Case Title: R.F. and R.F. v. Abbott Laboratories

Citation: 

Docket Number: a-66-98

State: new-jersey

Court: New Jersey Supreme Court

Date: 2000-02-29T00:00:00Z

Document:
(This syllabus is not part of the opinion of the Court. It has been prepared by the Office of the Clerk for the convenience of the reader. It has been neither reviewed nor approved by the Supreme Court. Please note that, in the interests of brevity, portions of any opinion may not have been summarized). GARIBALDI, J., writing for a majority of the Court. The primary issue in this appeal is whether plaintiff's cause of action is preempted by federal regulation. In September 1996, plaintiff R.F. received a transfusion of blood for surgery that was infected with human immunodeficiency virus (HIV), causing her to subsequently test positive for the virus. The blood had been screened for HIV with the first commercially-available HIV blood screening test, which was manufactured by Abbott. R.F. and her husband claim that Abbott's HIV blood test was defective because it failed to inform blood banks regarding limitations inherent in the test and the need to retest where results were negative but borderline. By 1983, scientists understood that AIDS was caused by a virus that could be transmitted through blood and blood products. This discovery created a national health crisis with respect to the availability of safe blood. The FDA took quick action by seeking help from both public and private sources in developing a screening test that could detect the virus in blood samples. Dr. Gallo of the National Cancer Institute published the first description of a screening test for the HIV virus (the ELISA or EIA test) in May 1984. ELISA tests functioned by detecting the body's immune response (or antibodies) to the virus or its components, rather than by detecting the virus itself. Shortly thereafter, the United States government published a Notice in the Federal Register soliciting private manufacturers to further develop, manufacture, and mass-distribute Dr. Gallo's prototype HIV screening test to the nation's blood banks. Abbott filed a response to the Notice and was granted a license by the FDA to develop and manufacture the prototype. The FDA considered the blood screening test as both a device under the Medical Device Amendments of 1976, 21 U.S.C. 360c to 360ee ( MDA ) to the federal Food, Drug and Cosmetic Act, and a biologic under the Public Health Service Act, 42 U.S.C. 201 to 300aaa ( PHSA ). However, its development, manufacture and field testing was overseen by the FDA's Office of Biologics and Research and Review ( OBRR ). Although Abbott's test kit was largely regulated by the OBRR as a biologic, the OBRR required that the test be listed as a medical device and its package insert drafted pursuant to the regulations for labeling medical devices. It was undisputed at trial that the FDA was intimately involved in the development, clinical trials, and license process of Abbott's proposed HIV blood screening test. This involvement continued after licensure with respect to the monitoring of the test results and the development of a Second Generation Test. As part of its license application, Abbott submitted a draft of the package insert. Abbott's draft suggested retesting of certain borderline negative samples (those within a specified range of the cutoff value _ the value that determines whether the blood sample is positive for the virus). The FDA, however, mandated that this provision be deleted. The testimony at trial was that the FDA concluded there was no scientific basis to believe that samples close to the borderline were more likely to be false-negative (actual positives that tested negative), and that this would effectively redefine the cutoff to the lower value for which there would be a new set of borderline samples. The warning and limitation language of the package insert was to a significant extent dictated by the FDA. The FDA's letter accompanying the license specifically indicated that if Abbott sought to amend the labeling or package insert, it would have to submit an amendment for review and approval before implementation. Moreover, the test labeling was subject to a similar FDA regulation governing biologics which required a change in labeling to be accepted by the FDA prior to the change becoming effective. During the post-license period, the FDA continued to monitor the field performance of the First Generation Test. Abbott was required to test a portion of every manufactured lot with control samples provided by the FDA, and submit its data from those tests and lot samples. Abbott was prohibited from distributing any portion of a lot before formal release by the FDA. The FDA also monitored the Test's performance by information collected from blood banks, other government agencies, and scientific publications. Representatives of the FDA testified that throughout the relevant 1985-86 period the Test was state-of-the-art. The development of the Second Generation Test began as soon as the First Generation Test was marketed in March 1985. Abbott submitted a license amendment for the Second Generation Test in July 1986, approximately one month prior to R.F.'s transfusion. The amendment indicated that the p41 enriched test would be better able to detect positive samples that were borderline or negative by the First Generation Test. Abbott requested immediate permission to market the improved test, but the FDA first required that Abbott conduct clinical trials with the proposed Second Generation Test. During those trials Abbott found a higher false-positive rate than expected and reformed the test in the laboratory and began clinical trials again. The Second Generation Test was approved for the market in January 1987. Abbott immediately withdrew the First Generation Test and notified customers about the availability of an improved test. Plaintiffs' main contention focused on whether Abbott provided adequate warnings within the package insert. Specifically, plaintiffs assert that Abbott was aware that the Test was producing false-negative results in the early part of 1986 for samples that produced results near the borderline or close to the cutoff value. Plaintiffs argue that Abbott was required under New Jersey law to warn of the incidence and the inherent dangerousness of borderline samples in a supplemental package insert and/or instruct blood banks to retest such borderline samples. Abbott filed two motions for summary judgment arguing that the express preemption provision of the MDA ( 21 U.S.C. 360k(a) ( Section 360k(a) ) preempted plaintiffs' state law claims. The trial court denied Abbott's motions. A five-week trial followed. The jury returned a verdict in favor of Abbott on all counts, concluding that Abbott had provided sufficient and adequate warnings and that the Test was not defective. Plaintiffs appealed. In an unpublished decision, the Appellate Division affirmed the judgment in favor of Abbott based on the conclusion that plaintiffs' claims were expressly preempted by the MDA. This Court granted plaintiffs' petition for certification and subsequently ordered the Appellate Division to reconsider and also to address plaintiffs' non-preemption arguments. In September 1998, in an unpublished opinion, the Appellate Division again held that plaintiffs' failure to warn claims were preempted by the MDA. However, it also held that if the claims were not preempted, plaintiffs were entitled to a new trial because the jury instructions were prejudicially confusing. This Court again granted plaintiffs' petition for certification. In September 1999, the case was presented to the Court at oral argument. After argument, the Court requested the parties to file supplemental briefs to address the extent to which Abbott and the FDA acquired evidence about the Test's safety after licensing, and whether Abbott had a duty or was permitted to change the package insert after receiving any after-acquired evidence. In plaintiffs' supplemental briefs they raised for the first time two new arguments: that the Test was not a medical device but solely a biologic and therefore principles of implied rather than express preemption should apply; and that even if Abbott was restricted from disseminating a new package insert, it should have issued additional warnings through the use of physician letters or similar means. 