The opinion of the court was delivered by: DEBEVOISE
Plaintiff is the United States which instituted this action on behalf of the Food and Drug Administration (FDA). The defendants are two prescription drug products, FIORINAL WITH CODEINE NO. 1 and NO. 2 (FWC No. 1 and FWC No. 2). The claimant is Sandoz Pharmaceutical Corporation (Sandoz) which manufacturers and distributes the FWC products.
This is an in rem seizure action brought under 21 U.S.C. § 334. The complaint for forfeiture alleges that the seized FWC No. 1 and FWC No. 2 are "new drugs" within the meaning of 21 U.S.C. § 321(p) which may not, without violating 21 U.S.C. § 355(a), be introduced into interstate commerce because a new drug application (NDA) has not been approved by the FDA pursuant to 21 U.S.C. § 355(b). Further, the complaint alleges that the FWC products are misbranded within the meaning of 21 U.S.C. § 352(f)(1) because their labeling fails to bear adequate directions for use, and they are not exempt from this requirement because they are unapproved "new drugs".
After the drugs were seized by the United States Marshal pursuant to court order, Sandoz intervened and filed a claim. In its answer it admitted that the court has jurisdiction, that the seized articles are drugs located within the jurisdiction of the court and that the seized articles were manufactured from one or more components which were shipped in interstate commerce. Sandoz denied that the FWC products are "new drugs" within the meaning of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 301, et seq. (the FDC Act) and that they are misbranded. Further, Sandoz defended on the ground that the case must be dismissed because the FDA did not develop an administrative record pursuant to 5 U.S.C. § 554 before it filed its complaint for forfeiture.
The FDA moved for summary judgment. It contends that to obtain judgment on the "new drug" charge it need only establish (i) that no NDA for the FWC products has been approved by the FDA (which Sandoz will admit) and (ii) that the FWC products are "new drugs". The FDA further contends that to obtain judgment on the misbranding charge it need only prove the same two facts and that the FWC products are prescription drugs (which Sandoz will admit). Thus, according to the FDA, the only contested issue is whether the FWC product is a new drug. The FDA submitted in support of its summary judgment motion exhibits and declarations of experts which, it contends, establish that there is no genuine issue of material fact and that the FWC product is indeed a new drug.
In response to FDA's motion Sandoz submitted declarations to support its contention that FWC No. 1 and FWC No. 2 are not new drugs and it moved pursuant to Fed.R.Civ.P. 56(f) for a continuance to permit discovery to oppose the motion for summary judgment.
II. The Applicable Statute and Regulations
The FDA Act establishes a system for the premarket clearance of drug products. 21 U.S.C. § 355. Under the Act as adopted in 1938, 52 Stat. 1040, no new drug could lawfully be introduced into commerce unless and until an NDA for that product had been filed with and approved by the FDA. See 21 U.S.C. § 355(a), 52 Stat. 1052. The 1938 Act defined a new drug as any product which, among other things, was not "generally recognized" by qualified experts as safe for its intended use. See § 201(p), 52 Stat. 1041.
Under the 1962 amendments a manufacturer seeking approval of an NDA was required to submit "substantial evidence" of the product's safety and effectiveness. The statute defined "substantial evidence" as "evidence consisting of adequate and well-controlled investigations, including clinical investigations . . . on the basis of which it could fairly and responsibly be concluded . . . that the drug will have the effect it purports . . . to have under the conditions of use prescribed . . . in [its] labeling. . . ." 21 U.S.C. § 355(d). Sandoz FWC products are exempt from the FDA's premarket clearance procedures only if they are "generally recognized" as safe and effective for their intended uses. 21 U.S.C. § 321(p).
