United States v. 50 Boxes [OF] ... Cafergot P-B Suppositories
Docket: Civ. A. 86-1630-WF
Court: District Court, D. Massachusetts; September 1, 1989; Federal District Court
An in rem forfeiture action has been initiated by the United States against the CPB Suppository under the Federal Food, Drug, and Cosmetic Act, arguing it qualifies as a "new drug" that requires FDA approval for interstate commerce. Sandoz Pharmaceuticals Corporation, the claimant, contests this, claiming the drug is exempt from approval as it has been recognized as safe and effective and falls under a 1962 "grandfather clause" for drugs marketed before that year. The United States seeks summary judgment, asserting that Sandoz's arguments do not satisfy the exemptions. The court acknowledges undisputed facts: CPB Suppository meets the definition of a drug, has been shipped in interstate commerce, and contains four active ingredients, two of which are also in the FDA-approved Cafergot Suppository. Sandoz first marketed CPB Suppository in 1955 without an NDA, possibly due to informal FDA indications it was not a new drug. In 1972, the FDA recognized Cafergot as effective but later classified CPB as an unapproved new drug in regulatory communications from 1977 and 1985, ultimately advising Sandoz to cease its sale. Sandoz attempted to contest the FDA's stance and submitted an NDA, which the FDA deemed incomplete. The court concludes that the motion for summary judgment by the United States should be granted.
The FDA rejected Sandoz's New Drug Application (NDA) for CPB Suppository, leading to an inspection that confirmed Sandoz continued shipping the product interstate. Consequently, the government initiated a forfeiture action. The court's discretion for granting summary judgment follows Rule 56 of the Federal Rules of Civil Procedure, which requires the absence of genuine issues of material fact and entitlement to judgment as a matter of law. The court must consider the record favorably for the non-moving party and demands substantial evidence from the plaintiff to counter summary judgment claims. In this case, the court found that the United States is entitled to summary judgment because Sandoz failed to provide adequate evidence that CPB Suppository is generally recognized as safe and effective or that it qualifies for exemption under a grandfather clause for drugs marketed before 1962. Since 1962, the FDA mandates that manufacturers demonstrate a new drug's safety and efficacy for approval, which Sandoz did not accomplish, despite its claim that CPB Suppository is not a "new drug" under 21 U.S.C. 321(p).
In the context of a motion for summary judgment, the district court's role is to determine if there is a dispute among experts regarding the "general recognition" of a drug's safety and effectiveness, rather than making a definitive assessment of the drug's actual safety and effectiveness, which falls under the FDA's jurisdiction due to its specialized expertise. A genuine dispute among qualified experts about a drug's safety or effectiveness can prevent a finding of "general recognition," which is essential for exemption from FDA approval requirements. If expert opinions sharply diverge, the government is entitled to summary judgment. Furthermore, even if there is general expert recognition of a drug's safety and effectiveness, this recognition must be supported by substantial evidence—defined as adequate and well-controlled scientific investigations, including clinical trials—as required for FDA approval. The legislative history emphasizes that mere case studies or expert opinions do not meet this standard, and only rigorous evidence is acceptable for claims of effectiveness. Consequently, any assertion that the evidence needed for a judicial exemption under 321(p) is less stringent than the evidence required for FDA approval is incorrect.
The court recognizes that while the Supreme Court's dicta in Bentex suggests that general recognition of a drug's efficacy can occur without rigorous scientific support required for a New Drug Application (NDA), the First Circuit Court of Appeals mandates that the same evidentiary standards for effectiveness apply to claims of "general recognition" under 21 U.S.C. § 321(p). Specifically, under 21 U.S.C. § 355(d), the FDA must reject applications lacking "substantial evidence" of the claimed effects, defined as evidence from well-controlled investigations by experts. The court is bound to apply this interpretation, which aligns with the Third Circuit's rejection of a more lenient evidentiary standard in United States v. 225 Cartons More or Less of an Article of Drug.
The standards established indicate that CPB Suppository qualifies as a "new drug," warranting summary judgment for the United States. The U.S. has presented sufficient evidence of expert disagreement on the safety and effectiveness of CPB Suppository, countering Sandoz's claim for exemption from FDA approval based on general recognition. Notably, Sandoz's own experts, including Dr. Robert Temple and Dr. Russell Katz of the FDA, affirm that there is no "substantial evidence" to support claims of safety and effectiveness for CPB Suppository. Despite Sandoz's assertions, their experts concede that the existing studies would not suffice for NDA approval. This lack of substantial evidence from Sandoz’s side further supports the United States' position, justifying summary judgment.
Sandoz's experts contend that despite the absence of conventional scientific studies required for FDA approval of a new drug, the long-standing use of CPB Suppository should qualify it for a judicial exemption as "generally recognized" by experts as safe and effective. However, this claim is legally flawed; substantial evidence is necessary to support expert consensus on the drug's safety and effectiveness. The court is poised to grant summary judgment to the United States unless the grandfather clause applies.
The grandfather clause from the 1962 FDA amendments does not exempt CPB Suppository from the new drug requirements it has not met. Since the FDA Act's inception in 1938, drugs have had to demonstrate safety, and the 1962 amendments added an effectiveness requirement. A drug can be exempt from the effectiveness requirement if it was commercially used prior to 1962 and meets four specific conditions: A) it must have been sold in the U.S. before 1962; B) it must not be classified as a "new drug" under the 1938 Act; C) it must not have an effective new drug application; and D) it must still be intended for use as specified in its 1962 labeling.