1. Preemption may be either expressed or implied. There are two types of implied preemption: field preemption, where the federal regulation is so pervasive as to make reasonable the inference that Congress left no room for the states to supplement it; and conflict preemption, where compliance with both federal and state regulations is impossible or where state law stands as an obstacle to the accomplishment of the purposes and objectives of Congress. Determining whether there is preemption is a fact-sensitive endeavor. State laws can be preempted by federal regulations as well as federal statutes. (pp. 30-33) 2. Before the Appellate Division, the parties focused on whether the the MDA's express preemption provision was applicable. The Court concludes, however, that based solely on principles of implied preemption, plaintiffs cannot maintain their State failure to warn claim. The FDA's exercise of control and initiative over the Test's development, packaging, and performance monitoring along with the unique circumstances under which the Test arose (a national health crisis), give rise to implied preemption. Plaintiffs' contention that Abbott was permitted to unilaterally change the package insert is without merit. (pp. 33-46) 3. The Court's ruling is not in conflict with its prior holdings, which are distinguishable. As stated above, preemption determinations are extremely fact-sensitive, and based on the record and context of a particular case. The FDA determined that it was unwise, and a threat to the nation's blood supply, to retest borderline negatives. It weighed the harm and danger to unfortunate people, like R.F., against the public's greater need for a safer blood supply. This was the FDA's decision, and this Court should not second guess it. (pp. 46-51) 4. Because of the court's preemption ruling, plaintiffs' other claims of trial error need not be addressed. The Court observes, however, that a review of the record establishes that Abbott did not receive any after-acquired information indicating that the Test's performance was inconsistent with the FDA's expectations. Therefore, the State law duty to warn of after-acquired evidence is inapplicable. Plaintiffs' argument to the contrary was based on the testimony of its expert, who was discredited at trial. (pp. 51-61) As MODIFIED, the judgment of the Appellate Division is AFFIRMED. JUSTICE STEIN, dissenting, is of the view that the majority's analysis exaggerates the legal significance of the FDA's regulatory role, understates the materiality of the factual dispute concerning information about the Test's deficiencies acquired by Abbott after licensing, and diminishes the precedential effect of this Court's federal preemption jurisprudence. CHIEF JUSTICE PORITZ and JUSTICES VERNIERO and JUDGE KING join in JUSTICE GARIBALDI'S opinion. JUSTICE STEIN has filed a separate dissenting opinion, in which JUSTICES O'HERN and COLEMAN join. JUSTICE LONG did not participate. R.F. AND R.F., Plaintiffs-Appellants and Cross-Respondents, v. ABBOTT LABORATORIES, Defendant-Respondent and Cross-Appellant. Argued September 14, 1999 -- Reargued November 29, 1999 -- Decided February 29, 2000 On certification to the Superior Court, Appellate Division. Brian Wolfman, a member of the District of Columbia and Arkansas bars, and George T. Baxter argued the cause for appellants and cross-respondents (Mr. Baxter, attorney). Kimball R. Anderson, a member of the Illinois bar, and Anne M. Patterson argued the cause for respondent and cross-appellant (Riker, Danzig, Scherer, Hyland & Perretti, attorneys). E. Drew Britcher submitted a brief on behalf of amicus curiae, The Association of Trial Lawyers of America_New Jersey (Leonard & Butler, attorneys). The opinion of the Court was delivered by GARIBALDI, J. In September 1986, plaintiff, R.F., received a transfusion of blood incident to surgery, that was infected with the human immunodeficiency virus ( HIV ), causing her to subsequently test positive for the presence of that virus. The blood which was transfused into R.F. had been previously screened for HIV infection at the Bergen Community Blood Center ( BCBC ) with the first commercially-available HIV blood screening test, manufactured by defendant, Abbott Laboratories ( Abbott ), available on the commercial market between March 1985 and January 1987. R.F. and her husband (collectively, plaintiffs ), claim that the HIV blood test used by the BCBC was defective under N.J.S.A. 2A:58C-2,See footnote 11 because its package insert failed to provide adequate instructions or warnings regarding the sensitivity limitations allegedly inherent in Abbott's test. Specifically, plaintiffs contend that in light of its knowledge that the test was not 100" sensitive, Abbott should have instructed blood banks to retest samples that were negative yet borderline, meaning samples that had yielded results close to the test's cutoff value. The cutoff value was a value defined by the federal Food and Drug Administration ( FDA ) in the test's instructional pamphlet, to be used by blood bank technicians to measure whether the HIV antibody was present in a donated blood sample. After a five-week trial, a jury found that Abbott had provided adequate warnings, and that the test was not defective. In an unpublished decision, the Appellate Division affirmed on other grounds holding plaintiffs' state law claims were preempted by the FDA's extensive scrutiny and monitoring of the defendant's test and dictates regarding the warning inserts. The primary issue presented in this appeal is whether federal regulation of Abbott's HIV blood screening test preempts plaintiffs' cause of action for defective design and failure to warn under N.J.S.A. 2A:58C-2. By 1983, scientists understood that AIDS was caused by a virus that could be transmitted through intra-venous drug use, blood transfusions, or sexual contact, and had identified certain high risk groups including: homosexual men, IV drug users, Haitian immigrants, and hemophiliacs (persons suffering from a blood clotting disorder requiring transfusions of large amounts of blood proteins to prevent bleeding). The discovery that the HIV virus could be transmitted through blood transfusions created a national health crisis with respect to the availability of safe blood, because donated blood was a high-risk source of infection, and the pool of qualified blood donors was reduced by both persons with AIDS, and members of the identified high-risk groups. As a result, as early as 1983, the United States Public Health Service recommended that physicians use transfusions sparingly, and encourage autologous (or self) blood donation. As the agency responsible for the safety of the blood supply, the FDA took action quickly to contain the AIDS epidemic by seeking help from both public and private sources. Initially, the FDA turned to the National Cancer Institute ( NCI ), where in May 1984, Dr. Robert Gallo had published the first description of a screening test that could detect the HIV infection in blood samples. Dr. Gallo's prototype screening test was an ELISA or EIA test, a generic term that describes Enzyme Linked Immunoabsorbant Assays. ELISA tests, which had been used for the detection of other blood-borne viruses such as