The 1962 amendments required the FDA to evaluate the effectiveness of all drug products, not grandfathered, which had been placed on the market since 1938. To do this, the FDA enlisted the services of the National Academy of Sciences - National Research Council (NAS-NRC), which, after investigation, made recommendations to the FDA regarding the effectiveness of therapeutic classes of products. As the FDA reviewed the NAS-NRC recommendations, it published drug efficacy study implementation (DESI) notices in the Federal Register which rated products as to their effectiveness for specific labeled indications. Products that were found to be effective were still regarded as new drugs and manufacturers were required to supplement their NDAs to conform to conditions imposed by the DESI notices. In the period shortly after adoption of the 1962 amendments the FDA issued informal opinions with respect to some drug products that they found were not new drugs. However, in 1968 the FDA adopted a regulation revoking all such opinions. 21 C.F.R. § 310.100(d). Thereafter virtually all prescription drug products which had come on the market since 1938 would be regarded as a new drug requiring either a full or, in certain narrowly defined cases, an abbreviated new drug application (ANDA).
In 1976 the FDA published a Compliance Policy Guide (CPG) which established enforcement priorities for proceedings against DESI-related drugs that were being marketed without approved applications. The sixth category included unapproved combination drugs that are related to drugs which had been found effective in the DESI program.
As noted above before a product can be exempted from the statutory, new drug preclearance procedures, it must be "generally recognized" by qualified experts as safe and effective for its intended uses. 21 U.S.C. § 321(p). The "general recognition" requirement does not involve the actual safety or effectiveness of the product. Rather, it is the product's reputation in the scientific community that is relevant. Further, the experts' opinion as to general recognition must be based upon well-controlled, clinical studies which are published; the opinions of experts may not be based upon uncontrolled data or upon their own personal experiences. Weinberger v. Hynson, Westcott & Dunning, Inc., 412 U.S. 609, 619, 37 L. Ed. 2d 207, 93 S. Ct. 2469 (1973). The general recognition of a product's safety and effectiveness must be documented by at least the same quality and quantum of evidence that would suffice to obtain FDA's approval of the product in the first instance. Weinberger v. Bentex Pharmaceuticals, Inc., 412 U.S. 645, 652, 37 L. Ed. 2d 235, 93 S. Ct. 2488 (1973).
Another particularly pertinent regulation is set forth in 21 C.F.R. § 300.50 and provides in part:
(a) Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug.
These, then, are the statutory and regulatory provisions which must be applied in determining the critical factual issue in the case, namely, whether FWC No. 1 and FWC No. 2 are generally recognized on the basis of well-controlled, published clinical studies to be safe and effective for their intended use.
Fiorinal is an analgesic marketed by Sandoz. Originally it contained the peripheral analgesic aspirin (200 mg), phenacetin (130 mg), the analgesic adjuvant caffeine (40 mg) and the barbiturate butalbital (50 mg). In 1983 pursuant to an FDA directive pertaining to products containing phenacetin, the phenacetin was removed and the quantity of aspirin was increased to 325 mg.
The FWC product consists of the Fiorinal ingredients plus varying amounts of codeine. FWC No. 1 contains 7.5 mg codeine; FWC No. 2 contains 15 mg codeine; FWC No. 3 (which is not a subject of seizure in the present case) contains 30 mg codeine. When phenacetin was removed from Fiorinal it was also removed from the FWC products. FWC is a widely prescribed combination product useful for severe tension headaches, post-surgical pain, and other forms of pain.
In 1962 Sandoz received from the FDA an informal written opinion that the FWC products were not new drugs. In July 1963 Sandoz began marketing FWC. In 1968 the FDA revoked all its informal opinions. 21 C.F.R. § 310.100(d).
In response to a 1973 DESI notice Sandoz submitted data to support its NDA for Fiorinal, but did not submit any data for its FWC products. On November 15, 1977, in response to this submission, the FDA published a DESI follow-up notice which stated that Fiorinal "has been evaluated as effective for . . . tension. . . headache" and that "such drugs are regarded as new drugs (21 U.S.C. § 321(p)."
