HAPPAS, J.S.C.
This opinion addresses the motions for summary judgment by defendants Wyeth, Inc., Wyeth Pharmaceuticals, Inc. (collectively "Wyeth"), Pfizer Inc.,
Premarin, Prempro, and Provera are FDA-approved prescription drugs. Studies in the 1970s and 1980s suggested that long term use of estrogen alone could increase the risk of endometrial hyperplasia. Scientists then studied and published articles indicating progestin to be effective in reducing the risk of endometrial hyperplasia associated with taking estrogen alone. Thereafter, medical associations began recommending the addition of a progestin when a physician prescribed estrogen to a nonhysterectomized woman.
Premarin and Prempro are the brand names for specific FDA-approved estrogen and combination estrogen plus progestin prescription drugs produced and marketed by Wyeth. Premarin consists of conjugated equine estrogen ("CEE") and was first approved by the FDA in 1942. Prempro
Provera is the brand name for an FDA approved progestin, specifically MPA, produced and marketed by Upjohn. The FDA approved Provera for marketing in 1959 to treat secondary amenorrhea, functional uterine bleeding, infertility, and related conditions due to hormone imbalance in the absence of organic pathology. The pregnancy-related indications were withdrawn in 1972. In 1998, after Dora stopped using Provera, the FDA approved the following indication: "to reduce the incidence of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving 0.625 mg conjugated estrogen." Letter from FDA to Pharmacia & Upjohn (Aug. 4, 1998). Provera continues to be approved by the FDA and on the market today.
Dora first complained to her physician in 1989 of experiencing menopausal symptoms. She was prescribed Premarin and Provera. However, she did not fill the prescription. She first filled a prescription for Premarin and Provera in February 1991.
The United States Food and Drug Administration ("FDA") is responsible for "promot[ing] the public health by promptly and efficiently reviewing [drug manufacturers'] clinical research and taking appropriate action on the marketing of regulated products in a timely manner." 21 U.S.C.A. § 393(b)(1).
All drugs must be FDA-approved before marketing in the United States. The sponsoring pharmaceutical company must submit a NDA to the FDA. The NDA requires, among other things, reports of investigation into the safety and effectiveness of the drug, the components and production methods used in the drug's manufacturing, and copies of draft labeling proposed for the drug. See 21 C.F.R. § 314.50. Once the drug is approved, the pharmaceutical company remains obligated to report to the FDA adverse drug experiences and any "significant new information... that might affect the safety, effectiveness, or labeling of the drug product." 21 C.F.R. § 314.81(b)(2)(i).
A pharmaceutical company seeking approval of additional indications for a drug must submit a supplemental new drug application ("sNDA"). The FDA reviews the sNDA, including the data from clinical studies supporting the change, with the same degree of scrutiny as the original NDA. The FDA will reject the sNDA or NDA if it finds that:
If after reviewing an application and all information it has about the product, the FDA determines that the available scientific evidence is inadequate to show that the product is safe or that it is not effective for its proposed use, the FDA will reject the sNDA. 21 C.F.R. § 314.125(b). Indeed, if the FDA concludes that there has not been sufficient study of the product to assure that it is safe for its proposed use, the FDA will reject the sNDA. 21 C.F.R. at § 314.125(b)(4).
In the context of prescription drugs, "[t]he term `labeling' means all labels and other written, printed or graphic matters (1) upon any article or any of its containers or wrappers, or (2) accompanying such article." 21 U.S.C.A. § 321(m). In 2006, the FDA codified the longstanding policy that labeling must "adequately inform[] users of the risks and benefits of the product and [be] truthful and not misleading." 71 Fed.Reg. 3922 (Jan. 24, 2006).
Proposed labeling is submitted as part of the NDA and reviewed by the FDA. Prescription drug "labeling must contain a
In addition to warning about risks from approved uses, the FDA has authority to impose warnings about off-label or unapproved uses when there is evidence of a clinically significant risk.
Generally, proposed changes in labeling are first submitted to the FDA for approval. 21 C.F.R. § 314.70(a)-(d). A limited exception is with the use of a changes being effected ("CBE") supplement. 21 C.F.R. § 314.70(c). When a new safety issue emerges with a product, the pharmaceutical company may temporarily add to the product's labeling under subsection (c), which describes "changes that may be made before FDA approval." 21 C.F.R. § 314.70(c).
In 1982, when the CBE procedure was proposed, the FDA stated, "`[t]hese supplements would describe changes placed into effect to correct concerns about newly discovered risks from the use of the drug.'" 73 Fed.Reg. 2849 (Jan. 16, 2008) (quoting 47 Fed.Reg. 46622, 46623 (Oct. 19, 1982)). Recently, the FDA reaffirmed its longstanding position. "[A CBE supplement] is appropriate to amend the labeling for an approved product only to reflect newly acquired information ... to add or strengthen a contraindication, warning, precaution, or adverse reaction only if there is sufficient evidence of a causal association." 73 Fed.Reg. 2848 (Jan. 16, 2008). The FDA explicitly defines "newly acquired" as "data, analyses, or other information
A pharmaceutical company that independently institutes a change in labeling may be subject to penalty or seizure if the drug is deemed misbranded by the FDA. See 21 U.S.C.A. § 333 (authorizing penalties); 21 U.S.C.A. § 334 (authorizing seizure); 21 U.S.C.A. § 355(e) (providing withdrawal authority); 21 C.F.R. § 7.45(a) (providing authority to request recall). A drug is misbranded "[i]f its labeling is false or misleading in any particular." 21 U.S.C.A. § 352(a). "If [the drug's] labeling lacks adequate warnings against use ... where its use may be dangerous to health, or if it is dangerous to health when used in the... manner ... prescribed, recommended, or suggested in the labeling thereof" the drug is misbranded. 21 U.S.C.A. § 352(f)(j). Distribution of misbranded drugs is prohibited by the FDCA. 21 U.S.C.A. § 331.
The FDA policy of regulating drugs and not the practice of medicine has been consistent since the creation of the agency in 1983, by the enactment of the FDCA. This policy was noted by the FDA at the 1991 advisory committee. "The FDA's job and legal mandate is not to regulate the practice of medicine but simply to regulate the availability of medications to the practicing population at large." Transcript of Fertility and Maternal Health Drugs Advisory Committee meeting 46:17-20 (June 20, 1991). Allowing physicians to prescribe for off-label use "is an accepted and necessary corollary of the FDA's mission to regulate in this area without directly interfering with the practice of medicine." Buckman Co. v. Plaintiffs' Legal Comm., 531 U.S. 341, 350, 121 S.Ct. 1012, 1018, 148 L.Ed.2d. 854, 862 (2001) (discussing FDA regulation of medical devices).