hepatitis, function by detecting the body's immune response (or antibodies) to a virus or its antigen components, rather than the virus itself.See footnote 22 Dr. Gallo's prototype test used a bead coated with an inactive form of the HIV virus, designed to detect the presence of HIV antibodies in donated blood samples. If HIV antibodies were detected, then it could be concluded that the patient's immune system had been exposed to (and had responded to) the HIV virus. The prototype was approximately 85" effective in detecting infected samples. The government applied for, and ultimately received, a patent for Dr. Gallo's HIV ELISA test. On May 3, 1984, soon after Dr. Gallo's publication, the United States government published a solicitation in the Federal Register ( Notice ) seeking private manufacturers who could further develop, manufacture, and mass-distribute Dr. Gallo's prototype HIV screening test to the nation's blood banks. See Request for Applications to Produce a Virus and an Assay System for Detection of Antibodies to the Virus Associated with Acquired Immune Deficiency Syndrome (AIDS), 49 Fed. Reg. 18899 (May 3, 1984). The Notice stated in part: The Department of Health and Human Services solicits applications to produce the HTLV-III[See footnote 33] virus and to develop and distribute [Dr. Gallo's prototype] assay system for the detection of antibodies to HTLV-III, the newly discovered virus associated with the AIDS Syndrome, under non-exclusive, royalty-bearing licenses from the Department . . . . [Id. at 18899.] The Notice sought private manufacturers who could: (1) grow the virus on a large scale; (2) develop an ELISA test kit for distribution to blood banks, phasmapherisis centers, hematology and disease laboratories, and medical research institutions; (3) provide nationwide distribution of the HIV test kit; and (4) monitor the field performance of the test in blood banks and research laboratories. Id. at 18899-18900. According to the terms of the Notice, a manufacturer was required to obtain a license from the FDA prior to releasing its test for commercial distribution. Id. at 18900. In view of the important public health considerations involved, responses were requested within 10 days from the date of the Notice. Ibid. Dr. Harry Meyer, Director of the FDA's Center for Drugs and Biologics from 1982 until September 1986, was involved in the selection of manufacturers for the development of Dr. Gallo's test. Dr. Meyer testified at trial that the government wanted to see the most efficient and rapid development not only [of] the initial test but for the research for future generations of the test[;] . . . [g]etting a good test out was about as high a priority as the government had at the time. On May 9, 1984, Abbott filed a response to the Notice demonstrating its capacity to develop and manufacture Dr. Gallo's prototype. In July 1984, after reviewing the application and meeting with a group of Abbott scientists and representatives to discuss their proposal, the FDA informed Abbott that it would be granted a license for the government's patent so that it could develop and manufacture the prototype, and cultivate the virus. According to Abbott's lead scientist in the development of the HIV assay, Dr. John Heller, Abbott's primary purpose in the test's development stage was to further improve th[e] assay regarding sensitivity,[See footnote 44] and also to scale up all of the procedures so that we could manufacture on the order of millions of tests a month. Dr. Heller testified that there was clearly a sense of urgency in Abbott's development of the test since the company knew that people were becoming infected through blood transfusion, [and] . . . that people were dying of AIDS as a result of blood transfusion. Four other manufacturers also were selected to develop Dr. Gallo's prototype. Genetic Systems, Inc., headed by plaintiffs' expert, Dr. Robert Nowinski, applied for, but did not receive, a license to develop and manufacture the government's prototype. However, Genetic Systems did ultimately manufacture an HIV blood screening test which was licensed by the FDA in 1986 (one year after Abbott's test was licensed), yet competed with Abbott's version of the test somewhat unsuccessfully in the commercial market. Although the FDA considered the blood screening test as both a device under the Medical Device Amendments of 1976, 21 U.S.C. 360c to 360ee ( MDA ) to the federal Food, Drug and Cosmetic Act, 21 U.S.C. 301 to 395 ( FDCA ), and a biologic under the Public Health Service Act, 42 U.S.C. 201 to 300aaa (the PHSA ), the development, manufacturing, and field performance of the HIV test, was overseen by the FDA's Office of Biologics Research and Review ( OBRR ). That is consistent with the FDA's 1982 designation of the Bureau of Biologics as the lead Bureau for regulating certain medical devices used in the processing or administration of biological products, such as the test kit. Working Relationship Agreement Among FDA's Bureaus of Medical Devices, Radiological Health, and Biologics; Availability of Document, 47 Fed. Reg. 15412, 15412 (April 9, 1982) ( Working Relationship Agreement ). The FDA clarified in the Working Relationship Agreement that biological medical devices, such as Abbott's HIV blood screening test, are subject to the provisions of both the FDCA and the PHSA. Ibid. Therefore, although the test kit was largely regulated by the OBRR as a biologic (because the virus was the main component of the test) the OBRR required that the test be listed as a medical device, and its package insert drafted pursuant to Labeling for In Vitro Diagnostic Products, 21 C.F.R. 809.10(b) (1985), a medical device regulation. It was undisputed at trial that the FDA was intimately and proactively involved in the development, clinical trials, and licensure process of Abbott's proposed HIV blood screening test. Dr. Meyer described the relationship between the FDA and the manufacturers as follows: It was an intense relationship, I mean, it was a very high pressured time. . . . There was a big stake in getting that test out, so we all recognized it was everybody's first priority. In all of the years I was in FDA and talking about priorities on hot drug development or hot biologic development, I can't think of any time there was more priority than that intense period of getting an effective AIDS test out. Dr. Meyer testified that during the development and licensure of the test, there was a continual dialogue between the FDA's scientific staff and the manufacturers regarding their progress and clinical results. Similarly after licensure, the FDA continued this dialogue with respect to the monitoring of the test, and the development of a Second Generation Test. Throughout the fall of 1984, Abbott developed the HIV test kit and submitted proposals to the FDA to conduct clinical trials. Abbott's completed test had the same basic components used by Dr. Gallo.See footnote 55 During December 1984, Abbott conducted clinical trials of its proposed assay that included approximately 10,000 random donors, including a sample group of AIDS and ARC patients (ARC patients are infected with the virus yet do not exhibit the symptoms of full-blown AIDS). The results of the trials using AIDS and ARC patients showed that the test was 98.3" effective in detecting the antibody in AIDS patients, and 65" effective in detecting the antibody in ARC patients. In addition, the FDA collected 30,000 samples from across the United States, distributing 6,000 samples to each of the five manufacturers developing Dr. Gallo's prototype. Each manufacturer tested the 6,000 samples with the proposed test, returned the data to the FDA, and then the FDA published the results. On December 19, 1984, Abbott sent all of its clinical data to Dr. Esber, Director of the OBRR Center for Drugs & Biologics, with the product license application for the proposed test. According to Marijane Sidote, Abbott's Director of Regulatory Affairs throughout the relevant time period, the FDA took the unprecedented step of asking for raw data points [for the clinical trials], and printouts from the machines, so they could independently examine and analyze the data. Moreover, Sidote testified that: [d]uring the next two-and-a-half months there was a continual communication between me and the FDA groups that were working on this product. They asked me for additional information in some cases. One of the things they asked us to do was to test samples that they had in their laboratory, so they sent us several thousand samples for us to test. The results of that were also reported, so there was considerable paperwork that I filed following the initial product license application. As part of the product license application, Abbott submitted a draft of the test's package insert. In the December 19, 1984 draft, Abbott suggested that the package insert state: Specimens with absorbance values within a . 