees lacked the education or experience re-

quired for their positions. For instance, the person

serving as regulatory affairs manager did not

have the minimum five years of regulatory expe-

rience required in the job description.

The company indicated it is conducting a

global personnel review and reviewing human

resources processes for developing job descrip-

tions and identifying and selecting personnel

for positions.

Acknowledging that these reviews are con-

tinuing, the agency says Abbott needs to provide

evidence of their completion and effectiveness. It

also notes that Abbott named a new regulatory af-

fairs manager, but that person doesn’t have the

required qualifications either.

Although Abbott has been corresponding

with the agency on these issues, the FDA only

addressed its first response, dated March 26, in

the warning letter. Abbott is taking the actions

necessary to address the concerns, Abbott

spokesman Greg Miley told GMP.

The warning letter is available at www.fda.

gov/ICECI/EnforcementActions/WarningLetters/

ucm219001.htm. — Mari Serebrov

Page 8 THE GMP LETTER August 2010

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FDA Sets Deadline for CSZ

External Quality Audit

Citing unapproved changes and systemic

failures ranging from nonconforming product to

complaint handling, the FDA has asked Cincin-

nati Sub-Zero (CSZ) to have an external consult-

ant audit its manufacturing and quality assurance

systems.

The company is to submit by Dec. 15 an ini-

tial audit with certification by its CEO that all the

corrections called for in the report have been ini-

tiated or completed, according to a July 13 warn-

ing letter. Subsequent reports and certifications

are due March 15 and June 15.

The letter stems from an October to De-

cember inspection of the Ohio-based company,

which manufactures patient body, blood and

fluid temperature-control products. The inspec-

tors noted that several of the devices had been

modified to an upper operating temperature of

48 C without FDA approval. The company must

submit 510(k) or PMA applications to cover

these changes.

483 Response

Although CSZ took more than 15 business

days to respond to the Form 483, the FDA ad-

dresses the company’s Jan. 27, Feb. 26 and April

9 responses in the letter, saying they are either in-

adequate or their adequacy cannot be determined.

For instance, CSZ submitted an action plan

to improve its supplier evaluation and resolve

nonconforming material issues as a result of sus-

pect breaches of sterile packaging and seal fail-

ures noted in a complaint.

This response is inadequate, the FDA says,

because “you have not determined the fundamen-

tal cause for a systemic failure to analyze com-

plaints, returned product, and other quality

sources, and no corrective action or preventive

action to correct the systemic failure has been

taken and determined to be effective.”

Similarly, the agency notes a systemic fail-

ure to evaluate nonconforming product in relation

to seven complaints, received in one year, of

leaks at the reservoir elbow of Blanketrol II and

III devices.

A third systemic failure involves the lack of

validation and verification of a corrective and

preventive action (CAPA) to address the cracking

of heater plates in Micro-Temp LT devices.

To address complaint-handling deficiencies

noted during the inspection, CSZ is conducting a

retrospective review of complaints going back to

June 2009. The FDA cannot determine the ade-

quacy of this response because the effectiveness

of the actions has not been determined, according

to the letter.

Other citations in the warning letter include:

● No validation protocol has been established

for the software used in the microprocessor

boards on the Blanketrol II, and the software

has not been validated. The company was

unable to determine how many software re-

visions had been released for the device and

what changes were made with each revision;

● Trending analyses provided to FDA inspec-

tors were incomplete;

● Employees did not inspect product in accor-

dance with company procedures;

● No installation qualification was performed on

the heat bar sealer used to seal sterile devices;

● Medical device reports (MDRs) were not sub-

mitted to the FDA for a patient who received

second-degree burns from CSZ’s hyper/

hypothermia system and for Cupravidus

Pauculus infections associated with a blood

temperature-control system; and

● CSZ did not follow its own procedures in

not submitting MDRs for the injuries, which

it had attributed to user error.

CMZ declined to comment. The warning let-

ter is available at www.fda.gov/ICECI/Enforce

mentActions/WarningLetters/ucm219661.htm.

— Mari Serebrov

August 2010 THE GMP LETTER Page 9

Devicemakers May Leave China

Following Labor Struggles

Ongoing labor unrest in China has some

U.S. devicemakers looking elsewhere for a manu-

facturing base.

“I’ve noticed device companies are looking

more at their options outside of China in the last

year versus three years ago,” Sean Correll, director

of consulting services at Emptoris, a supply and

contract management solutions company, told GMP.

China has been the place to go for cheap la-

bor since the 1980s, but a recent string of worker

suicides and strikes has forced a number of U.S.

companies to raise wages for an increasingly re-

sentful workforce, Ravi Ramamurti, a professor

of international business and director at North-

eastern University’s Center for Emerging Mar-

kets, says in a recent analysis.