Off-label activity has been defined by the FDA as a "use for indication, dosage form, dose regimen, population or other use parameter not mentioned in the approved labeling." Janet Woodcock, M.D., A Shift In The Regulatory Approach, PowerPoint, at slide 3 (June 23, 1997), http://www.fda.gov/cder/present/ diamontreal/regappr/sld003.htm (last visited July 3, 2008). Off-label prescribing of drugs is both legal and ethical. The New Jersey Legislature declared "`off-label' use of an FDA-approved drug [to be] legal when prescribed in a medically appropriate way." N.J.S.A. 26:1A-36.9(e).
The FDA has long acknowledged that undue restrictions on off-label use could have adverse health consequences. In 1982, the FDA Drug Bulletin informed the medical community that "[o]nce a [drug] product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling." 12 FDA Drug Bulletin 4, 5 (1982). The agency went on to state that
Following the accepted medical standard of care, physicians frequently prescribe drugs for off-label or unapproved uses.
The medical community's understanding of the benefit of prescribing progestin to reduce the risk of endometrial hyperplasia in women with a uterus taking estrogen is reflected in the prescription data presented at the 1990 advisory committee meeting. Transcript of Fertility and Maternal Health Drugs Advisory Committee meeting 207:12-17, 227:6-10 (Feb. 1, 1990). Comparing the medical reason for prescribing Provera, from 1977 to 1987, "[t]here is an increasing trend toward the use of estrogens and progestins in the treatment of menopause, and it looks like both are continuing to increase." Transcript of Fertility and Maternal Health Drugs Advisory Committee meeting 61:20-22 (Feb. 1, 1990). "The most common diagnosis in 1977 was amenorrhea ... and in 1987 we see that the major diagnosis is now menopausal symptoms." Id. at 57:18-21.
The FDA draws on its own expertise and enforcement powers as well as the expertise of outside medical authorities. The FDA may "establish such technical and scientific review groups as are needed to carry out the functions of the Administration." 21 U.S.C.A. § 393(e). Technical and scientific review groups are commonly referred to as advisory committees. The FDA can seek the opinion of an advisory committee at any time. "Advisory committees provide independent advice and recommendations to the FDA on scientific and technical matters related to the development and evaluation of products regulated by the Agency." New Drug Application (NDA) Process at Advisory Committee, http://www.fda.gov/cder/ regulatory/applications/NDA.htm (last visited July 3, 2008). Advisory committee meetings are open to the public. The advice from an advisory committee is not binding on the FDA. The advisory committee is composed of "scientific experts such as physician-researchers and statisticians, as well as representatives of the public, including patients." Ibid. The scientists must be "qualified by training and experience to evaluate the safety and effectiveness of the drugs ... and ... to the extent feasible, possess skill and experience in the development, manufacture, or utilization of such drugs." 21 U.S.C.A. § 355(n)(3)(A). At least two of the panelists must be "specialists or have other expertise in the particular disease or condition for which the drug under review is
In 1984, the FDA convened the Fertility and Maternal Health Drugs Advisory Committee to assess the safety and efficacy of estrogen taken alone and in combination with progestin.
The committee met again in 1990 and 1991. The presentations and discussion at the 1990 meeting focused on the risk of cancer in the breast and endometrium (uterine lining) and proper labeling.
The committee concluded in 1984, 1990, and again in 1991, that there was insufficient evidence to determine the effects of progestin with estrogen therapy on the risk of breast cancer. In 1984, the committee reported "[t]here is a dearth of data on the safety of long-term estrogen therapy or the addition of progestins. The bulk of evidence indicates that estrogens are not associated with an increased risk of breast cancer." Minutes of FDA Fertility and Maternal Health Drugs Advisory Committee 10 (Apr. 26-27, 1984).
In 1990, "the committee felt that the addition of progestins to estrogen replacement therapy decreases the risk of endometrial cancer. They do not believe that there is sufficient data about the effects of progestins added to estrogen replacement therapy on the risk of breast cancer." Transcript of Fertility and Maternal Health Drugs Advisory Committee meeting 227:6-10 (Feb. 1, 1990). To the question "[d]oes the addition of progestins to estrogen therapy alter the risk of breast cancer in postmenopausal women? The committee unanimously responds that there are insufficient data to make a statement at this time." Transcript of Fertility and Maternal Health Drugs Advisory Committee meeting 207:12-17 (Feb. 1, 1990).
In her opening remarks to the 1991 advisory committee, Golden stated:
After a lengthy discussion the committee did not recommend any change to the labeling of estrogen or progestin or the clinical use of HRT. As one member of the committee commented, concerning the risk of "breast cancer, there are no data about the added progestins, we are all concerned that there might be a higher rate over a long period of time, but that is true of estrogen alone or estrogen plus progestin." Transcript of Fertility and Maternal Health Drugs Advisory Committee meeting 244:21-24 (June 21, 1991). At the close of the 1991 meeting, the consensus was that "the committee does not feel that the data are adequate to answer the question of whether or not progestins alter any breast cancer risk that might be induced by ERT [estrogen replacement therapy]. This is certainly one area where more data are needed and will be forthcoming." Id. at 225:2-6.
In addition to having advisory committees composed of outside experts, the FDA formed a working group of seven FDA scientists to assess the use of estrogens and progestins together and review the information submitted with the Prempro NDA. See Center for Drug Evaluation and Research, Guidance for Clinical Evaluation of Combination Estrogen/Progestin-Containing Drug Products Used for Hormone Replacement Therapy of Postmenopausal Women 1 (Mar. 20, 1995) (publication "[prepared by the FDA HRT Working Group").
The FDA has promulgated class labeling guidelines for a limited number of drugs. Estrogen and progestin products, including Premarin, Prempro and Provera, have been among the pharmaceuticals subject to FDA class labeling guidelines and guidance. Class labeling guidelines for progestin and estrogen drug products were first issued in the 1970s. 42 Fed.Reg. 37646 (July 22, 1977) (progestin drug products); 41 Fed.Reg. 47573 (Oct. 29, 1976) (estrogen drug products).
