swallowed. Capsules have an encasement which dissolves in the digestive tract permitting release of the active ingredients. If these inert ingredients were a concern of Congress for a novel drug, it is entirely unclear to me why they would not be of similar concern in the manufacture of a "me-too" product. It was conceded at oral argument that the quality of the inert ingredients may be related to efficacy. Tr. at 17-19. If the tablet is too hard, or the binder indigestible so that the active ingredients are not released properly or timely, the drug's efficacy may be impaired or destroyed. If the covering of a capsule is not readily digestible, the same result may occur.
In addition, as noted above, an NDA must contain a description of manufacturing methods, facilities and controls. Congress obviously deemed such factors of importance in determining whether a new drug should be approved. If they are important with respect to a novel compound, again I am entirely unclear why they are not equally germane to the marketing of a "me-too" drug.
Under § 355(d) the NDA must be disapproved if "the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity." If these factors, which have nothing to do with the safety and efficacy of the active ingredients, as such, are of sufficient import to deny approval of a novel compound, it does not make sense to me to say that they are irrelevant to a "me-too" drug.
I cannot divorce consideration of the meaning of "new drug" in § 321 from its application in § 355. Reading the two sections of the same statute together, it should be clear that Congress was concerned with such things as quality control, bioavailability and bioequivalence of the drugs prescribed for and consumed by the public.
It is argued that Congress made a legislative determination that such factors should be weighed in NDA approval of a novel compound, but eschewed them with respect to their later "me-too" counterparts. While that result may rationally obtain if one looks only at § 321, consideration of the statute as a whole seems to me to lend greater credence to the alternative interpretation advocated by the FDA. Clearly, if I were construing the meaning of "new drug" without binding authority, I would opt for the FDA's construction.
Although the statute is susceptible of the construction given it by the FDA, it may also legitimately be construed in the fashion of the Lannett court. It is a settled tenet of statutory construction that where a statute is reasonably susceptible to alternative constructions, and one of those constructions has been given the statute by the agency charged with its administration and enforcement, the latter is to prevail. Udall v. Tallman, 380 U.S. 1, 85 S. Ct. 792, 13 L. Ed. 2d 616 (1965). See also Lehigh & New England Ry. Co. v. I.C.C., 540 F.2d 71, 80 (3d Cir. 1976); McInnis v. Weinberger, 530 F.2d 55, 63 (1st Cir. 1976), and cases cited therein. Strangely, this canon is mentioned neither in the Lannett opinion nor in the FDA's brief in that case.
There is additional support in the statute for the proposition that all drugs including "me-too" drugs were desired by Congress to be subject to pre-marketing approval. Section 355(e) provides the Secretary (of HEW) with power to disapprove an approved NDA and this power may in an appropriate crisis be exercised in advance of hearing. Withdrawal of an approved NDA under this section provides an effective, efficient and speedy method of removing from the market a drug found to be dangerous. If "me-too" drugs are marketed without pre-marketing approval, such approval cannot be withdrawn and the FDA would be left to cumbersome and time consuming case-by-case institution of condemnation actions to rid the market of dangerous "me-too" drugs.
In fact, if "me-too" drugs are marketed without pre-marketing clearance the FDA may not even know that they are about. In the absence of an approved NDA or ANDA for a "me-too" drug, I am told, the only way the FDA would know which drugs a particular manufacturer was marketing would be from the semi-annual reports required by 21 U.S.C. § 360(j)(2), 21 C.F.R. § 207. Tr. at 95. Thus, a "me-too" drug without pre-marketing clearance could be in commerce for as long as six months before the FDA would be aware of its existence.
The prospect of a medical crisis requiring the immediate withdrawal of an approved drug is not just an idle In terrorem argument by the FDA. See Tr. at 93-95. Though such things are rare, they do occur. When they do the prospects for disaster are immense, with tragic long term results. Fortunately, the Thalidomide tranquilizers were not marketed in the United States, although they were in Europe. After their release it was found that they were teratogenic, that is they caused fetal skeletal deformities if taken during the first trimester of pregnancy.
