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H U M A N & A N I M A L D R U G S • B I 0 L o G I C S • M E D I C A L D E V I C E S Incorporating DICKINSON's FDA and DICKINSONs FDA INSPECTION A monthly newsletter focusing on early drugideviceit+'ologic regulatory policy, compliance and field enforcement, and personnel developments inside the Food and Dnig Administranon. Published by Ferdic, Inc., P.O. Box 367, Las Cruces, NM, 88004-0367. James G. Dickinson, Editor, (505) 527-8634 • Fax: (505) 527-8858. RudoltApodaca, Consulting Editor, (410) 730-1889. Annual subscription: $685. Contents copyrighted. FDA is opposing NEJM attack on placebo controls "I hope it doesn't have any implications for the future of placebo controls - he's wrong in almost everything he says." That was CDER director of Drug Evaluation I Robert J. Tem- ple's first reaction to a call in the 8/11 New England Journal of Medicine by Boston Uni- versity School of Public Health's Kenneth J. Rothman for a ban on most uses of placebo controls in FDA-reviewed drug studies. Temple 0 is writing a rebuttal of Rothman's NEJM "Sounding Board" article, which (cont. p. 23) Courts in conflict on limits to device preemption law On opposite sides of the country last month, U.S. district courts disagreed on whether FDA's regulatory loosening at 21 CFR 808.1(d)( l) of the preemption language in the Medical Device Amendments (21 USC 521(a)) has any power - and thus, whether it can permit civil litigants to sue manufacturers of devices that are in vio- lation of FDA requirements- The FDA regula- Highlights: Hatch seeks to "de-Kesslerize" FDA ........................ 3 No "blanket" approach to device approvals............ 4 What's best? 4 reviewers or 326 cellular phones?.. 5 Takeda fails on process flow design ......................... 6 Daily Freedom of Information Log ........................... 8 Latest FDA Warning Letters .......................................10 Device exodus key is efficacy rule of Congress .....13 "Phenomenal" potential in electronic tracking .......14 EMI and medical devices: it's time to act .................16 Foreign firms want to do the right thing: Davis.......17 IPAX faulted over hazards in sterility failures..........18 Why delays in FDA's reporting of recalls? ...............19 Track Il: Air Techniques responds well to 483 .........19 Take compliance away from Centers? ......................20 How FDA dropped the compounding ball ........•.•.....24 Cabot Medical has begun marketing the Seitzinger Tripolar® cutting forceps, used in lieu of stapling devices during medical procedures such as hyster- ectomies and appendectomies. Unlike stapling de- vices, the forceps do not have to be removed for reloading during surgical procedures. This reduces surgery time, expense and patient trauma. Cabot's 510(k) was approved 7/27 on the basis of four predi- cate devices: the Cameron-Miller Corson bipolar for- ceps, the Richard Wolfe K/eppinger bipolar forceps, the Karl Stores endoscopy American bipolar grasp- ing forceps and Eder Instrument Corp.'s micro-co- agulation forceps. tion in question interprets the statute to "not preempt state or local requirements of general applicability where the purpose of the require- ment relates either to other products in addition to devices (e.g., requirements such as general electrical codes and the Uniform Commercial Code (warranty of fitness)), or to unfair trade practices in which the requirements are not limited to devices." In Santa Ana, CA, federal judge Gary L. Taylor ruled 8/1 in the Province of Ontario vs. Shiley Inc. that private litigants are not preemp- ted by 21 USC 521(a), but in Boston, MA 8/23, federal judge Mark L. Wolf ruled in Linda Talbott et al vs. C.R. Bard et al that they are

• • September 1994 supported him, Wolf said. And the fact that Bard had committed fraud on FDA did not make any difference, because "Congress did not intend to establish a fraud on the FDA exception to the express preemption established by § 521." not happy ... Wolf wasn't happy with his conclusions, however. On the third page of his 37-page memorandum and order, he acknowledged that "this decision may cause some, including those who enacted the law, to question whether com- plete preemption of private rights of action is the most fair and effective means of balancing the legitimate, competing interests of promot- ing innovation and reasonably assuring the safety of complex medical devices." And again, at the conclusion of his order, Wolf suggested that Congress's "decision" to sup- plant individual action with FDA enforcement made the agency's Bard actions an issue. Congress made no such decision, ar- gues plaintiff's attorney Jeffrey A. New- inan (Newman, Heineman & Itzkowitz), who immediately lodged notice of appeal of Wolf's order. A close study of the entire legislative history of the Food, Drug and Cosmetic Act showed him that in 1936 Congress extensively debated the issue and decided not to preempt private rights of action; in 1976 Congress effectively let that stand by not mentioning it at all in the writing of the Medical Device Amendments. In his 8/1 ruling on Shiley's motion to dismiss, Judge Taylor teased the legal principles apart more carefully, and agreed only selectively with the King vs. Collagen First Circuit opinions. correct, but ... The appellate judges were correct in uphold- ing preemption with respect to negligence claims, since FDA regulates design, manu- facture, marketing and sale. Taylor wrote; like- wise, they were correct in upholding preemp- tion of misbranding and failure to warn