Originally Published MDDI April 2004
In recent years, much progress has been made in relations between the agency and manufacturers. Could a victory by Democrats reverse this positive trend?
James G. Dickinson
Fewer but Faster PMAs, 510(k)s in 2003 | AdvaMed Seeks MDUFMA Adjustments | FDA Expands Tissue Registration Rules | Complaining about FDA in Public | Respironics Cited by FDA | Abbott Making Headway with FDA | FDA Seizure at PerkinElmer
As the general elections in November approach, is FDA-industry collaboration at risk with a possible Democratic victory? This question was very much on the minds of attendees of FDLI's Advanced Medical Device Issues conference in Washington, DC, in February.
At the event, CDRH deputy director for science and regulatory policy Philip Phillips struck a particularly responsive chord with the audience. Given a progression of recent reforms, he said, there are now greater opportunities than ever for broad FDA-industry collaboration.
FDA “has reached out to collaborate with industry in mutually beneficial ways,” Phillips said. As examples, he cited agency-sponsored workshops to help industry achieve compliance and various efforts to streamline the approval process. Modular reviews, third-party reviews, the product development protocol alternative to the PMA process, and other mechanisms have all helped expedite product reviews, he said.
The agency's current attitude toward collaboration, Phillips said, represents a significant shift in its approach to regulation. He contrasted this new posture to the agency's previous practice of maintaining what he called “a certain distance from the industry it regulated.”
As a career civil servant, Phillips was not engaging in partisan politics in pointing out these gains. Some of them, indeed, began under President Clinton. But his point was not lost on listeners well aware of Democratic primary campaign rhetoric decrying special interests and proindustry initiatives.
Beyond this topic, Phillips urged greater use of electronic labeling for medical products. He said that while there was initial resistance to the concept of e-labeling by some within FDA, eperi- ence with it has been generally positive.
Phillips also advised device sponsors to give careful consideration to what data FDA are likely to require in both the pre- and postmarket phases of clinical studies. To sponsors, a two-year premarket study of hip and knee replacement devices as required by FDA might seem long, he said. But physicians and consumers expect these devices to function in normal use for a decade or even a great deal longer. In any case, FDA is certain to require extensive postmarket studies to evaluate their performance over time.
“Multiyear randomized clinical trials are expensive,” Phillips noted. “But sponsors may find it advantageous to go the extra mile to gather more than minimal data to satisfy FDA in the pre-market phase.” The reason, he said, is not simply that such information will be needed anyway. Rather, by “offering greater reassurance to physicians and consumers, additional information can aid substantially in . . . later marketing efforts.”
Even without a change in political control in Washington, another speaker, attorney John Reiss, foresaw potential legal constraints on the industry. A partner in the Philadelphia law firm of Saul Ewing LLP, he predicted increased scrutiny of device industry practices “within the next five years.” This development would follow the pattern of the drug industry, which has been the target of court actions and multimillion-dollar fines.
Reiss warned the audience about U.S. Attorney Jim Sheehan, who has won a number of spectacular settlements against drug companies. Sheehan, he said, is “pleasant on a personal basis,” but also a “very aggressive guy” who could also be “unreasonable.” Reiss said that “Sheehan is hot against such practices as market share discounts, and running afoul of the law can be very, very expensive, as well as bad PR.”
Fewer but Faster PMAs, 510(k)s in 2003
The number of premarket approval applications FDA approved last year fell by 24%, from 41 in FY02 to 31 in FY03, according to new data released by CDRH. However, in 2003 the center reviewed PMAs five days faster than it did in 2002. “Total average elapsed time for PMAs from filing to approval decreased from 364 days in FY02 to 359 days in FY03,” CDRH said in its news release. But the “non-FDA component” of review time was 35% slower last year, increasing from 52 to 70 days. As a result, total average PMA review time increased to 221 days from 213.
One of the largest improvements last year, according to the release, came in PMA supplement reviews: average review time for supplements decreased 11%, from 105 days in FY02 to 93 in FY03.
For 510(k)s, which also dipped in number, CDRH said that on average it cleared those three days faster than last year. Average review time for 510(k)s dropped from 79 to 76 days.
In an accompanying Office of Device Evaluation (ODE) performance report, CDRH said it received 54 original PMAs last year, 5 more than in FY02. “The total number of PMAs in inventory (active and on hold) at the end of this fiscal year increased from 73 in FY02 to 83,” the report said. “The number of active PMAs under review decreased at the end of FY03 to 35, compared to 42 the previous year, and those on hold increased from 31 in FY02 to 48 in FY03. The total number of PMA actions decreased from 237 to 198 actions. These actions included 54 filing decisions, 87 scientific review decisions, and 57 approval/approvable/not approvable decisions.” Out of 57 original PMA decisions made last year, 31 PMAs were approved, 16 PMAs were approvable, and 10 were classified as not approvable.
