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R.F. v. Abbott Laboratories

February 29, 2000

R.F. AND R.F., PLAINTIFFS-APPELLANTS AND CROSS-RESPONDENTS,
v.
ABBOTT LABORATORIES, DEFENDANT-RESPONDENT AND CROSS-APPELLANT.



The opinion of the court was delivered by: Garibaldi, J.

Argued September 14, 1999 -- Reargued

November 29, 1999

On certification to the Superior Court, Appellate Division.

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, *fn1 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 In an unpublished decision, the Appellate Division affirmed on other grounds holding plaintiffs' state law claims were preempted by the "FDA's extensive scrutiny and monitoring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.

I.

A. Facts

In 1981, five cases of a rare pneumonia, were reported in healthy young men in Los Angeles. However, it was not until 1982 that the Centers for Disease Control ("CDC") identified the infection as the autoimmune deficiency virus ("AIDS"). In the ensuing years, the number of newly-reported cases of AIDS grew exponentially:

1982: 593

1983: 3,000

1984: 6,900

1985: 8,000

1986: 14,000

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. *fn2 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[ *fn3 ] 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,[ *fn4 ] 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. *fn5 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 ñ 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. *fn6 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:

1. Specimens with absorbance values less than that of the Cutoff Value are negative by the criteria of ABBOTT HTLV III EIA.

2. Specimens with absorbance values greater than or equal to the Cutoff Value are considered reactive by the criteria of the ABBOTT HTLV III EIA and should also be retested before interpretation using the original sample source.

3. Specimens which have been found to be repeatably reactive [or repeatably above the Cutoff Value] are interpreted to be positive for antibody to HTLV III . . . [(emphasis added).]

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. Specificity *fn7 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).] *fn8

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. *fn9 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.

Dr. Meyer testified that "[t]he other big avenue of information . . . [was] the Centers for Disease Control." Dr. Meyer explained that the CDC was:

supporting all the testing activity by all the state health networks throughout the country, and they were all using this type of test, and they had an enormous amount of experience in using tests of this sort . . . I and people on my staff [we]re in more or less continual dialogue with the CDC.

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 ...


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