A labeling guideline is a mandatory requirement. Warning language in the labeling produced by the pharmaceutical company must be consistent with the labeling guideline. A class labeling guidance is an informal document that does not bind or otherwise obligate the agency or a person referring to them and are not formal agency opinions. 55 Fed.Reg. 18762 (May 4, 1990) (revoking estrogen class labeling guidelines and instituting class labeling guidance). The FDA sparingly issues class labeling guidelines and guidance. Class labeling guidelines and guidance ensure consistency in labeling of all products in the same chemical or pharmacologic family.
The estrogen product class labeling guidelines promulgated in 1976 were revised by the FDA in October 1987 and February 1990. On May 4, 1990, the FDA revoked estrogen "guideline texts" and stated its intent to issue "informal labeling guidances." 55 Fed.Reg. 18761-62 (May 4, 1990). Labeling of estrogen products continue to be subject to FDA labeling guidance and must include a patient package insert containing information concerning the drug's benefits and risks. 21 C.F.R. § 310.515.
In 1989, the FDA revised the progestin product class labeling guidelines to reflect new scientific information about the risk of congenital abnormalities. 54 Fed.Reg.
In 1992, the FDA reviewed the medical literature and scientific data concerning HRT and issued revised class labeling guidance for both progestin and estrogen products. In January 1992, the FDA issued new guidance for progestin drug products, adding language to address the use of progestins in combination with estrogens.
DDMAC is the branch of the FDA responsible for reviewing prescription drug advertising and promotional labeling to ensure that the information contained is not false or misleading. DDMAC issues three types of letters to pharmaceutical companies: advisory, untitled, and warning.
Advisory letters address promotional materials submitted to the FDA before publication. Pharmaceutical companies may voluntarily submit proposed promotional materials to the FDA for review and comment. The FDA provides this service to ensure marketing materials are in compliance with the regulations before they are publicly disseminated. See Center for Drug Evaluation and Research, 2005 Report to the Nation: Improving Public Health Through Human Drugs 45 (2005), http://www.fda.gov/cder/reports/rtn/2005/rtn2005.pdf.
An untitled letter "addresses promotion violations that are less serious than those addressed in warning letters." CDER Handbook, Untitled Letter, http://www. fda.gov/cder/handbook/ (last visited July 3, 2008). "In such letters, DDMAC usually requests that a company take specific action to bring the company into compliance within a certain amount of time, usually 10 working days. There is no requirement that the agency take enforcement action." Ibid.
Warning letters "are issued only for violations of regulatory significance. Significant violations are those that may lead to enforcement action if not promptly and adequately corrected." FDA Regulatory Procedures Manual § 4-1-1 (2008), http://www.fda.gov/ora/compliance_ref/rpm/pdf/ch4.pdf. FDA centers are instructed to "issue warning letters, not untitled letters, for promotional activities if the nature of the activity is such that the center would support further regulatory action." Id. at § 4-1-5. Unlike untitled letters, which can be issued by any FDA compliance official, "warning letters are issued by the DDMAC Division Director and receive concurrence from appropriate officials in the Center for Drug Evaluation and Research. Companies have 15 working days to respond to the warning letter. Warning letters are put on display at the time of issuance in FDA's Freedom of Information Office." CDER Handbook, Warning Letter, http://www.fda.gov/cder/handbook/ (last visited July 3, 2008).
The WHI study filled a void in the medical community's research and understanding of the risks and benefits of HRT. As noted by the FDA medical officer reviewing the Prempro NDA, there are challenges in understanding what relationship, if any, HRT had with the development of breast cancer. These challenges include "the long latency between exposure to promotional agents and detection of clinical tumors ... [in addition] prospective studies take many years to conduct and require extremely large sample sizes to ensure statistically meaningful treatment group comparisons." Medical Officer's Review of Original and Resubmitted NDA Submissions 6-7 (Dec. 30, 1994).
The Post-menopausal Estrogen and Progestin Intervention ("PEPI") study was a feasibility precursor to the WHI. PEPI was designed to test the effects of various dosage regimens of estrogen and estrogen plus progestin on lipids, clotting factors, glucose homeostasis, and bone mineral density over a three-year period. Rossouw, supra, 50 J. Am. Med. Women's Ass'n at 51. The results of PEPI, published in 1994, helped establish the appropriate dosage of progestin necessary to protect women from endometrial hyperplasia, which was then used in the WHI study of HRT. Ibid.
Wyeth agreed to provide Premarin and combination estrogen plus progestin (later approved by the FDA as Prempro) and corresponding placebos for the study. Since the FDA had yet to approve a combination estrogen plus progestin, the NIH was required to submit an investigational NDA before conducting the WHI study. See 21 C.F.R. §§ 312.1 to 312.160 (requiring submission of an investigational NDA for use of non-FDA-approved drugs in medical studies). Wyeth had previously filed, in 1983, an investigational NDA in order to proceed with studies using combination estrogen and progestin. Wyeth agreed to allow the NIH to reference the confidential research information contained in Wyeth's investigational NDA concerning Prempro.
The WHI clinical trials on the long-term use of estrogen and progestin in postmenopausal women ended after approximately 5.2 years. Rossouw, supra, 288 J. Am. Med. Ass'n at 330. In July 2002, the WHI study was stopped due to an increased risk of invasive breast cancer. The WHI reported an overall relative risk of 1.26 for breast cancer associated with long-term (more than five years) hormone therapy use and subsequent analysis of this data reported an adjusted relative risk of 1.24. When the WHI study results were released, the Premarin and Prempro labeling listed a relative risk of 1.3 to 2.0. The labeling was subsequently modified to include the results of the WHI, including the lower relative risk of invasive breast cancer.
The Provera labeling has been significantly revised on multiple occasions since
In December 1991, the FDA approved changes to the Provera labeling. These changes included additional language in the "Precautions" section addressing the use of progestins in combination with estrogens:
The "Precautions" section also included a discussion of the risks of adding a progestin to estrogen therapy:
The FDA did not add language to the Provera label concerning the risk of breast cancer associated with the combination use of estrogen and progestin. Subsequently, in January 1992, the FDA issued revised guidance for all progestin drug products, which included the precautionary language listed above. Although the progestin product labeling guidance was silent concerning the risk of breast cancer associated with HRT, the FDA added such warning language to the revised estrogen product labeling guidance issued in August 1992. See Labeling Guidance for Estrogen Class Products Physician Labeling, supra n. 22, 5.