ODE's report said it received 4247 original 510(k)s (down from 4320), 1856 supplements (up from 1780), and 1690 amendments (down from 2385). “The median review time, i.e., the time it took to review 50% of the 510(k)s, has been falling from a high of 164 days in FY93 to 72 days in FY03,” ODE said.
AdvaMed Seeks MDUFMA Adjustments
With House passage on January 27 of changes to the Medical Device User Fee and Modernization Act (MDUFMA), AdvaMed urged both House and Senate to quickly resolve differences between this and an earlier Senate version.
“Final passage in early 2004 is critical because FDA recently completed [its] initial training of third-party inspectors,” AdvaMed said in a statement. “However, companies cannot access this program until technical changes are enacted.”
According to AdvaMed, the bills make technical and clarifying corrections to MDUFMA, including the following:
• An amendment to the third-party inspection program. As written, the law requires companies to certify both that foreign countries recognize an FDA inspection and that the companies market their products in a foreign country that recognizes the third-party inspection. The change would allow a company to meet either one or both.
• An 18-month moratorium on implementation of the MDUFMA section that requires all manufacturers to place their name or brand on their devices. This delay would allow Congress and FDA more time to consider the implications of the provision and any needed policy changes.
FDA Expands Tissue Registration Rules
FDA said in a January 21 statement that more types of tissue establishments must register with the agency and list each cell or tissue produced. The agency says the move “is an important step in FDA's implementation of three new regulations to be finalized under the agency's plan to regulate tissues in a more comprehensive, risk-based approach. The goal of the plan is to promote tissue safety without imposing unnecessary restrictions on research, development, or availability of new or existing products.”
Under a rule issued three years ago, only traditional tissue establishments that have been regulated by FDA since 1993 have been required to register and list their products. Such companies typically comprise those that process bone, ligaments, skin, and tendons. The new rule broadens this to include those that deal with human sperm, reproductive tissue, and other human cellular products, such as stem cells derived from blood sources including umbilical cord blood. For the first time, for all these products, FDA said, a complete database of human cells and tissue-based product establishments and products will be maintained. This will significantly increase FDA's base of knowledge about these establishments and products and improve the effectiveness of communications about their risks to the public.
FDA also said it would soon issue a new interim rule on heart valves and dura mater. The agency wants to ensure that they remain subject to regulation as medical devices until the new regulatory framework for tissues is complete. At that point, these devices will become subject to regulation as tissues, and will no longer be regulated as devices.
To view FDA's statement, visit www.fda.gov/bbs/topics/NEWS/2004/NEW01007.html.
Complaining about FDA in Public
It isn't often that a medical device company issues a news release to complain about FDA harassment. But that's what happened in February when Midvale, UT–based Utah Medical Products, a women's health device maker, found itself embroiled in its fourth inspection in three years.
FDA had issued the company a six-page warning letter in September 2001. At issue were inadequate corrective and preventive action procedures involving alleged failure to identify all potential sources of quality data, such as in-process rejects, medical device reporting, maintenance records, or quality audits. FDA also charged that the firm's device history records were inadequate because acceptance records did not demonstrate that devices were manufactured in accordance with the device master records.
FDA conducted a follow-up inspection in early 2002 and another in 2003. Then, Utah Medical Products complained in the release, FDA cut off all formal dialog with the company. This lasted until three investigators, medical device specialists from around the country, showed up at its facility in February to conduct a surprise inspection. Eight days later, the investigators had still to detail, as promised, any observations during daily close-out sessions, according to the company's Washington, DC, counsel Larry Pilot (McKenna, Long and Aldridge).
In its news release, Utah Medical Products quoted CEO Kevin Cornwell as saying, “I am concerned that the FDA intends to further tarnish [our] good reputation through a motivation that has nothing to do with the safety or effectiveness of our devices.” He said he was “disappointed and bewildered” by FDA's actions. The agency's own Web site says a normal quality inspection needs only about five days, he says, whereas his company has so far “endured” more than 53 “inspector days” of inspection. The multiple inspections, he added, “have not identified any health risk associated with our devices.”
After FDA placed a hold on the processing of export certificates for the company, Utah Medical last year filed suit to remove it. Attorney Pilot said that so far FDA has raised no issues about the safety of Utah Medical Products' devices. It continues to manufacture and distribute them in both domestic and international markets. However, foreign sales have slipped owing to the export certificate hold, he said.