claims. However, the 1976 Amendments "would not preempt claims that the manufacturer negli- gently failed to comply with the FDA's reau- lations, since a finding of wrongdoing would merely impose those regulations already im- posed by the statute, and would not be 'different from or in addition to' those imposed by the Dickinson's FDA REVIEW: Page 3 (Amendments)." In Boston, Judge Wolf dealt with this scenario, argued by plaintiffs, by cit- ing another First Circuit opinion in Mendes vs. Medtronic (1994): "One way to ensure that a factfinder applies a standard not adding to or differing from FDA regulations is to supplant the common law standard with FDA's require- ments. We find nothing to support that Con- gress intended such a radical, unwieldy form of preemption, particularly where Congress did not intend to create a private riQht of action under the Federal FD&C Act." y Copies of both orders are available by fax or other written purchase order, to subscribers only, for $40 or $25 each if ordered singly. Fax: 505-527-8858. Hatch's draft bill shows rift: seeks to "de-Kesslerize" FDA The "de-Kesslerization" of FDA appears to be the remedy that Utah Senator Orrin G. Hatch would prescribe for what ails the agency in its medical device review woes, according to a summary document describing his yet-to-be- introduced Medical Devices Program Reform Act. Hatch, who mentored Commissioner David A. Kessler both as a direct employee on his staff for four years until 1984 and as a candidate for the FDA leadership, has broken with his protege over a number of basic policy principles, including Kessler's penchants for higher scientific standards for product approv- als and tougher enforcement. Another keen sup- porter of Kessler's candidacy, former chief• counsel Peter Barton Hutt (Covington arid Burlington), has also broken with him, mainlN over food regulation and enforcement. Others, including fo»nerly close insiders, chafe at his "neglect" of their FDA interests when sexier issues like breast implants, food labeling and tobacco regulation appear to serially consurne him. In his summary of the proposed bill, which was driven by the Utah Biomedical Industry Council's wish-list of FDA reforms (see follow- ing story), Hatch displays the depth of the rift, completely downgrading Kessler's top priority (enforcement) by not mentioning it at all. And Hatch would rewrite FDA's Kessler-devised mission statement to declare that the agency improves the public health by, with respect to medical devices, expeditiously approving safe

Page 4: Dickinson's FDA REVIEW September 1994 NO "BLANKET" APPROACH TO DEVICE APPROVALS: ALPERT by Lucia Greene CDRH director of device evaluation Susan Alpert, who flew into Salt Lake City last month to address the Utah International Medical Device Congress, has disabused the industry of misper- ceptions that FDA uses a blanket approach to all devices, and doesn't distinguish adequately between special situations. After the meeting, at which an industry position paper calling for a separate FDA Office of In Vitro Devices was circulated, Alpert told FDA Review that under current regulations, IVD devices are being handled in a way that is appropriate for them. "They have their own set of regulations and their own set of standards and their own guidances - so they are in fact treated quite differently and uniquely to their particular format, " she said. There are sensitivity and specificity criteria, special formats for the presentation of testing data and an emphasis on looking at controls, validation, and stability of testing; plus they have their own regulations on labeling. Alpert disagrees with the industry's argument that because IVDs are not implanted and don't come in contact with the patient, they can't pose a risk. "The risk may be misdiagnosis, an error in the test that may lead to intervention on the patient, either lack of intervention or significant intervention, such as surgical intervention and medical treatments that have severe side-effects. So we feel that they have a great deal of impact on diagnosis and care of patients and they are not without risk." Alpert said that while many at the Utah conference felt that IVDs should be handled in some fashion other than as medical devices, "that is clearly not ours to decide." As for user fees, FDA is aware of the financial burden these impose on small companies such as those that make up the bulk of the IVD industry. Alpert said that the agency is drafting a "bundling" policy whereby a company can combine different products into a single 510(k), and thus a single user fee. I hF i~~Z S W T' r' and effective products, removing unsafe and ineffective products from the market, encourag- ing education in the safe and effective use of products, and facilitating world trade in safe and effective products. According to the Hatch summary, FDA would be directed to change its operational directives with respect to devices to: • regulate medical devices by focusing on overall improvement of public health; • set realistic priorities to concentrate resources on the greatest threats to public health, recognizing that resources will never be sufficient to enable FDA to discharge to the full breadth of its statutory respon- sibilities; • promote necessary scientific research; • employ a sufficient number of qualified staff to achieve its mission; • exercise its authority fairly and firmly, to safeguard and improve the well-being of patients while respect- ing the legal rights of those who discover, develop, manufacture and market products; • balance the appropriate