10" range of the Cutoff Value should be retested to confirm the initial results. (emphasis added). However, in their January 29, 1985 response, according to Sidote, the FDA mandated that [this provision] be deleted. Dr. Heller testified that the FDA decided not to instruct blood banks to retest borderline negative samples because: (1) there was no scientific basis for the belief that samples close to the borderline were more likely to be false-negative than negative samples with results well-below the cutoff; and (2) such a provision would effectively redefine the cutoff to the lower value for which there would be associated a new set of borderline samples. Dr. Heller testified that in defining the test's cutoff value, the FDA specifically indicated [to Abbott] that they had reentered all of the raw data and redid the statistical analysis to determine that the cutoff was in the appropriate place. During this process, the FDA and Abbott balanced the goal of maximized sensitivity with the problem of having an abundance of false-positive results. The appearance of false-positive results was a major concern throughout the development of the First and Second Generation Tests, since false-positive results not only caused a blood bank to destroy that particular sample, but also disqualified the donor from future blood donations, thereby further limiting the qualified source of donated blood. The FDA's active role in setting the test's cutoff was confirmed by Dr. Meyer who testified that, although Abbott contributed to the discussion, the FDA ultimately determined the appropriate cutoff value.See footnote 66 Dr. Meyer also testified more generally that the FDA virtually wrote parts of th[e] package [insert], and one way you could see that, if you look at each of the manufacturer's package [inserts] for that test at that time, there are sections of them . . . that are virtually identical. In addition to rejecting the provision requiring negative samples to be retested, according to Sidote the FDA made very extensive changes to [Abbott's package insert] draft[s], giving [them] specific language that they wanted us to put in the package insert. Similarly, Dr. Heller testified that the FDA dictated . . . a lot of the language in the package insert, and also dictated how the tables [reflecting the clinical trial data] would be arranged and the order in which material would appear within the package insert. Dr. Meyer confirmed this testimony stating the FDA was intimately involved with Abbott in their packag[e] labeling exactly indicating what the uses and limitations of the test [we]re. The affidavit of P. Ann Hoppe, who was at all relevant times the Deputy Director/Acting Director of the FDA's Division of Blood and Blood Products of the Center for Biologics Evaluation and Research, confirmed that the warning and limitation language of the package insert was to a significant extent, dictated by the FDA : Specifically, with respect to Abbott's package insert, the warnings and statements relating to the limitations of the test were not only appropriate, but also were supported by extensive clinical data that the FDA reviewed. In addition, the language contained in the insert was approved by the FDA and, to a significant extent, dictated by the FDA. . . . Not only did the FDA approve the data in the insert, but the FDA also went to great lengths to assure consistency among manufacturers in the type of information that was available to users in the package insert. All of these licensed products have very common elements in their package inserts, if not identical language in some respects, because the FDA participated in the drafting of what should be contained therein. [(emphasis added).] In particular, the FDA essentially authored three critical sections of the test's package insert entitled: INTERPRETATION OF RESULTS, LIMITATIONS OF PROCEDURE, and SENSITIVITY AND SPECIFICITY. Those sections appeared in identical form in each of the five manufacturers' package inserts; none of them mentioned borderlines, and none of them instructed users to retest initially negative samples. The INTERPRETATION OF RESULTS section of the completed package insert instructed blood bank technicians: Both the LIMITATIONS OF PROCEDURE and the SENSITIVITY AND SPECIFICITY sections indicated that the Test was not 100" sensitive in detecting the HIV antibody in truly infected blood samples. Specifically, the LIMITATIONS OF PROCEDURE section states in part: A negative test result does not exclude the possibility of exposure to or infection with HTLV III (emphasis supplied). Similarly, the SENSITIVITY AND SPECIFICITY section sets forth a textual explanation of Abbott's clinical trials which revealed: 1. Sensitivity based on an assumed 100" prevalence of HTLV III antibody in AIDS patients is estimated to be 98.3%. 2. SpecificitySee footnote 77 based on an assumed zero prevalence of HTLV III antibody in random donors is estimated to be 99.8%. Moreover, Table III of the package insert, which summarized Abbott's clinical trial data, concluded that Abbott's test was positive in 57 (98.3") of 58 AIDS patients and 72 (67.3") of 107 ARC patients. On March 1, 1985, after the package insert was completed, the OBRR issued a license that authorized Abbott to manufacture and sell in interstate and foreign commerce HTLV III in an in vitro ELISA test, hereinafter referred to as the Test or the First Generation Test. In an accompanying letter to Abbott, the FDA set forth several conditions of the license, including that (1) Abbott submit ongoing stability studies of the Test for review by the OBRR; (2) Abbott submit a sample of every lot of the Test and await FDA approval before that lot is commercially-distributed; and that (3) Abbott report all significant product defects or product complaints concerning the use of the Test. In addition, the FDA's letter accompanying the license specifically indicated that if Abbott sought to amend the labeling or package insert of the Test, it w[ould] be necessary . . . to submit an amendment to either [the] product or establishment license application for review and approval prior to implementation. Moreover, the Test's labeling was subject to a similar, promulgated FDA regulation for biologics, 21 C.F.R. 601.12, which stated: (a) General Important proposed changes in location, equipment, management and responsible personnel, or in manufacturing methods and labeling, of any product for which a license is in effect or for which an application for license is pending shall be reported to the Director, Office of Biologics Research and Review, by the manufacturer, and unless in case of emergency, not less that 30 days in advance of the time