We have had in this country similar tragic episodes that are readily identified. The sordid story of Mer/29 is summarized in Roginsky v. Richardson-Merrell, Inc., 378 F.2d 832 (2d Cir. 1967). That medication was designed to lower blood cholesterol levels. It did. It also caused cataract growth and was removed from the market. Then there is the saga of the Cutter polio vaccine. Supposed to be inactive polio virus so as to set up the body's immunological reactions, one batch of it contained live virus which caused polio. See Gottsdanker v. Cutter Laboratories, 182 Cal.App.2d 602, 6 Cal.Rptr. 320, 79 A.L.R. 290 (1960). Still another crisis developed surrounding the marketing of the broad-spectrum antibiotic, Chloromycetin. This drug has frequently demonstrated a life-saving ability, but it can be injurious, even fatal, if its use is not carefully monitored. Its most serious side effect is the development of aplastic anemia. Salmon v. Parke, Davis & Co., 520 F.2d 1359, 1361 (4th Cir. 1975). After a series of deaths in 1952 associated with this drug, the FDA ordered new warning labels. When further injury and deaths were reported, the FDA in 1961 added even stricter labeling requirements for the drug, 21 C.F.R. § 146d.301(c) (1962).
If an approved drug is found after experience to have disastrous and unanticipated long term side effects sufficient to require its immediate removal from the market, the Secretary can act immediately against the pioneer drug by withdrawing its NDA approval prior to an expedited hearing. 21 U.S.C. § 355(e). Marketing after such action could lead to criminal prosecution. 21 U.S.C. §§ 331(d), 333(a) and 333(b); See United States v. Park, 421 U.S. 658, 95 S. Ct. 1903, 44 L. Ed. 2d 489 (1975); United States v. Dotterweich, 320 U.S. 277, 64 S. Ct. 134, 88 L. Ed. 48 (1943); Tr. at 96-98. No such easy route to eliminate dangerous "me-too" drugs exists and, as recited above, condemnation actions would be the necessary resort. See Tr. at 24. I doubt that in such an emergency Congress intended that some drugs could be withdrawn by immediate disapproval of an NDA while their "me-too" counterparts could only be forced from the market by condemnation.
By my latest count, 31 states have enacted generic substitution laws. See, e.g., N.J.Stat.Ann. 24:6E-1 et seq. (West Supp.1978); Pa.Stat.Ann. tit. 35, §§ 960.1 960.7 (Purdon Supp.1978); Del.Code Ann. tit. 24, § 2589 (1976). Although these laws vary, they all provide a mechanism whereby the less expensive generic equivalent of a name brand drug may be substituted when the name brand is prescribed. It was established at oral argument that no post-1962 pioneer or "me-too" drug has to date been marketed without pre-marketing clearance by the FDA. Tr. at 39-41. In fact, all drugs approved by the FDA under the 1938 Act for safety only that are still being marketed have now been approved for efficacy as well. "Grandfathered" in are only those drugs marketed under the 1906 Act whose labeling has not changed. See 21 U.S.C. § 321(p)(1). I do not believe that it takes an evidentiary hearing to recognize that the medical profession in permitting generic substitution places great reliance on this pre-marketing FDA approval. Since doctors can disavow generic substitution when writing a prescription, it should be obvious that they will have greater motive to do so if they realize that their patient may be getting a medication that the FDA has not approved. Tr. at 44. In addition to considerations of quality, purity, bioavailability and bioequivalence, it would seem logical that doctors also would be concerned with medico-legal exposure.
Thus, it appears to me that not only is there room in the statute to support the construction given it by the FDA, which should be given great deference, but policy considerations as well support that interpretation.
II. Pharmadyne's Post-Lannett Actions Giving Rise To This Case.
Following the Lannett decision, Pharmadyne, without FDA pre-marketing clearance, put on the market diethylproprion hydrochloride, furosemide, and chlorothiazide with reserpine.