The court emphasizes that the grandfather clause is a strict exemption from a comprehensive safety regulation, placing the burden of proof on Sandoz to satisfy all four conditions. The undisputed facts show that CPB Suppository does not meet at least three of these requirements: its labeling has materially changed since 1962, it did not qualify as a "new drug" in 1962 due to insufficient scientific evidence, and it was covered by a new drug application for Cafergot. The legal issue regarding labeling is clear-cut, as the current label suggests uses that differ significantly from those recommended in 1962.
The comparison of two affidavits highlights significant changes in the labeling of WANS and CPB Suppository since 1962. For WANS, the earlier label specified its use for eleven conditions related to nausea and vomiting, while the newer label permits use for any condition causing these symptoms. Additionally, the original label included children as a recommended user group, which the newer label does not. The revised label includes a warning about the drug's association with Reye’s Syndrome, leading the Court of Appeals for the First Circuit to determine that these changes disqualified WANS from the grandfather clause protection.
Similarly, in the case of CPB Suppository, the 1962 label advised use for treating existing headaches, whereas the current label expands its indication to include headache prevention. The older label also recommended use for children, a suggestion not present in the current version. The newer label adds warnings about potential ergotism, sepsis, hypersensitivity, and other harmful side effects, as well as increasing the recommended dosage from four to five suppositories per week. These changes indicate that new health information has emerged, which Sandoz deemed significant enough to alter the labeling.
Furthermore, even if CPB Suppository met the labeling criteria of the grandfather clause, it would still be classified as a "new drug" under the 1938 FDA Act because it would require general recognition of safety by qualified experts based on valid scientific tests conducted prior to 1962. Dr. Katz asserts that no adequate data existed in 1962 to support the general recognition of safety for CPB Suppository, confirming that no laboratory or clinical tests were provided that could have led experts to conclude it was safe before October 10, 1962.
Sandoz contends that CPB Suppository was generally recognized as safe as of 1962, supported by expert affidavits citing knowledge of its ingredients, literature reviews, and clinical experience. However, the court finds that such expert knowledge does not constitute the “contemporaneous, valid scientific tests” required for proving safety, as outlined by the First Circuit. None of the experts claim any laboratory tests were conducted on CPB Suppository, corroborating the U.S. assertion that no valid safety tests existed prior to October 1962. Furthermore, the pre-1962 literature lacks documented scientific testing and is characterized as low quality, relying instead on anecdotal clinical experiences without controlled studies. Consequently, Sandoz's evidence fails to demonstrate that CPB Suppository was generally recognized as safe before 1962, classifying it as a “new drug” not protected under the grandfather clause. Informal FDA communications from 1955, which suggested otherwise, were later revoked in 1968 and deemed non-determinative due to changes in the definition of “new drug” after the 1962 Amendments.
The excerpt addresses the application of the grandfather clause concerning the CPB Suppository and its coverage by the NDA of Cafergot as of October 9, 1962. It establishes that CPB Suppository fails to meet the requirement of not being "covered" by another drug's effective NDA, as defined by 21 C.F.R. 310.6. The term “covered” refers to drugs that are "identical, similar, or related" to those with an effective NDA. In this context, CPB Suppository is considered "related" to Cafergot, sharing equal amounts of its two active ingredients, and its labeling is nearly identical to that of Cafergot. Sandoz's efforts to gain FDA approval for CPB Suppository as a supplement to the Cafergot NDA further support its relatedness.
Sandoz contends that 21 C.F.R. 310.6 should not apply retroactively and that the regulation pertains only to particular drug formats. However, the text of 310.6(b)(1) encompasses a broader range, including drugs related by chemical structure or pharmacological properties. Sandoz’s own experts acknowledge the similarity between the two products, and it is clear that the effectiveness of CPB Suppository is reliant on the ingredients of Cafergot. The court rejects Sandoz's interpretation of the regulation and maintains that the terms “similar” and “related” in the regulation are not redundant, affirming that CPB Suppository is indeed covered by Cafergot’s NDA based on these definitions.
Sandoz argues that the drugs in question, Cafergot and CPB Suppository, should not be treated similarly to the ineffective drugs from the USV case, asserting that a broad interpretation of "covered by" is unnecessary for the FDA Act's purposes. However, this argument is refuted on multiple grounds. Firstly, CPB Suppository may not be recognized as safe and effective. The Supreme Court's interpretation in USV mandates that all prescription drugs post-1938 comply with effectiveness requirements to prevent manufacturers from exploiting regulatory gaps. Consequently, Sandoz fails to demonstrate that CPB Suppository qualifies for the grandfather clause established by the 1962 amendments. The United States has successfully argued for summary judgment, classifying CPB Suppository as a "new drug" requiring FDA approval for sale, leaving the FDA responsible for assessing its safety and efficacy. The motion for summary judgment is granted, with the United States instructed to propose an order by September 19, 1989. Additionally, it is noted that no clinical studies on CPB Suppository exist, and the studies conducted on CPB tablet do not provide substantial evidence due to differing ingredient proportions. The grandfather clause stipulates specific criteria for drugs commercially used before the amendments, which CPB Suppository does not meet given significant label changes since 1962.