Small Companies

The situation is further complicated by Chi-

na’s decision to let its currency, the yuan, appre-

ciate, Philip Cheng, a life sciences attorney based

in Shanghai, told GMP.

“For some companies, this is perhaps a larg-

er factor than the rising demand in increased

wages among migrant workers in China’s facto-

ries,” Cheng said. “Nevertheless, in combination

with yuan appreciation, this creates a formidable

challenge for small to medium-size U.S. medical

device companies which depend heavily on Chi-

na’s low-cost labor force.”

These changes may push small to midsize de-

vice companies that are relatively new to the Chi-

nese market to consider retreating to other low-cost

labor havens such as India or Vietnam, he said.

But larger device companies that have invest-

ed millions of dollars in Chinese plant infrastruc-

ture are likely to stay put, Cheng said. For larger,

established companies, “these factors just mean ex-

pectedly higher operating costs in an environment

that is still relatively cheap compared to the more

developed parts of the world,” he added.

Merrill Weingrod, CEO of China Strategies,

a consulting firm, agreed that most device com-

panies would likely stay in China because of the

complexities of manufacturing their products and

the likelihood that they get some of their compo-

nents from other China-based companies.

“There is no question that costs will rise in

China, but costs will rise in other countries for

the same reasons they went up in China,” Wein-

grod told GMP.

Rising costs abroad may have resulted in some

U.S. devicemakers moving part of their operations

home, but many companies are probably a long

way from considering a full relocation to the U.S.

Market Size

“There are just too many pluses on the Chi-

na side of the equation,” Cheng said. He pointed

to the emergence of the Chinese healthcare mar-

ket and the country’s recent macro-economic

policies to increase medical coverage as incen-

tives for device companies to stay put.

Another benefit that’s hard for devicemakers to

walk away from is the highly educated and techni-

cally skilled workers in China. “Foreign companies

see the talent pool here as endless,” Cheng said.

Meanwhile, U.S. devicemakers are gearing

up for more competition in China as Chinese de-

vicemakers have begun developing their own

Class III devices.

“This may drastically hurt business for Class

III medical device companies in the West,” Ames

Gross, president of Pacific Bridge Medical, an

Asian consulting firm, told GMP. “Even if the

quality of the Chinese devices is only 65 percent

as good as an American device, and on top of that

up to 50 percent cheaper … the government

would likely choose the Chinese device.”

— Virgil Dickson

Page 10 THE GMP LETTER August 2010

GE Relaunches CV Diagnostic

After Manufacturing Trouble

A GE Healthcare ultrasound contrast agent

with a history of serious adverse events has made

its way back to the market.

Optison, a microbubble used in cardiovascu-

lar (CV) diagnostics, returned to the market last

month after a one-year hiatus. Citing manufactur-

ing difficulties, GE had stopped shipping the

product last June.

Kimberly Wolf, a GE spokeswoman, declined

to elaborate on the manufacturing problems, but she

noted that the company has worked diligently over

the past year with its third-party manufacturer to

monitor and assist with the troubleshooting process

and to implement a solution.

It was the second time in Optison’s 12-year,

FDA-approved history that it was removed from

the market due to manufacturing issues. The first

time, it was recalled for nearly two years because

of a lack of adequate sterility assurance during

aseptic manufacture. That recall ended in 2007.

GE relaunched the product because “there is

a need for Optison in the marketplace,” Wolf said.

Microbubbles are minimally invasive and

enable physicians to clearly see heart structures

in poor patient images, which are commonly

caused by intervening fat and lung tissues. They

are a preferred option to exposing patients to ion-

izing radiation or dye, Steven Feinstein, a profes-

sor of medicine and director of echocardiography

at Rush University Medical Center, said.

Optison and its only competitor, Definity,

marketed by Lantheus Medical Imaging, have

raised safety concerns that led to the FDA order-

ing boxed warnings in 2007 of serious cardiopul-

monary reactions, including fatalities. Despite the

adverse events and warning, the American Soci-

ety of Echocardiography has argued that the ben-

efits of using the microbubbles outweigh the

risks. — Virgil Dickson

August 2010 THE GMP LETTER Page 11

Devicemakers Question Wisdom

Of Sharing Inspection Info

Proposals aimed at increasing the FDA’s trans-

parency could reveal device trade secrets and poten-

tially threaten national security, devicemakers say.

One area of concern is a proposal by the

FDA Transparency Task Force to disclose the

name and address of an inspected facility, along

with the type of FDA-regulated products involved.

“There may be some circumstances where … that

could raise national security issues,” AdvaMed

says, especially when a company is producing a

device to treat soldiers during a war.