Without discussing the details of the dispute, Pilot said that, regrettably, situations like this arise because of FDA's imperfect FDA-483 and warning letter process. Part of the problem, he said, is that the inspectional process often is not adequately supervised by FDA district offices and the centers. There is a tendency for those who review a 483 or warning letter to uncritically assume that the agency's position is correct when that is not always the case, he said. “Warning letters are expressions of opinion by the agency,” he said, and not necessarily factual. Whether or not the allegations in a warning letter are supportable is to be determined ultimately by negotiation or litigation, he said.
Pilot also questioned the credentials of FDA's medical device specialists who inspect firms across the country. “How does one become a specialist,” he asked, if the investigator has no experience in industry or past responsibility in developing or implementing a quality system? Pilot criticized FDA's practice of continuing to use “paper checkers” to find fault with firms' quality systems, especially when their only basis for making observations is in the context of reviewing documents.
Pilot said the dispute has been discussed with FDA's Office of the Commissioner to no avail. Requests for dispute resolution have been denied. Meanwhile, the company said, the current inspection was continuing “without an apparent end in sight.” In the news release, CEO Cornwell called for “Congressional representatives who have a keen interest in the public welfare to use our experience in a formal investigation of FDA practices.”
Respironics Cited by FDA
As a result of a lengthy list of problems uncovered in an inspection last summer at Respironics' Carlsbad, CA, facility, FDA's Los Angeles district office issued a warning letter in January, calling for a regulatory meeting with company officials “to discuss the corrective and preventive actions taken since the completion of our inspection.” FDA said that concerns to be discussed at the meeting included the following:
• Design procedures and design history for the company's Esprit ventilator, especially software changes made to the device.
• Procedures for handling all written and oral complaints.
• Procedures for conducting internal and external audits.
• Procedures for reviewing and conducting investigations of products that do not conform to their specified requirements.
• Procedures for submitting required reports to FDA, such as medical device reporting reports, corrections and removals, and recalls.
The warning letter said the inspection found that the Esprit ventilator was adulterated within the meaning of the quality system regulation. In addition, according to the warning letter, the device was misbranded for several reasons, including the company's failure to provide information to FDA when problems arose and corrections were made.
Included in the letter were descriptions of incidents involving patients. Although the cited incidents were reportable, the letter said, the company took up to two years to notify FDA, saying it had initially determined that the incidents were not reportable or did not pose a risk to health. FDA rejected these explanations.
Abbott Making Headway with FDA
FDA has cleared 11 Abbott Laboratories diagnostic assays for hepatitis, prostate specific antigen (PSA), and alpha-fetoprotein produced at its formerly troubled Lake County, IL, facility. In 1999, it was the focal point of a federal court consent decree that cost the company a $100 million fine; in 2002, Abbott was hit with a $112 million disgorgement penalty after failing an FDA reinspection there.
The company says the newly cleared tests are performed on its Architect, AxSym, and IMx immunoassay instrument systems. It says the approvals are related to a December 2003 determination that the Lake County facility is in substantial conformity with the quality system regulation.
According to Abbott, two of the hepatitis assays (HAVAB and HAVAB-M) are used to aid in diagnosis of infection by the hepatitis A virus. Its HCV hepatitis assay is used for qualitative detection of antibodies to the hepatitis C virus. Three total-PSA tests are used to aid in diagnosis and management of prostate cancer. Three free-PSA tests can be used in conjunction with total-PSA results as an aid in discriminating between cancer and benign prostate disease. The two alpha-fetoprotein tests approved are used in testicular cancer management and detection of fetal open-neural-tube defects, respectively, the company says.
FDA Seizure at PerkinElmer
FDA said in early February that the Northern District of Ohio federal court had issued a seizure warrant for various “adulterated” neonatal chemistry and isoelectric focusing diagnostic kits at PerkinElmer Life Sciences Inc. in Norton, OH. The agency said the test kits are used to screen for genetic diseases in newborns and for hemoglobin and central nervous system diseases, such as sickle cell anemia and multiple sclerosis, in adults.
An FDA talk paper said inspections at the firm revealed that it had “continually failed to follow the requirements of the quality system regulation when manufacturing in vitro diagnostic kits” and that the company had “failed to take appropriate corrective actions.”
On February 13, the company said it had just received FDA approval to resume marketing the seized devices. It said it will submit them to additional testing and provide users with information that will allow them to test the products.
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