Throughout the time Dora ingested Provera, 1991 to 1996, the label listed "known or suspected malignancy of breast" as a contraindication. In July 1997, Upjohn submitted a sNDA seeking approval of an indication that would authorize
When Premarin was approved in 1942, the label was silent regarding any risk to the breast or endometrium. See Transcript of Fertility and Maternal Health Drugs Advisory Committee meeting 43:14-16 (Feb. 1, 1990). By 1950, a contraindication had been added warning physicians not to prescribe "where there is a familial or personal history of mammary or general malignancy." Id. at 43:16-18. In 1962, the contraindication was changed to a caution, recommending cyclic use. Golden explained the history of the Premarin labeling at the 1990 advisory committee meeting:
A boxed warning was added in 1977, after epidemiologic studies provided conclusive evidence of the risk of endometrial cancer. A warning about the breast was also included. Id. at 44:12-25.
In 1986, Wyeth submitted a sNDA seeking approval of another indication for Premarin. Upon reviewing this sNDA, the FDA approved Premarin for use to prevent osteoporosis. In 1991, when Dora filled her first prescription for Premarin, the drug was approved for treatment of moderate to severe vasomotor symptoms associated with menopause, atrophic vaginitis, atrophic urethritis and osteoporosis prevention. See Physicians' Desk Reference 2434 (1991).
Under "Warnings" the Premarin labeling included the following language:
The Premarin labeling also included the following under "Precautions:"
Wyeth acted quickly to revise the Prempro and Premarin labeling to incorporate the results from the WHI study of HRT released in July 2002. On or about August 28, 2002, Wyeth sent 550,000 letters including revised labeling to physicians. In bold type the letter cautioned, "because of the potential increased risks of cardiovascular events, breast cancer and venous thromboembolic events, use of PREMPRO, PREMPHASE, and PREMARIN should be limited to the shortest duration consistent with treatment goals and risks for the individual woman, and should be periodically reevaluated."
Before approving the Prempro NDA in 1994, the FDA required multiple changes to the labeling. The final FDA-approved labeling warned about the potential risk of breast cancer.
Under "Warnings" the Prempro labeling included the following language:
Under "Precautions" the labeling stated, "[w]hile the effects of added progestins on the risk of breast cancer are also unknown, available epidemiologic evidence suggests that progestins do not reduce, and may enhance, the moderately increased breast cancer risk that has been reported with prolonged estrogen replacement therapy (see Warnings)." Id. at 2804 (emphasis omitted).
In 1995, the one-pill version of Prempro was approved and the labeling was modified to include a section discussing cases of breast cancer reported in a recently published study. These changes were reflected in the 1997 Physicians' Desk Reference.
As part of the approval of Prempro, the FDA obtained a commitment from Wyeth to "conduct a comprehensive investigation of breast cancer risk in users and nonusers of the [Prempro] NDA regimens at appropriate and reasonable cost." Letter from the FDA to Wyeth-Ayerst Lab. 2 (Dec. 30, 1994). The FDA wrote, "[t]he most feasible approach appears to be a case-control study in areas of the United States when and where the NDA regimens are used extensively." Ibid. In August 1995, Wyeth submitted a draft protocol synopsis for such a study. On November 8, 1995, FDA officials met with Wyeth representatives to discuss the phase IV commitment. Dr. Bruce Stadel, a FDA epidemiologist, noted that the initiation of the phase IV case-control study would be eight or nine years away. He expressed "second thoughts" about the wisdom of conducting the phase IV case-control study, as the WHI would likely provide the same type of data. He asked Wyeth to submit a report evaluating whether the phase IV case-control study would be superfluous. According to Wyeth, the WHI researchers were also concerned that a separate study would interfere with recruitment of participants for the WHI study and not provide any new data. In September 1997, Wyeth submitted a comprehensive evaluation of WHI, Women's International Study of Long-duration Oestrogen After Menopause ("WISDOM") and the proposed case-control study. Letter from Wyeth-Ayerst Research to FDA (Sept. 25, 1997). The FDA concluded that Wyeth's continuing support
A pharmaceutical company "that communicates adequate information on the dangers and safe use of the [prescription drug] product, ... taking into account the characteristics of, and the ordinary knowledge common to, the prescribing physician[]" will not be liable for a failure to warn under the PLA. N.J.S.A. 2A:58C-4. The New Jersey Legislature went further than those in other states and accorded deference to the FDA's determination of appropriate labeling of prescription drugs by including a rebuttable presumption in the PLA.
The parties agree that the PLA accords a rebuttable presumption of adequacy based on FDA approval. However, they dispute the effect and operation of the rebuttable presumption. Plaintiffs contend that the presumption follows N.J.R.E. 301, whereby a plaintiff can rebut the presumption by showing some evidence tending to disprove the adequacy. Plaintiffs argue that once such evidence is shown, the presumption will vanish, leaving them with the burden of proving the label's inadequacy. Defendants, thereafter, would be entitled to no probative benefit from the presumption. Defendants contend, however, that N.J.R.E. 301 does not purport to identify the substantive evidence required to overcome the presumption of adequacy under the PLA. Therefore, plaintiffs' reliance on expert opinions that defendants' warnings should have said something different is misplaced because those opinions are not based on the evidentiary predicate required to overcome the presumption of adequacy.