benefits/risks when review- ing an approval application, and base decisions upon sound scientific and legal analysis. Explain the decision carefully and thoroughly to those affected; • recognize in its policies, procedures and decisions that no device or other medical product can be used wholly without risk in every situation; • encourage compliance by providing manufacturers and health care providers with clear written guidance; • invite active participation by the public when estab- lishing regulatory policies; • achieve regulatory consistency and predictability in policies; • encourage and participate in educating public and professionals on device use and regulation; and • facilitate world trade by eliminating unnecessary domestic regulation and reconciling divergent U.S. and foreign regulatory systems. Hatch's summary includes a section directin~ FDA to submit a "Device Review Revitaliza- tion Plan" to Congress, developed in consult- ation with a newly-established industry-FDA working group. This plan would deregulate many Class I and Class II products, substitute postmarket performance evaluation require- ments for premarket review, set up a timetable for device approvals with a view to reducing the backlog of overdue submissions by the end of FY '96, regularly update guidelines and sim- plify the standard 510(k) form, provide FDA staff consultations with industry submitters,

i publish clinical information requirements, limit well-controlled trials to those cases in which adequate experience is not available or where patient selection may bias interpretation of results, isolate the review of manufacturing changes for currently marketed products from other 510(k) submissions, and make numerous other approval process and inspection reforms being sought by the device industry. The proposed Hatch bill would also de- Kesslerize FDA by reinstating the top manage- ment structure that existed before Kessler be- came commissioner. What's best? 4 reviewers or 326 cellular phones? Utah's Senator Orrin Hatch wants the agency to surrender all but one of its 326 cellular phones (almost half of the HHS total of 864) and with the $277,000 so saved hire four new medical device reviewers. "In a year," he told the Senate in a budget debate recently, "I under- stand four examiners could review almost 200 applications. This seems to me to be a much more beneficial use of our tax money than sup- port of mobile telephones." If there were a "deep need for 326 people to have immediate access to phones, then I think we should supply each with a roll of quarters to use the pay phones, like most Americans do," Hatch said. Later, his amendment limiting FDA to one cellu- lar phone and directing the agency to apply the moneys so saved to "medical device approval activities" was adopted and is now included in the agency's draft FY '95 budget being reviewed in House-Senate conference. Top FDAers deny that the agency's use of cellular phones is wasteful. As a law-en- forcement agency, most of the use is by field investigators who spend a lot of time in unproductive travel, when they would oth- erwise be out of contact with supervisors. Although Hatch cited an anonymous FDA informant who complained about being issued a cellular phone they didn't want and never used, FDA's use of cellular phones was cleared a year ago after a cost-benefit analysis by Dep- uty Commissioner for Management and Sys- tems Mary Jo Veverka. A high official told FDA Review that if the American people want Dickinson's FDA REVIEW: Page 5 = ELECTRONiC FiLES RULE ` ` APPLIES-TO ALL Contrary to the belief of some; FDA's 8/31 proposed rule on electronic signatures and electronic records applies to all regulated products, not just drugs, according to the pub- lished notice. An advance notice of proposed rulemaking 7121/92 drew few comments from outside the pharmaceutical industry. . - . . The proposed rule includes a signature-to-: document binding requirement to protect; against falsification and a requirement that' submitters certify that their electronic signa-= ture system guarantees the authenticity, valid-- ity and binding of any electronic signature. Biometric/behavioral links would not: be re- quired "at this time.", , : Comments on the proposed rule are being received until 11/29. - Federal Register8/31 FDA to operate efficiently, then the use of cel- lular phones, especially in field work, is justi- fied. FDA employees spend a lot of "dead" time in cars or on the Metro moving about the Washington area and to and from in- spections and to deny them the productivity that's released by cellular phones would be "penny wise and pound foolish. " Hatch's suggestion that FDAers be equipped with rolls of quarters and sent to pay phones when in transit was called an invitation to sim- ply ignore work. It may be noted that Senator Hatch's own staff use cellular phones, as do many others on Capitol Hill. In Senate floor debate, Agriculture chairman Dale Bumpers (D-AR) pointed out that FDA's cellular phone use may not be excessive by the standards of other agencies: USDA has 1,504 cellular phones, Commerce 209, Energy 4,300, EPA 305, FEMA 2,776, HUD 85, Interior 1,844, Justice 3,880, Labor 250, Transportation 1,854, Treasury 1,648, the VA 276. Scheman quits; Kessler moves to fill top slots ~ O "Even when David asked me to do this three ~p years ago, I knew it was not what I intended to Cn do with the rest of my life - but I'm awfully C~ Qlad I did it." That was Deputy Commissioner W for External Affairs Carol Scheman's response = 9/1 when asked about her decision to resign and 00 „_Q G~