such changes are intended to be made. (b) Manufacturing methods and labeling Proposed changes in the manufacturing methods and labeling may not become effective until notification of acceptance is received from the Director, Office of Biologics Research and Review. [Changes to be reported, 21 C.F.R. 601.12 (1985) (emphasis added).]See footnote 88 As indicated by its drafting of the package insert warnings, the FDA was aware of the limitations of Abbott's First Generation Test (and ELISA tests in general) at the time of its development. Specifically, the FDA understood that since all ELISA tests detected the presence of antibodies to virus, and not the presence of viruses themselves, the tests were by design subject to a window period during which an infected individual does not have detectable levels of antibodies, causing the test to produce false-negative results. That window period is the length of time required for the body to produce enough antibodies to be detected. In 1985-86, the scientific community could not predict precisely how long the window period was for HIV. The FDA understood that it was possible that there were individuals infected with the HIV virus who had not yet produced HIV antibodies and, therefore, could donate infected blood (fully capable of spreading the disease) that could not be screened by any of the manufacturers' ELISA tests. Accordingly, prior to the introduction of the Test onto the market, the FDA conducted a mass-mailing campaign to blood banks and physicians regarding the use and limitations of the first HIV blood screening tests. On February 19, 1985, the FDA sent a memorandum to all registered blood banks in the United States, including the BCBC, regarding the impending licensure of the first HIV antibody blood screening tests. The FDA's memorandum, summarizing an attached copy of the CDC's January 11, 1985 newsletter, explicitly described the limitations of the tests as follows: . . . [A] negative antibody test result does not necessarily mean that one is free from virus. Antibody may not have developed, or be undetectable, if infection was recent. There is at least one report that 4 of 96 individuals carried the virus for 6 months without developing detectable antibodies. See Provisional Public Health Service Inter-Agency Recommendations for Screening Donated Blood and Plasma for Antibody to the Virus Causing Acquired Immunodeficiency Syndrome, Morbidity and Mortality Weekly Report, Vol. 34, No. 1 (Centers for Disease Control) (Jan. 11, 1985). Soon thereafter, the FDA sent out a similar Dear Doctor letter to all licensed physicians in the United States, including R.F.'s physician, expressly warning of the above limitations.See footnote 99 Dr. Meyer testified that the FDA's circulation of these letters was an unusual and exceptional measure, which demonstrated the enormous effort that was made not only by [the FDA] but also by industry and others to fully inform users of [the new test of] what could be expected of it. In view of the recognized limitations of the First Generation Test, the development of a Second Generation Test began as soon as the Test was licensed in March 1985. In developing the Second Generation Test, Abbott focused on isolating an antibody that could function as an early marker of the infection, and therefore improve the Test's sensitivity in the window period. During this post-licensure period, the FDA continued to monitor both the field performance of the First Generation Test and Abbott's development of a Second Generation Test. Dr. Meyer testified that once the Test was marketed, there was a whole host of monitoring efforts by the FDA, and that there was a lot of discussion on the monitoring of the test and its performance in practice. In fact, by FDA order, Abbott tested a portion of every manufactured lot of the Test with a control panel of samples provided by the FDA. Abbott then submitted its data from those tests, and a sample of each lot, to the FDA. After reviewing the data, and possibly testing the sample lot themselves, the FDA would notify Abbott by letter or fax whether the lot was approved for sale. Abbott was prohibited from distributing any portion of a lot before a formal release was received from the FDA. According to Dr. Meyer, the FDA monitored the Test's performance not only through information collected from Abbott and the other manufacturers, but also from blood banks, other government agencies, and scientific publications. Moreover, throughout the relevant time period, Dr. Meyer represented the FDA on the AIDS Executive Task Force, a group of representatives from government agencies (such as the NIH and CDC) who met to discuss AIDS-related issues. With respect to the blood banks, Dr. Meyer explained that: all of the users [of the Test] . . . are blood banks that are under [FDA] regulation, so the major blood bank organizations were doing a great deal of tracking of performance, and those blood bank organizations reported to us. You might even have major blood banks that had the results and report directly to us. Then in addition[,] . . . .[in] those early months after [the Test] came out, we asked for and promptly got reporting I think on an every two week interval from essentially, I think it was well over 50 percent of the blood and plasma phoresis facilities in the country monitoring their experience repeat reactive rates. The CDC . . . was doing a lot of direct research on the performance of the [T]est after the [T]est came out. [At a meeting of the AIDS Executive Task Force,] one of the critical articles that I heard the preliminary report [of was] the big public workshop we had at the NIH on performance of tests in July 1985, . . . that was a report largely done by the CDC . . . [T]hat gave us a great deal of information. Similarly, in her affidavit P. Anne Hoppe stated that: [o]nce Abbott's test was in wide use in the field, there were ongoing communications between Abbott and the FDA relating to the test's performance. . . . As a result of the ongoing communication between the FDA, the blood banking industry and manufacturers such as Abbott, the FDA was well-informed about test performance in the field. . . . It is significant to note that had the FDA felt that Abbott's test was defective or that Abbott's warnings were inadequate based upon reliable and significant new information, the FDA would have taken action to protect the public's interest. According to the trial testimony, the field performance data, as well as independent scientific research, reinforced the FDA and Abbott's initial belief that the incidence of false negative results were not clustered around the cutoff, but rather were distributed randomly below the cutoff value. In that regard, both Dr. Thomas Zuck, the Director of the FDA's Division of Blood and Blood Products, and Dr. Meyer testified that throughout the relevant 1985-86 time period the Test was state of-the-art. In fact, Dr. Meyer testified: I can say without qualification whatsoever that all those [F]irst [G]eneration [T]ests were equivalent, there weren't any that were significantly better than any others. Similarly, Dr. Meyer testified that there [was] never any serious question that Abbott's test or anyone else's test was not within the specs that were described in the package circular. That testimony was confirmed by Dr. Zuck, who testified that the FDA had no concerns about the sensitivity of the Test during the post-licensure period. On July 28, 1986, approximately one month prior to R.F.'s transfusion, Abbott submitted a product license amendment for the Second Generation Test, which indicated that the p41 enriched test would be better able to detect positive samples that were borderline or negative by the First Generation Test. (emphasis added). In other words, the improved test was