The diethylproprion hydrochloride put out by plaintiff purports to be a "me-too" of Tenuate Dospan which is marketed by Merrell. The medication is a sustained release anorectic, designed for use in control of obesity. It is related to the amphetamines and the PDR
for Tenuate Dospan lists the manifestations of overdosage and the treatment therefor. It should be obvious that, as with any sustained release medication, if the quality control is not such that the release is adequately sustained and there is rapid "dumping" of the contents of the capsule, overdosage may result, and therapeutic efficacy would be lost.
Plaintiff's furosemide purports to be a "me-too" of Hoechst's Lasix, approved for years as a diuretic and recently approved as an anti-hypertensive. Pharmadyne markets the drug for both indications.
It is these two drugs which the FDA has sought to condemn, principally on the theory that they are "new drugs" being marketed illegally without NDA or ANDA approval. The thesis of the plaintiff is that it has the right to market these drugs without pre-marketing clearance under Lannett and it asks this court to restrain the condemnation actions insofar as they seek relief on the ground that these products are new drugs.
The government resists an injunction on various grounds, including this court's alleged lack of jurisdiction to enter one.
III. The Government's Deference Argument.
Relying on IMS Ltd. v. Califano, 453 F. Supp. 157 (C.D.Cal.1977), the government points out that the FDA has jurisdiction to provide a ruling to Pharmadyne on the status of its drugs and asks the court to refer the issue to that body. There is no question that under IMS Ltd. and Weinberger v. Bentex Pharmaceuticals, supra, this court has the option of deferring to the FDA on this issue. However, a court should not require the doing of a superfluous act and it is apparent that to refer this issue to the FDA would lead to a foreordained result.
As noted above, I construe Lannett to restrict inquiry on the new drug issue to the question whether the therapeutically active ingredients of the new product are chemically identical and quantitatively identical to the active ingredients of an established product that passes the test and has become an old drug under § 321(p)(1). Lannett thus casts aside considerations such as quality of non-active ingredients, propriety of manufacturing and packing methods, bioavailability, bioequivalence, shelf life and the like. If the issue of the new drug status of plaintiff's product is referred to the FDA, that agency, unless under a command not to do so, will employ its construction of § 321(p)(1) that new drug means new drug product and will hold the two medications in issue here to be new drugs. Tr. at 109-10, 118-22.
On the other hand, if I order the FDA to evaluate Pharmadyne's two products under the Lannett dictum as I have interpreted it, there would be no alternative but for the FDA to find that they are not new drugs. The FDA conceded at oral argument that if thus restrained it would agree that furosemide and diethylproprion hydrochloride are generally recognized among qualified experts as safe and effective for their therapeutic indications. Tr. at 125. There has been no assertion that the active ingredients of plaintiff's products are not identical qualitatively and quantitatively to the pioneer drugs they copy. Thus, to send the issue of their status to the FDA would be of no avail.
IV. The Jurisdictional Argument.
Citing Ewing v. Mytinger & Casselberry, 339 U.S. 594, 70 S. Ct. 870, 94 L. Ed. 1088 (1950); Parke, Davis & Co. v. Califano, 564 F.2d 1200 (6th Cir. 1977) and Natick Paperboard Corp. v. Weinberger, 498 F.2d 125 (1st Cir. 1974), the Government insists that this court has no jurisdiction to enjoin the FDA from bringing condemnation actions. Those cases can, of course, be read to sustain that broad proposition. Their general reasoning is that there can be no review of the administrative decision that there is probable cause to initiate such an action, and that due process rights are satisfied by the hearing afforded within the context of the seizure action.
I am unwilling to attribute to the judiciary complete impotence in the face of an arbitrary agency assault by the bringing of multiple seizure actions across the nation in defiance of the settled law of the land. If that were the case, as Pharmadyne seems to say it is, I should think a court would and could interfere. However, this issue need not be reached, for even if there were clear power to issue the injunction plaintiff seeks, it would not be exercised in this case.