New Jersey courts have recognized that before the FDA warning presumption will be deemed rebutted, the plaintiff must produce a specific type of evidence demonstrating intentional misconduct by the manufacturer. See William A. Dreier, John E. Keefe, Sr., & Eric D. Katz, New Jersey Products Liability & Toxic Torts Law § 15:4 at 443 (2008). The New Jersey Supreme Court first defined the specific type of evidence needed to overcome the presumption of adequacy granted by the PLA in Perez v. Wyeth Lab. Inc., 161 N.J. 1, 24, 734 A.2d 1245 (1999). The exception to the presumption of adequacy crafted in Perez was reaffirmed by the Supreme Court in Rowe v. Hoffman-La Roche, Inc., 189 N.J. 615, 626, 917 A.2d 767 (2007). The Perez Court held "for all practical purposes, absent deliberate concealment or nondisclosure of after-acquired knowledge of harmful effects, compliance with FDA standards should be
Presently, the presumption of an adequate warning based on compliance with FDA regulations will be deemed rebutted only if the following proof is presented: (i) deliberate concealment or nondisclosure of after-acquired knowledge of harmful effects ("Perez/Rowe exception") or (ii) manipulation of the post-market regulatory process ("McDarby exception") Rowe, supra, 189 N.J. at 626, 917 A.2d 767; Perez, supra, 161 N.J. at 25, 734 A.2d 1245; McDarby, supra, 401 N.J.Super. at 63, 949 A.2d 223. The Court in Perez, explained that compliance with FDA regulations provides "compelling evidence that the manufacturer satisfied its duty to warn the physician." Perez, supra, 161 N.J. at 24, 734 A.2d 1245 (emphasis added). In contrast, the McDarby exception requires substantial evidence of manipulation of the post-market regulatory process. McDarby, supra, 401 N.J.Super. at 71, 949 A.2d 223. In McDarby, the court focused on the intentional misconduct of the pharmaceutical manufacturer after market approval and found that the Perez/Rowe exception did not apply to the facts of the case. Id. at 71, 949 A.2d 223. Although plaintiffs may present expert testimony in an attempt to rebut the statutory presumption, Prince v. Garruto, Galex & Cantor, 346 N.J.Super. 180, 188-89, 787 A.2d 245 (App.Div.2001), the presumption in favor of the adequacy of FDA-approved warnings will not be deemed rebutted unless plaintiffs produce the type of evidence identified in Perez, Rowe, or McDarby.
Plaintiffs argue that the Perez presumption deals only with direct-to-consumer ("DTC") prescription drug advertising cases and is not generally applicable to failure to warn claims. This court disagrees. Prior to Perez, the statutory presumption of adequacy was analyzed in Feldman v. Lederle Laboratories, 125 N.J. 117, 592 A.2d 1176 (1991), cert. denied, 505 U.S. 1219, 112 S.Ct. 3027, 120 L.Ed.2d 898 (1992) ("Feldman II"). The Court in Perez acknowledged its earlier analysis of the presumption in Feldman II. Perez, supra, 161 N.J. at 24, 734 A.2d 1245. Given the Court's statement in Perez that "the same rebuttable presumption should apply," the presumption discussed in Perez and Feldman II must be appraised under the same standard. Ibid. Contrary to plaintiffs' argument, the presumption crafted in Perez was not confined to DTC advertising.
Prior to Perez, Rowe, and McDarby, the presumption of adequacy was governed by N.J.R.E. 301. See Feldman II, supra, 125 N.J. at 157, 592 A.2d 1176; Dreier, supra, 30 Seton Hall L.Rev. at 811 ("[p]rior to Perez, the common understanding of the statutory presumption of adequacy flowed from Feldman II and was to be governed by New Jersey Rule of Evidence 301"). The Court in Feldman II acknowledged the uncertainty as to the
The PLA grants a presumption that an FDA-approved prescription drug label is adequate. The ultimate decision of the FDA to provide or not provide certain information in a prescription drug label cannot be criticized unless a plaintiff has provided evidence of the pharmaceutical company's deliberate concealment or non-disclosure of after-acquired knowledge of harmful effects, or if the pharmaceutical company was found to have manipulated the post-market regulatory process. The court in McDarby specifically addressed the defendant pharmaceutical company's manipulation of the post-market regulatory process which caused the product's warning to be diluted and delayed the dissemination of information determined by the FDA to belong in the drug's labeling.
Plaintiffs have failed to present any evidence of deliberate concealment or nondisclosure of after-acquired knowledge by either Wyeth or Upjohn. In fact, plaintiffs' expert, Parisian, has testified that she has "not seen any evidence" that "Upjohn had information about the risk of breast cancer associated with Provera or Provera in conjunction with estrogens that it failed to disclose to the FDA." Parisian admitted that in 1994 the scientific studies examining whether progestin added to estrogen increased the potential risk of breast cancer were "confusing." As to Wyeth, Parisian was asked the following:
Next, the court must consider whether plaintiffs have presented evidence of manipulation by defendants of the post-market approval regulatory process. The court disagrees with plaintiffs' argument that the McDarby requirement of substantial evidence of inadequacy is not limited to manipulation of the post-market approval regulatory process. The court will analyze separately plaintiffs' proofs as they relate to both Wyeth and Upjohn.
The first theory asserted by plaintiffs is that Wyeth should have done more to study the risks of combining estrogen and progestin. Plaintiffs contend that Wyeth should have studied the risk of breast cancer following the increased use of progestin in combination with estrogen to combat endometrial hyperplasia. If Wyeth conducted proper studies, plaintiffs assert, Wyeth would have been obliged to propose far stronger language warning of the breast cancer risk in the Prempro NDA. Plaintiffs argue that Wyeth did nothing despite the FDA expressing concerns about the risk of breast cancer from HRT. As to Prempro, Wyeth's alleged failure to test occurred during the pre-approval period; thus, plaintiffs' failure to test claim does not fall within the McDarby exception. As for Premarin, the McDarby exception also does not apply. Unlike the facts in McDarby, the risk of breast cancer was not newly discovered, the FDA was knowledgeable of the risk, and neither the FDA nor any of its advisory committees requested Wyeth conduct specific testing. Nonetheless, the court will address plaintiffs' failure to test allegation.
The court in McDarby recognized that the FDA's "pre-market approvals of drugs are generally thorough in nature." McDarby, supra, 401 N.J.Super. at 64, 949 A.2d 223. The court quoted approvingly the view of a former FDA commissioner that "on the day of new drug approval... the FDA's determinations about labeling ought not to be subject to reexamination by courts or juries in failure-to-warn cases." Id. at 82, 949 A.2d 223 (citing David A. Kessler & David C. Vladeck, A Critical Examination of the FDA's Efforts to Preempt Failure-To-Warn Claims, 96 Geo. L.J. 461, 466 (Jan. 2008) (hereinafter "Kessler & Vladeck")). Plaintiffs argue that the FDA could not require Wyeth to do a study until Wyeth actually came within the FDA's authority and that did not occur until 1994 when Wyeth asked the FDA to approve Prempro. The facts show that Premarin and Prempro have been extensively regulated by the FDA since the approval of Premarin in 1942, as evidenced by the FDA labeling guidelines and guidance for estrogen products. The FDA has been continuously involved in the development, review, and approval of Premarin and Prempro, including ongoing review and approval of their labels.