intended to be better able to detect all positive samples that falsely registered below the cutoff by the First Generation Test. Although Abbott requested immediate permission to market the improved test, the FDA first required that Abbott conduct clinical trials with the proposed Second Generation Test. During the clinical trials, Abbott found a higher false-positive rate than expected and therefore, reformed the test in the laboratory and began the clinical trials again. After submitting the second round of clinical trials to the FDA, the Second Generation Test was approved for the market in January 1987. Abbott immediately withdrew the First Generation Test, and sent a Western Union mailgram to customers stating that the test improved the sensitivity and specificity of the First Generation Test. On September 4, 1986, prior to the approval of the Second Generation Test, R.F. received a unit of blood that was infected with the HIV virus during orthopedic surgery in Valley Hospital in Ridgewood, New Jersey. The unit of blood was previously tested for HIV infection at the BCBC on August 26, 1986, with the First Generation Test. When tested, the unit of blood was borderline negative with a result of 0.121, slightly below the cutoff value for a positive reading of 0.128.See footnote 1010 On November 4, 1986, the same blood donor again donated blood at BCBC. That donation, also tested with the First Generation Test, was found to be above the 0.128 reading and therefore, HIV positive. A review of the BCBC's records determined that blood from the earlier donation had been transfused into R.F.. On September 4, 1987, R.F. was notified that she was infected with HIV. B. Procedural History On June 20, 1989, plaintiffs filed a complaint against Abbott and others, including R.F.'s treating physician, BCBC, and Valley Hospital. Prior to trial, plaintiffs settled their claims against the all defendants other than Abbott for $1,500,000. With respect to Abbott, plaintiffs alleged: (1) breach of implied and express warranties; (2) inadequate warnings; (3) strict products liability; (4) negligence; and (5) willful, intentional, and wanton disregard for the rights and safety of others. Plaintiffs' main contention focused on whether Abbott provided adequate warnings within the package insert. Specifically, plaintiffs assert that Abbott was aware that the Test was producing false-negative results in the early part of 1986 for samples that produced results near the borderline (or close to the cutoff value) of the Test. As a result, plaintiffs argue Abbott was required under New Jersey law to warn of the incidence and the inherent dangerousness of borderline samples in a supplemental package insert, and/or instruct blood banks to retest such borderline samples.See footnote 1111 On September 23, 1993 Abbott filed a motion for summary judgment on the grounds that the express preemption provision of the MDA, specifically 21 U.S.C. 360k(a) ( Section 360k(a) ),See footnote 1212 preempted plaintiffs' state law claims. Relying on Feldman v. Lederle Laboratories, 97 N.J. 429 (1984) ( Feldman I ) and Feldman v. Lederle Laboratories, 125 N.J. 117 (1991) ( Feldman II ), the trial court denied Abbott's motion, holding that it would be inconsistent with congressional intent to deny private citizens a tort remedy based on the FDCA, since it is a statute designed to protect the public's health and welfare; and moreover, there were material issues of fact regarding whether Abbott complied with federal warning requirements. Abbott's motion for leave to seek an interlocutory appeal of that decision was denied. In 1996, Abbott again filed a motion for summary judgment alleging federal preemption of the state law claims. On September 12, 1996, the trial court denied that motion largely based on the United States Supreme Court decision in Medtronic v. Lohr, 518 U.S. 470, 116 S. Ct. 2240, 135 L. Ed. 2d 700 (1996). Beginning in September 1996, the trial court conducted a five-week jury trial to determine Abbott's liability. All the evidence before this Court was before that jury. The jury returned a verdict in favor of Abbott on all counts, concluding that Abbott had provided sufficient and adequate warnings, and that the Test was not defective. The trial court entered judgment for Abbott on November 29, 1996. The plaintiffs appealed. In an unpublished decision, the Appellate Division affirmed the judgment in favor of Abbott based on the conclusion that plaintiffs' claims were preempted by the MDA. The panel reasoned that the FDA's inaction with respect to the recall of the Test or modification of the Test's package insert should be construed as approval in light of: (1) the agency's extensive role in the development of the Test and the inserts; (2) the agency's continued monitoring of the Test; and (3) the agency's retention of jurisdiction to recall the Tests and to direct the amendment of the package inserts. The panel emphasized that Abbott was prohibited from altering the Test or the package inserts prior to the FDA's completing its review of Abbott's data, a task that was not accomplished until early 1987. On July 15, 1998, this Court granted the plaintiffs' petition for certification, and subsequently ordered the Appellate Division to reconsider the plaintiffs' preemption arguments in light of Baird v. Am. Med. Optics, 155 N.J. 54 (1998), and Medical Devices; Preemption of State Product Liability Claims, 62 Fed. Reg. 65387 (Dec. 12, 1997) (to be codified at 21 C.F.R. pt. 808);See footnote 1313 and to consider the plaintiffs' non-preemption issues raised on appeal. 154 N.J. 606 (1998). In September 1998, in an unpublished decision, the Appellate Division again held that plaintiffs' failure to warn claims under N.J.S.A. 2A:58C-2(b) were preempted by the MDA. However, that court held that if the claims were not preempted, plaintiffs were entitled to a new trial because the jury instructions were prejudicially confusing. We again granted plaintiffs' petition for certification. 158 N.J. 72 (1999). In September 1999, the case was presented to the Court at oral argument. After the case was argued, we informed the parties by letter that the case was to be set down for further argument, and that they were to file supplemental briefs to answer four questions: (a) What new evidence did Abbott acquire after the licensing of the Test regarding its safety? (b) Did Abbott have a duty, or was it permissible, to change the Test's package insert or issue a warning after receiving the alleged after-acquired evidence? (c) If the FDA possessed the alleged after-acquired evidence, did this alter Abbott's duties with respect to the Test's warnings? (d) Was there a federal regulatory scheme in place during the summer of 1985 that was in conflict with the state product liability law requiring manufacturers to inform users of after-acquired safety evidence? In response to that letter, the parties submitted supplemental briefs and appendices. In plaintiffs' supplemental briefs they raised for the first time two new arguments: (1) that the Test was not a medical device, but solely a biologic, and therefore principles of implied rather than express preemption under Section 360k, should apply; and (2) that even if Abbott was restricted from disseminating a new package insert, it should have issued additional warnings through the use of a Dear Doctor letter, telegram, or other similar means. Determining whether federal law preempts state law is a fact sensitive endeavor, based on a court's review of fragments of statutory language, random statements in the legislative history, and the degree of detail of the federal regulation. Erwin Chemerinsky, Constitutional Law: Principles and Policies, 5.2 (1997). However, preemption 'is not to be lightly presumed.' Turner v. First Union Nat'l