If implemented, the FDA and the Depart-

ment of Homeland Security should determine

which companies may be exempt, AdvaMed says.

The proposal is one of 21 included in a re-

port the task force released in May. Comments on

the report were due last month.

A recommendation to expand recall disclo-

sures beyond what is currently released raised red

flags for the Medical Imaging & Technology Al-

liance (MITA).

While the group supports providing more

information about Class I recalls, it says dis-

closing more about Class II and Class III re-

calls “may alarm the public without further

safety benefit.”

MITA and AdvaMed also support a proposal

to release public notices when a recall is complet-

ed. AdvaMed advises releasing such notices with-

in 60 days of when a company says its recall is

complete and including the completion date in

the notice.

As for the other proposals that would affect

devicemakers, AdvaMed says posting summaries

of the most common inspection observations,

current agency work plans and recently filed

court cases are positive steps. — Virgil Dickson

Group Demands FDA Release

UDI Regulation Immediately

Tired of waiting for a proposed rule to be re-

leased on a unique device identification (UDI)

database, an advocacy group is asking the FDA

to issue a regulation immediately.

The Advancing Patient Safety Coalition

(APSC) sent a letter last month to FDA Commis-

sioner Margaret Hamburg reminding her that it

has been three years since Congress passed the

FDA Amendments Act, which requires the cre-

ation of a UDI system. Now is the time to act, the

coalition says.

“It is taking the agency an unreasonable

amount of time to publish a proposed rule,” the

organization says. “Moreover, the FDA has been

working on this issue for years before the legisla-

tion was passed. With each day that elapses with-

out a UDI system in place, patients’ lives are put

at needless risk.”

The delay puts consumers at risk of being

implanted with defective, counterfeit or recalled

products, according to the coalition, which com-

prises consumers, hospitals and physicians.

With no UDI in place, the FDA lacks the

ability to track adverse device events or locate re-

cipients of faulty, recalled products. “UDI is the

missing link to protect the safety of patients by

improving processes for device recalls and cor-

rections,” the letter says.

The agency expected to release a proposed

rule for a UDI database this summer, Jay Crowley,

CDRH’s senior adviser for patient safety, said earli-

er this year, adding that the agency’s goal is to have

a final rule in place by next April (GMP, April).

But FDA spokesman Dick Thompson was

vague last month about when the proposed rule

is likely to be released. “At this point, all we

can say is that the rule is still under develop-

ment,” Thompson told GMP. “It is a high pri-

ority within the agency, and we hope to issue it

in 2010.”

Industry also has voiced frustration with

the continued delay. “UDI is coming, but not

fast enough for us,” Robert Samec, a vice pres-

ident of regulatory affairs at CareFusion, said

at an FDA workshop on home-use devices in

May.

In the past, members of APSC have pub-

licly expressed their concerns that the FDA was

dragging its feet on UDI. During a public meet-

ing on the topic in February 2009, Linda Rouse,

director of federal affairs for Premier and a

member of APSC, pointed out that the agency

had been looking to begin work on the database

since 2004.

“Don’t think that we’re not very close to be-

ing done,” Crowley responded.

Once implemented, the database will require

certain baseline information for each device. The

minimum dataset should include identification

(manufacturer, make, model and unique attributes)

and information for safe use, such as indications,

contraindications and necessary accessories.

— Virgil Dickson

Page 12 THE GMP LETTER August 2010

President: Cynthia Carter; Publisher: Matt Salt; Editorial Director: Pamela Taulbee; Executive Editor: Mari Serebrov

Copyright © 2010 by Washington Business Information Inc. All rights reserved. The GMP Letter (ISSN 0196-626X), an executive briefing on FDAenforcement and quality systems requirements for medical devices and diagnostics, is published monthly, 12 issues, for $945. Photocopying orreproducing in any form, including electronic or facsimile transmission, scanning or electronic storage is a violation of federal copyright law and isstrictly prohibited without the publisher’s express written permission. Subscribers registered with the Copyright Clearance Center (CCC) may repro-duce articles for internal use only. For more information, contact CCC at www.copyright.com or call (978) 750-8400. For site licenses for multipleusers or to purchase multiple copies, contact Alka Desai at (703) 538-7669.

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False data in clinical trials isn’t new. What is new is the aggressive role the FDA expects drugand device companies and CROs to play.

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Responding to FDA 483s spells out best practices for managing the post-inspec-tion process so you don’t get callbacks from the FDA. Think of it as “483s forDummies” — a plain-English step-by-step guide that goes beyond boilerplateadvice and digs into specifics that help you fashion a top-quality response to yournext Form 483.

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