If the court were to accept plaintiffs' theory that Wyeth failed to test before filing its NDA, then in any failure to warn case, the presumption of adequacy accorded an FDA-approved drug labeling could be nullified by a plaintiff contending that the FDA would have approved a different warning had the defendant manufacturer done additional tests before filing its NDA. Moreover, plaintiffs' argument that one need look no further than the differences between the Prempro labels pre-and post-WHI to show how inadequate the Prempro label was prior to the WHI study is flawed. The presumption will have no real effect if it is sufficient to rebut the presumption with evidence that the manufacturer subsequently strengthened the warning. Inherent in the drug approval process is the expectation that warnings will be revised and often strengthened over time. McDarby acknowledged that at the time of approval, the FDA's knowledge base may be close to perfect, but also highly limited because, at that point, the drug has been tested on a relatively small population of patients. McDarby, supra, 401 N.J.Super. at 64, 949 A.2d 223 (quoting Kessler & Vladeck, supra, at 466). There is no reason to believe that the New
If the FDA had any doubt about the warning it approved in 1994, the agency had the authority to revisit that warning and revise it as a condition for approval of the one-pill Prempro in 1995 or the 0.625 mg CEE/5.0 mg MPA dose of Prempro in 1998. In fact, when the FDA approved the one-pill Prempro in 1995, the agency directed Wyeth to add the breast cancer results from the PEPI trial to the warning. Plaintiffs' contention that Wyeth failed to conduct safety studies leading to inadequate warnings on its drugs is without merit, given the FDA's extensive regulatory record of Premarin and Prempro.
According to plaintiffs, Wyeth also manipulated the regulatory process by putting specific representations in the Prempro label which it knew to be untrue, and minimized or discounted studies that showed an increased breast cancer risk. Upon reviewing the voluminous exhibits and documents submitted by both parties, the court finds these arguments to be unsupported by the evidence. Alternatively, plaintiffs attempt to overcome the presumption of adequacy by citing the letters from the FDA to Wyeth concerning marketing materials. Plaintiffs identify eight letters sent to Wyeth from the FDA. Six of the eight letters were advisory pre-review letters. These letters show interactions with the FDA about draft ads or promotional materials, which Wyeth had voluntarily submitted pre-public dissemination to obtain FDA comment. The remaining letters sent to Wyeth were untitled. Wyeth was never issued a warning letter. A full review of the relevant documents reveals that the FDA actively exercised its regulatory authority and took prompt and effective action. Furthermore, Wyeth promptly addressed all recommendations and concerns raised by the FDA. The letters referred to by plaintiffs fail to demonstrate any intentional misconduct by Wyeth, a necessary requirement before the adequate warning presumption will be deemed rebutted.
Lastly, plaintiffs argue that Wyeth manipulated the regulatory process by "ghost writing" articles. Wyeth is alleged to have conceived and drafted medical articles relating to HRT, which were then published in peer-reviewed journals by authors who did not acknowledge Wyeth's involvement. Plaintiffs do not dispute the medical accuracy of the information contained in the relatively small number, approximately thirty-seven, published articles initiated by Wyeth.
Plaintiffs assert that they have submitted substantial evidence of post-market manipulation of the regulatory process as to Upjohn. Plaintiffs first argue that the presumption of adequacy has been rebutted as to Upjohn because Provera was not approved by the FDA for treatment of menopausal symptoms nor use in combination with estrogen. When Dora ingested Provera, the labeling did not contain a risk of breast cancer warning. In 2007, a warning about the risk of breast cancer was added to the Provera labeling. As shown in the timeline below, plaintiffs' argument must be rejected.
In July 1977, the FDA promulgated regulations requiring the use of certain warning information in the labeling for progestin drug products. In 1989, the FDA revised the guidelines based on new scientific data, primarily to update information about the risk of congenital abnormalities. There is no dispute that the Provera labeling was consistent with these guidelines. In 1984, 1990, and then again in 1991, the FDA convened advisory committees to assess the safety and efficacy of estrogen, progestin and the use of both drugs together. The advisory committees addressed whether use of HRT was associated with an increased risk of breast cancer and discussed the proper labeling of these drugs.
In December 1991, the FDA approved changes to the Provera labeling that included precautionary language about the use of progestins and estrogens. Upjohn was instructed by the FDA to use the exact language reviewed and approved by the FDA. In January 1992, after the advisory committee meetings and the FDA's extensive assessment of HRT, the FDA issued revised labeling guidance for progestin products. The guidance included detailed language in the contraindications, warnings, precautions, and adverse reactions section. The revised FDA guidance included language addressing the use of progestins in combination with estrogens. Yet again, with respect to the specific question of what should be said in the labeling for Provera concerning the risk of breast cancer, the FDA found no justification for inclusion of any specific warning language and did not include such language in the guidance. The Provera labeling was consistent with the FDA guidance. In fact, plaintiffs' expert testified that the FDA's 1992 labeling guidance represented the best thinking of the FDA. In the same year, 1992, the FDA issued revised labeling guidance for all estrogen products that included a revised specific warning concerning the risk of breast cancer.
The FDA was well aware that physicians were prescribing progestin products off-label with estrogen products. Prior to reviewing the sNDA submitted by Upjohn in 1997, for the approval of an indication that would authorize the marketing of Provera for use in combination with conjugated estrogen, the FDA was involved with reviewing and ultimately approving the NDA for Prempro in 1994. When the FDA ultimately approved the use of Provera with estrogen in 1998, it ratified the 1992 progestin product labeling guidance and again found no reason to include a breast cancer warning. The 1998 label was a reflection of the FDA's continuing judgment and "best thinking" that a warning about the risk of breast cancer should be in the estrogen labeling rather
The FDA repeatedly reviewed and approved the Provera labeling. At the same time, the FDA was actively involved with gathering and assessing information regarding the safety of estrogen, progestin and combined hormone therapy. When Dora was taking Provera, the FDA had not approved it for use in combination hormone therapy. However, the FDA was well aware that Provera was being prescribed off-label with Premarin. Plaintiffs proffer no evidence that once Dora's physicians decided to prescribe estrogen to treat her menopausal symptoms, they would not have followed the accepted medical standard of care of prescribing a progestin to protect against the risk of endometrial hyperplasia associated with taking estrogen alone.