Bank, ___ N.J. ___, 1 999 WL 1126238, at *6 (Dec. 9, 1999) (quoting Franklin Tower One, L.L.C. v. N.M., 157 N.J. 602, 615 (1999)). When a federal regulation conflicts with state law, the same preemption rules apply. Fidelity Fed. Sav. & Loan Ass'n v. de la Cuesta, 458 U.S. 141, 153-54, 102 S. Ct. 3014, 3022-23, 73 L. Ed. 2d 664, 675 (1982). Despite the dissent's implication to the contrary, see post at ___ (slip op. at 22-23), the United States Supreme Court has held repeatedly that state laws can be pre empted by federal regulations as well as federal statutes. Hillsborough Cty. Fla. v. Automated Med. Laboratories, Inc., 471 U.S. 707, 713, 105 S. Ct. 2371, 2375, 85 L. Ed. 2d 714, 721 (1985) (citations omitted). As long as the agency (1) intended to preempt state law; and (2) acted within the scope of its delegated authority, federal regulations will displace conflicting state laws. Fidelity Fed., supra, 458 U.S. at 153-5, 102 S. Ct. at 3022-23, 73 L. Ed. 2d at 675. Although the language is compelling, it has little relevance to this case. It was the FDA's concern for the public's health that led it to specifically dictate the limitation and warning language of the Test's package insert that are the basis of plaintiffs' claims. Moreover, the Court's finding in Feldman II _ that even if the drug manufacturer could not have provided a warning, it could have suspended production of the drug _ demonstrates the difference between this case and that matter. Feldman II, supra, 125 N.J. at 153. Although not perfect, the first ELISA HIV blood screening tests were the best devices available to the blood banks to prevent the spread of the HIV virus through transfusions from the nation's blood supply. This is not a case where a manufacturer is shielding itself from a claim by use of the general mandates of the FDA. As the United States Supreme Court has observed, prior cases on pre-emption are not precise 'guidelines' [since] . . . each case turns on the peculiarities and special features of the federal regulatory scheme in question. City of Burbank v. Lockheed Air Terminal Inc., 411 U.S. 624, 638, 93 S. Ct. 1854, 1862, 36 L. Ed. 2d 547, 556 (1973). Preemption determinations are very fact-sensitive. They are very much based on the record and context of a particular case. Chemerinsky, supra, 5.2.5. An examination of the cases relied on by our dissenting brethren reveals that they have forgotten that well-recognized principle. In Hillsborough, the Supreme Court found that the FDA did not intend its regulations to be exclusive. Hillsborough Cty. Fla., supra, 471 U.S. at 714-15, 88 L. Ed. 2d at 721, 105 S. Ct. at 2375-76. The FDA expressly explained in a statement accompanying the original issuance of the regulations in question that [t]hese regulations are not intended to usurp the powers of State or local authorities to regulate plasmapheresis procedures in their locality. Id. at 471 U.S. at 715, 85 L. Ed. 2d at 722, 105 S. Ct. at 2375. Faced with that clear statement of the FDA's intent, the Supreme Court found that neither Congress nor the FDA either expressly or impliedly preempted state and local regulations of plasamerpheresis. Likewise, Hurley v. Lederle Laboratories Div. of Am. Cyanamid Co., 863 F.2d 1173, 1179-80 (5th Cir. 1988) and Roberson v. E.I. DuPont De Nemours & Co., 863 F. Supp. 929, 933 (W.D. Ark. 1994), are distinguishable from this case because in those cases the manufacturer had withheld material information from the appropriate agency that might have affected the agency's decision regarding the content of the warning. Similarly, in Silkwood v. Kerr-McGee Corp., 464 U.S. 238, 257, 104 S. Ct. 615, 626, 78 L. Ed. 2d 443, 458 (1984), the Court found that when federal standards have been violated, paying both federal administrative fines and state tort damages does not frustrate any purpose of the federal remedial scheme. There is no evidence that Abbott withheld any material evidence from the FDA regarding the field performance of the Test. Indeed, the record undisputedly establishes that the FDA was involved in the development and the active monitoring of the First Generation Test, as well as in the development of its Second Generation Test. As the agency in charge of the nation's blood, the FDA determined that it was unwise, and a threat to the blood supply, to retest for false borderline negatives. The FDA weighed the harm and danger to unfortunate people, like R.F., against the greater necessity for the public's need for a safer blood supply. The record establishes that the scientific community knew that the Test had to be improved and continuously worked towards that goal. The FDA constantly monitored Abbott's Test and was always aware not only of Abbott's research, but also of the research of the scientific community to improve the Test. This was the FDA's decision; we should not second guess it. SUPREME COURT OF NEW JERSEY A-66/ 67 September Term 1998 R.F. AND R.F., Plaintiffs-Appellants and Cross-Respondents, v. ABBOTT LABORATORIES, Defendant-Respondent and Cross-Appellant. STEIN, J., dissenting. Underlying this appeal are the allegations of plaintiffs concerning R.F.'s receipt in September 1986 of a transfusion of a unit of blood that was infected with the human immunodeficiency virus (HIV) causing her subsequently to test positive for the presence of that virus. Prior to R.F.'s hip-replacement surgery in 1986 she expressed concern to her surgeon about the safety of donated blood, but was assured by him that blood donated to the Bergen County Blood Center (Blood Center) would be tested and could safely be used in the event she required a blood transfusion during surgery. The blood unit received by plaintiff was supplied by a donor to the Blood Center and was tested for HIV antibodies on August 26, 1986 using defendant Abbott Laboratories' (Abbott) HTLV III test kit. When that unit of blood was tested, it tested negative for the HIV virus with a test result of 0.121. The Abbott Test Kit instructed users that the cut-off value for a negative unit was 0.128, and that units of blood with readings below that cut-off level should be used and not retested. The essence of plaintiffs' contentions in this litigation is that Abbott knew, on the date the infected unit of blood was tested at the Blood Center and for several months prior thereto, that its test tended to report HIV positive samples of blood as false negatives to a substantially greater extent than did the tests of its two primary competitors; that prior to the date the infected unit of blood was tested Abbott had submitted to the FDA a product license amendment to obtain approval for a revised test that would be better able to detect positive samples that were 'borderline or negative' by the First Generation Test, ante at ___ (slip op. at 24); and that Abbott failed to warn users of its test concerning its tendency to record false negative readings and failed to request authorization from the FDA to issue such a warning to users. Notwithstanding those contentions, the Court today holds that plaintiffs' state law failure-to-warn claim is impliedly preempted -_ not expressly preempted pursuant to the Medical Device Amendments of 1976, 21 U.S.C.A. 360k, to the Federal Food, Drug, and Cosmetic Act, 21 U.S.C.A. 301 to 397 (FDCA), as the Appellate Division held -- because of the comprehensiveness of the regulatory control over the Abbott Test exercised by the FDA. Because in my view the Court's preemption analysis exaggerates the legal significance of the FDA's regulatory role, understates the materiality of the factual dispute concerning information about the test's deficiencies allegedly acquired by Abbott after licensing of its test in March 1985, and diminishes the precedential effect of this Court's federal preemption jurisprudence, I am compelled to dissent. Has