In 1977 and 1978 Sandoz filed ANDAs with the FDA for its FWC products, the difference between an abbreviated and full NDA being that the abbreviated application need not contain full reports of clinical studies to prove the product's safety and effectiveness. 21 C.F.R. § 314.55(a). On both occasions the FDA rejected the applications because it had not made a specific finding that such short-form applications were appropriate for the FWC products and because the approved products, plain Fiorinal and Trigesic with Codeine, upon which Sandoz sought to "piggy back" its ANDA applications for the FWC products, contained different ingredients from the FWC products. FWC contains codeine; Fiorinal does not. FWC contains butalbital; Trigesic with Codeine does not.
Sandoz did not appeal these decisions but in 1978 filed a Notice of Claimed Investigational Exemption for a New Drug (IND). The IND has been maintained since that date.
In March 1978 FDA officials informed Sandoz that the FWC products were new drugs, requiring a full NDA. Sandoz was also informed, among other things, of the studies that would be required for approval of an NDA and that FWC No. 1 containing 7.5 mg codeine would probably not show effectiveness.
By letters dated December 5, 1984 and January 11, 1985, Sandoz responded to the November 15, 1984 regulatory letter and asked that the agency not take immediate regulatory action against FWC and further requested that the FDA allow FWC products to remain on the market pending review and approval of a soon-to-be submitted NDA. On February 1, 1985 Sandoz submitted an NDA for the FWC products.
On February 20, 1985 Sandoz submitted a third request that the FDA accept an ANDA for the FWC products, stating among other things that "Fiorinal with Codeine is identical to . . . Fiorinal with the exception of a single active ingredient, codeine phosphate, . . . the ingredients of Fiorinal with Codeine are in the same therapeutic class as the ingredients in Fiorinal, [and] there are ample data to establish that the addition of codeine to . . . Fiorinal can be expected to have the same effect as Fiorinal."
On April 16, 1985 the FDA advised Sandoz that a preliminary review of its NDA for the FWC products indicated that the application was not approvable.
On April 26, 1985 Sandoz wrote the FDA and advised that it was taking the position that the FWC products were not new drugs. It cited a long history of safe and effective use and referred to "an extensive series of clinical investigations which have given rise to a general recognition of the safety and effectiveness of the product and the contribution thereto of each of its active components."
The April 26 letter was accompanied by the declarations of Dr. Donald Dalessio and Dr. Neil Raskin. Dr. Dalessio based an opinion about the safety and effectiveness of FWC products upon his experience in prescribing the drug for a 15 year period and upon published and unpublished material which Sandoz provided him. He referred specifically to the published studies of MacDonald and Ehrenreich and of Madore and Chiricosta and to a Sandoz multicenter study which had been submitted to the FDA in support of Sandoz' NDA.
On May 16, 1985 Sandoz submitted to the FDA the declaration of Dr. Arnold P. Friedman attesting to the general recognition of the safety and effectiveness of FWC products. None of the three declarations which Sandoz submitted differentiated between the three FWC formulations.
On October 3, 1986 the complaint in this action was filed and on January 12, 1987 the United States Marshal seized the FWC products.
IV. The Published Clinical Studies
The critical issue in this case is whether Sandoz' FWC products are generally recognized among qualified experts as safe and effective. Safety does not appear to be a contested issue, and thus the present inquiry is confined to the FWC products' effectiveness and to the effectiveness of each of their constituent drugs. The opinions of the experts as to general recognition must be based upon well-controlled clinical studies which are published. The parties in this proceeding refer to six such studies in support of and in opposition to the motion for summary judgment.
A. Madore, P. and Chiricosta, A., "Analgesic Effect of Fiorinal with Codeine," Anesthesia and Analgesia, Vol. 46, No. 4 July-Aug. 1967 : This study used FWC No. 3 which contained 30 mg of codeine. The FWC No. 3 formulation differed from that which is presently marketed in that it contained 130 mg phenacetin and 200 mg aspirin. Today's ...