The decision of Dora's physicians to prescribe Provera off-label, and the fact that the FDA had not yet approved Provera for the particular indication for which it was prescribed to Dora, does not rebut the statutory presumption of adequacy to which the Provera labeling is entitled. During the time period when Dora was prescribed Provera, the drug was subject to both scientific and regulatory scrutiny. The FDA had the authority to require a specific risk of breast cancer warning in the labeling and was sufficiently knowledgeable on this issue to determine whether such a warning was necessary. The FDA's decision not to include a risk of breast cancer warning on the Provera label was deliberate and informed. Plaintiffs cannot use the fact that Provera was prescribed off-label to rebut the statutory presumption of adequacy. When the FDA approved such use in 1998, shortly after Dora stopped taking Provera, the risk of breast cancer was not included in the labeling. This approval confirmed the FDA's earlier decision that a risk of breast cancer warning was not necessary. Plaintiffs' argument that because Provera was prescribed off-label the "FDA could not possibly have concluded there was no need for Upjohn to warn about the safety of Provera and estrogen on the risk of breast cancer" is not supported by the submitted facts.
Even if the court were to accept plaintiffs' argument that the FDA is powerless to require specific warnings regarding drugs that are prescribed off-label unless there is a "pending application before the FDA," the Provera timeline reveals that Provera was before the FDA on pending applications in 1991 and 1998. On both occasions, the FDA found the inclusion of any specific warning language associating combination use with an increased risk of breast cancer to be unverified. The FDA did not include such language in the progestin guidelines, guidance, or Provera labeling. This was, in part, because in 1992, the FDA also issued revised class labeling guidance for estrogen products which included a warning about breast cancer.
In considering the specific examples of conduct presented by plaintiffs of Upjohn's alleged post-market manipulation of the regulatory process, and after reviewing the volumes of exhibits submitted by all parties, this court concludes that plaintiffs' proofs are insufficient to establish that Upjohn manipulated the post-market regulatory process. The proofs submitted by
The court recognizes that some of the conduct of Wyeth and Upjohn cited by plaintiffs may have been less than exemplary. However, the actions and/or inactions of defendants have to be viewed in light of plaintiffs' failure to warn claim and the presumption of adequacy established by our Legislature. Plaintiffs have not presented compelling or substantial evidence of the type necessary to rebut the presumption of adequacy.
The FDA has been actively involved in the labeling and monitoring of Premarin, Provera, and Prempro for several decades. The FDA was well informed of the prevalent practice of prescribing Provera off-label in combination with Premarin for the treatment of menopausal symptoms for years prior to the approval of Prempro, the first FDA-approved combination HRT. The FDA had authority under 21 C.F.R. 201.57 (1988) (prior to 2006 amendments) to include language in the labeling to warn about health hazards associated with off-label use. During each of the three advisory committee meetings held by the FDA in 1984, 1990, and 1991, the FDA acknowledged the increasing practice of prescribing progestin with estrogen to treat menopausal symptoms. The FDA knew there was a risk of breast cancer in women who ingested estrogen alone or in combination with progestin. At the advisory committee meetings, experts, including FDA representatives and practitioners, discussed the breast cancer risk and what warnings were scientifically supported and appropriate to list in the labeling.
The risk of breast cancer was not newly discovered after the approval of Prempro. Plaintiffs concede that before Dora ingested HRT, the worldwide medical literature included published studies suggesting that the combination of synthetic progestin and estrogen could increase the risk of breast cancer. Plaintiffs' case-specific expert, Dr. Richard Hirschman, testified that the potential of breast cancer and HRT was commonly understood in the medical community long before Dora ever used it. All known data on the subject of HRT and the risk of breast cancer were reviewed by the FDA, the advisory committees, and the FDA's HRT working group.
During the post-market regulatory process, the FDA remained actively involved in regulating, monitoring, and requesting changes in the labeling of Premarin, Provera and Prempro. The FDA specified language in the labeling by promulgating class labeling guidelines and guidance. This differs from other drugs, such as Vioxx, where the FDA "did not have the [statutory] authority to compel labeling changes, but instead had to negotiate [all] changes with the drug's sponsor." See McDarby, supra, 401 N.J.Super. at 65, 949 A.2d 223. The shortcomings of the FDA emphasized in McDarby are not implicated here. The FDA utilized a comprehensive and scientific process to decide whether to approve Prempro and/or change the labeling or approve additional indications for Premarin and Provera. The FDA was actively involved in the post-market surveillance of these drugs. During the period of time that Dora used defendants' drugs, neither Wyeth nor Upjohn resisted labeling changes proposed by the FDA due to emerging safety concerns, unlike the defendant in McDarby, which rejected many of the FDA-proposed labeling changes. Id. at 85-86, 949 A.2d 223. There is no evidence in this case that defendants actively sought to dilute the labeling recommendations of the FDA, nor is there evidence that defendants ever intentionally withheld any risk information from the FDA. Wyeth promptly took action in response to the results released from the WHI study, which included sending thousands of letters to inform physicians of the results and updating the labeling for Premarin
As previously set forth, the FDA had the regulatory authority to require a specific breast cancer warning in the labeling of Provera, Premarin, or Prempro, and was sufficiently knowledgeable on this issue to determine whether such a warning was necessary. The FDA's decision not to include a more specific breast cancer warning in its labeling guidelines or guidance was both deliberate and informed. Any flaws in the FDA process are the responsibility of the United States Congress and the Executive Branch to correct, as they are in the best position to evaluate the pharmaceutical regulatory process. Alternatively, the New Jersey Legislature can elect to alter the rebuttable presumption afforded pharmaceutical manufacturers by the PLA, should they wish to do so. However, at the present time, the New Jersey Legislature and the New Jersey Supreme Court have acknowledged the FDA's authority and experience in determining appropriate warnings in the labeling of prescription drugs.
The proofs are sufficient to conclude that plaintiffs have failed to set forth either compelling or substantial evidence necessary to overcome the presumption of adequacy relating to the Premarin, Provera, and Prempro labels approved by the FDA.
In addition to claims under the PLA, plaintiffs' complaint contains causes of action for negligence, breach of implied warranty, breach of express warranty, fraud and misrepresentation, and negligent misrepresentation. Plaintiffs' complaint also asserts a claim under the New Jersey Consumer Fraud Act ("CFA"). Plaintiffs voluntarily dismissed their claims for negligence, breach of implied warranty, and breach of express warranty. Defendants move for summary judgment on the basis that the PLA subsumes plaintiffs' non-PLA causes of action.
In addition to other causes of action, plaintiffs' complaint asserts a claim under the CFA.