Abbott Laboratories demonstrated by a preponderance of the evidence that the blood supply was unavoidably unsafe at the time of plaintiff R.F.'s transfusion and that the risk of HIV infection could not be completely eliminated through testing? [(emphasis added).] As the Appellate Division observed, the issues before the jury included whether the defendant's product was 'unavoidably unsafe' . . . and the adequacy of the warning . . . , not whether the blood supply was unsafe irrespective of defendant's test. (emphasis added). The interrogatories on the verdict sheet addressed to the two other statutory defenses, N.J.S.A. 2A:58C 3a(1) and (2), also incorrectly directed the jury to consider whether the blood supply was unavoidably unsafe, rather than requiring the jury to focus on the alleged deficiency in Abbott's test. Moreover, interrogatory number six on the verdict sheet, addressing the failure to warn claim, incorrectly enhances the plaintiffs' burden by requiring the jury to find not only that the warnings accompanying Abbott's test were inadequate to warn the Blood Center of the limitations of the test, but also that the test was not reasonably fit, suitable or safe when it left Abbott's control. That interrogatory stated: Taking into consideration your answer to question no. 5, have the plaintiffs demonstrated by a preponderance of the evidence that the warnings and instructions that accompanied the Abbott Laboratories test were inadequate to warn the Bergen Community Blood Center of the limitations of the test, and that the test was not reasonably fit, suitable or safe when it left the control of Abbott Laboratories? The appropriate burden of proof for a plaintiff to sustain a failure-to-warn claim is that the product causing the harm was not reasonably fit, suitable or safe for its intended purpose because it . . . failed to contain adequate warnings or instructions. (emphasis added). N.J.S.A. 2A:58C-2. Interrogatory number six, however, required the plaintiffs to prove not only that Abbott's warnings were inadequate, but in addition, that the Abbott test also was not reasonably fit, suitable or safe. See Feldman v. Lederle Laboratories, 125 N.J. 117, 144 (1991) (Feldman II); Freund v. Cellofilm Properties, Inc., 87 N.J. 229, 242 (1981). I am fully in accord with the Appellate Division's conclusion that the lengthy charge as a whole and the [jury] interrogatory were prejudicially confusing in light of the focus of the inquiry on the blood supply, not the defendant's test. Plaintiffs allegations concerning Abbott's knowledge that its blood test frequently produced false negative results and was less sensitive in detecting HIV contaminated blood than were the tests of its primary competitors was corroborated by other sources. The trial court, in twice denying Abbott's motions for summary judgment, referred to a June 28, 1993 Wall Street Journal article included in plaintiff's certifications that discussed a pending congressional investigation concerning the sensitivity problem with the original Abbott test. Similarly in Genetic Systems Corp. v. Abbott Laboratories, 691 F. Supp. 407 (D.D.C. 1988), the United States District Court for the District of Columbia, in an opinion granting summary judgment to the American National Red Cross (Red Cross) and partial summary judgment to Abbott on plaintiffs' anti-trust claims, made factual findings that took note of the substantial dissatisfaction within the Red Cross in the summer and fall of 1986 over the lack of sensitivity of the Abbott blood test. In July 1986, studies presented at the National Institutes of Health Conference on AIDS indicated that the Abbott AIDS test then in use by the Red Cross was less sensitive to detecting contaminated blood than the test of Genetic Systems. That same month, Victor W. Schmitt, Vice President of Medical Operations of the Red Cross, inquired of Genetic Systems how long it would take for it to supply all Red Cross Regions with their requirements for AIDS tests. Genetic Systems advised the Red Cross that it could do so within four weeks. In the meantime, the Red Cross continued to use the Abbott test and Abbott sought FDA approval of a new, "improved" AIDS test. IV In Lederle, the consequence of defendant's failure to warn was permanently stained teeth. In Abbott's case, the consequences are a matter of life and death. In the absence of express congressional action, this Court should deny Abbott's claim that it is immunized from state tort law liability for failure to warn users of its blood test of the devastating consequences that could result from a false-negative test reading of HIV contaminated blood. Because of those consequences, the Court's implied preemption analysis simply is too flimsy to support preemption of plaintiff's state law tort claim. I would remand this matter for retrial of plaintiffs' state law failure-to-warn claim. Justice O'Hern and Justice Coleman join in the dissent. NO. A-66/67 R.F. AND R.F., Plaintiffs-Appellants and Cross-Respondents, v. ABBOTT LABORATORIES, Defendant-Respondent and Cross-Appellant. DECIDED February 29, 2000 Chief Justice Poritz A manufacturer or seller of a product shall be liable in a product liability action only if the claimant proves by a preponderance of the evidence that the product causing the harm was not reasonably fit, suitable or safe for its intended purpose because it: a. deviated from the design specifications, formulae, or performance standards of the manufacturer or from otherwise identical units manufactured to the same manufacturing specifications or formulae, or b. failed to contain adequate warnings or instructions, or c. was designed in a defective manner. [N.J.S.A. 2A:58C-2 (emphasis added).] On February 28, 1985, at a meeting for the final review of Abbott's package insert, the FDA and I discussed the method for calculation of the test's cutoff value. The decision as to how to calculate the cutoff value, as reflected in Abbott's package insert, was in accordance with the requirements of the FDA. Except as provided in subsection (b) of this section [when a state or political subdivision applies for an exception], no State or political subdivision of a State may establish or continue in effect with respect to a device intended for human use any requirement _ (1) which is different from, or in addition to, any requirement applicable under this chapter to the device, and (2) which relates to the safety or the effectiveness of the device or to any other matter included in a requirement applicable to a device under this chapter. [ 21 U.S.C. 360k(a).] . . . (2) Labeling changes requiring supplement submission--product with a labeling change that may be distributed before FDA approval. (i) An applicant shall submit, at the time such change is made, a supplement for any change in the package insert, package label, or container label to accomplish any of the following: (A) To add or strengthen a contraindication, warning, precaution, or adverse reaction; (B) To add or strengthen a statement about abuse, dependence, psychological effect, or overdosage; (C) To add or strengthen an instruction about dosage and administration that is intended to increase the safety of the use of the product; and (D) To delete false, misleading, or unsupported indications for use or claims for effectiveness. (ii) Pending approval of the supplement by FDA, the applicant may distribute a product with a package insert, package label, or container label bearing such change at the time the supplement is submitted. The supplement shall clearly identify the change being made and include necessary supporting data. The supplement and its mailing cover shall be plainly marked: "Special Labeling Supplement--Changes Being Effected." [Changes to an Approved Application, 21 C.F.R. 601.12(f)(2) (1999).]