The PLA, N.J.S.A. 2A:58C-1 to -11, was enacted in 1987 to "re-balance the law `in favor of manufacturers.'" Rowe, supra, 189 N.J. at 623, 917 A.2d 767 (quoting Dreier, Keefe, & Katz, New Jersey Products Liability & Toxic Torts Law, supra, § 15:4). The PLA provides the exclusive remedy for harm caused by a product. A products liability action is defined as "any claim or action brought by a claimant for harm caused by a product, irrespective of the theory underlying the claim, except actions for harm caused by breach of an express warranty." N.J.S.A. 2A:58C-1(b)(3).
The Supreme Court decision in In re Lead Paint Litigation, 191 N.J. 405, 924 A.2d 484 (2007), which was recently relied upon by the Court in Sinclair v. Merck & Co., 195 N.J. 51, 948 A.2d 587 (2008) is determinative of whether plaintiffs' CFA claim is barred by the PLA. In Lead Paint, twenty-six municipalities and counties sought to recover, from manufacturers and distributors of lead paints, the costs of detecting and removing lead paint from homes and buildings, of providing medical care to residents affected with lead poisoning, and of developing programs to educate residents about the dangers of lead paint. 191 N.J. at 408-09, 924 A.2d 484. Although the complaints initially sought recovery through a wide variety of legal theories, the Court was called upon to consider only whether the plaintiffs had stated a cognizable claim based on the common law tort of public nuisance. Ibid. The Supreme Court held that the PLA encompasses virtually all possible causes of action relating to harms caused by consumer products:
The essential essence of the claims asserted by the plaintiffs in Lead Paint was that the defendants failed to warn of the dangers of lead paint; thus, plaintiffs' exclusive remedy was the PLA. Id. at 437, 924 A.2d 484. The Court noted that the harms plaintiffs sought to vindicate were addressed in the context of a products liability claim:
In the case at bar, plaintiffs contend that the purchase of defendants' products and their receipt of less than what they were promised is an economic loss separate and distinct from the physical injury suffered by Dora as a result of her ingestion of defendants' products. Plaintiffs argue that the "PLA's codification of a separate remedial scheme for Dora's physical injuries does not preempt the CFA's creation of a damages action for plaintiffs' purely economic losses." However, the central focus of plaintiffs' lawsuit and the "essential nature of their claims" is that Wyeth and Upjohn failed to warn of the dangers of their drugs. See Lead Paint, supra, 191 N.J. at 437, 924 A.2d 484.
In McDarby, the Appellate Division applied the Lead Paint ruling to a pharmaceutical drug case and found that the plaintiffs' CFA claims were subsumed within the PLA. McDarby, supra, 401 N.J.Super. at 95, 949 A.2d 223. The court found the core of the plaintiffs' argument to be that the pharmaceutical company failed to warn of known dangers from its product, resulting in alleged economic harm to the plaintiffs. Id. at 97, 949 A.2d 223. The economic harm upon which the plaintiffs based their claims was found to be encompassed within the definition of harm set forth in the PLA. Ibid.
The New Jersey Supreme Court rendered its opinion as to whether the CFA is subsumed within the PLA less than one week after the McDarby decision. In Sinclair, the Court found that the plaintiffs sought to avoid the requirements of the PLA by asserting their claims as CFA claims. Sinclair, supra, 195 N.J. at 65, 948 A.2d 587. Sinclair was a products liability action wherein the plaintiffs sought to recover the costs of medical monitoring without alleging a physical injury.
Plaintiffs in this case allege that they were victims of fraudulent conduct recoverable under the CFA because defendants misrepresented the safety of their products by failing to warn plaintiffs of their dangers. To allow plaintiffs to seek damages for loss of their co-payments as a result of purchasing defendants' drugs under a theory of consumer fraud will "create a cause of action entirely inconsistent with the PLA's comprehensive legislative scheme." See Lead Paint, supra, 191 N.J. at 439, 924 A.2d 484; see also Sinclair, supra, 195 N.J. at 65, 948 A.2d 587.
Plaintiffs' CFA claim merely charges that defendants misrepresented the safety risks of their products, thus causing Dora's injury. "This classic articulation of tort law duties, that is, to warn of or to make safe, is squarely within the theories included in the PLA." Lead Paint, supra, 191 N.J. at 437, 924 A.2d 484. In New Jersey "the PLA is paramount when the underlying claim is one for harm caused by a product." Sinclair, supra, 195 N.J. at 66, 948 A.2d 587.
For the aforementioned reasons, plaintiffs' CFA claim is subsumed by the PLA.
Plaintiffs' fraudulent misrepresentation and negligent misrepresentation claims are also subsumed by the PLA for the same reasons cited above. The court will briefly discuss the evolution of these common law claims and their viability today when asserted in a products liability action. The PLA enacted on "July 22, 1987, applies to product liability actions
New Jersey state and federal courts have consistently dismissed product liability claims based on common law theories, with the exception of express warranty, when those theories allege harm caused by a product. See Brown v. Philip Morris, 228 F.Supp.2d 506, 516 (D.N.J.2002).
Whether the PLA subsumes plaintiffs' fraud claims has also been an issue that has been addressed by our courts. In Brown, the court relied upon two earlier district court decisions that showed support for the PLA subsuming the plaintiffs' strict liability, negligence and fraud claims. 228 F.Supp.2d at 517. The first case relied upon by the court in Brown was Walus v. Pfizer, 812 F.Supp. 41 (D.N.J.1993). In Walus, the plaintiff asserted theories of negligence, strict liability, failure to warn, fraud, misrepresentation, and negligent and intentional infliction of emotional distress. Id. at 42. After analyzing the PLA and cases interpreting it, the court granted summary judgment to the defendants. Id. at 45. With regard to the fraud claim the
After reviewing plaintiffs' complaint, there is no doubt plaintiffs' common-law causes of action, including their fraud and misrepresentation (count V) and negligent misrepresentation (count VII) claims involve harm caused by a product under the PLA.
For the reasons set forth above, plaintiffs' CFA claim and causes of action for fraudulent misrepresentation and negligent misrepresentation are subsumed by the PLA; thus, such claims are dismissed. Plaintiffs have failed to provide the specific type of evidence necessary to overcome
In addition, the boxed warning about limb reduction birth defects was removed from the labeling "since the content is no longer deemed sufficiently serious to warrant the use of the box." Ibid.
In the "Precautions" the following language was added:
[Id. at 7.]