V. Pharmadyne's Basis For Injunctive Relief.
Pharmadyne does not contend that the Lannett decision is res judicata to it. Obviously, this is not so, for Pharmadyne was not a party to that action. The argument is that the FDA having litigated and lost on its interpretation of § 321(p)(1) should adhere to it unless and until Lannett is overturned by the Supreme Court. Pharmadyne, a New Jersey corporation located in Hackensack, insists that it has a right to rely on a decision of the Third Circuit and to market its products in accord with Lannett, and that the FDA should be estopped in its attempt to relitigate the rule of Lannett in other circuits. Heavy reliance is placed on Blonder-Tongue Labs. v. University Foundation, 402 U.S. 313, 91 S. Ct. 1434, 28 L. Ed. 2d 788 (1971), and the critiques of the government's circuit-shopping litigation policies set forth in the concurring opinions in May Dept. Stores Co. v. Williamson, 549 F.2d 1147, 1149 (8th Cir. 1977), and Goodman's Furniture v. United States Postal Serv., 561 F.2d 462, 465 (3d Cir. 1977). The issue in the latter two cases was whether the Postal Service was subject to garnishment proceedings against the wages of its employees pursuant to state court judgments. In May Dept. Stores, Judge Lay would have applied Blonder-Tongue estoppel to the government's continued relitigation of this issue, which, by the time of the Goodman's Furniture decision, had been presented six times in the Courts of Appeals and 19 times in the district courts. Goodman's Furniture, supra, 561 F.2d at 463 nn. 1, 2. In Goodman's Furniture, Judge Weis was extremely critical of this governmental forum shopping. Both Judges Lay and Weis, however, recognized the beneficial effects of the "percolation" process, but held that principle to be inapplicable to the issue before them.
Pharmadyne's argument has a great deal of surface plausibility. There is an appellate decision in its favor on the core issue of this case within the circuit of its location. Its marketing of the drugs in question is in accord with the considered dictum of Lannett. It points to the essential unfairness of having to meet and re-meet the Lannett issue in successive seizure actions brought in other circuits in studious avoidance of the Third Circuit by the FDA.
There may come a time when the government's repetitious litigation of the same issue will be put to an end by Blonder-Tongue estoppel. But for reasons stated below, assuming the power to apply such estoppel exists, this case does not present an appropriate vehicle for its exercise.
VI. The Basis For Denial Of Injunctive Relief.
Blonder-Tongue did not announce an immutable fiat. Its basic holding is that a patent owner who has litigated and lost on the issue of his patent's validity is thereafter estopped from asserting such validity in succeeding litigation involving other parties. Mutuality of estoppel was set aside. However, the case carries within itself safeguards against the unjust application of its own estoppel doctrine. The patent owner may avoid estoppel in later litigation if he can demonstrate (1) lack of a fair opportunity to litigate validity in the earlier action; (2) application in the basic case of erroneous legal standards; or (3) a failure of the initial court to grasp the technical subject matter. 402 U.S. at 333-34, 91 S. Ct. 1434. The Supreme Court took pains to point out that no word formula could be supplied which would lead to automatic and correct rulings on the estoppel issue, and said: ". . . the court in the second litigation must decide in a principled way whether or not it is just and equitable to allow the plea of estoppel in the case before it." 402 U.S. at 334, 91 S. Ct. at 1445.
A grant of preliminary injunctive relief is, after all, a matter of the exercise of sound judicial discretion in which one of the paramount considerations must be the public interest.
There are several reasons why I believe that the injunctive relief requested should not be afforded on the basis of the Lannett dictum.
First, Pharmadyne's reliance is on dictum, albeit a considered one. Thus, Lannett may not be an apt candidate for Supreme Court review, and the projection of the argument that the FDA should seek such review rather than go circuit-shopping loses some vitality.
Second, what I believe to be the inherent weaknesses of the Lannett dictum have already been explored at length. It cannot be over-emphasized that Lannett heralds a drastic change in the introduction into commerce of new drug products. Until now, no new drug products covered by the 1962 amendments have been introduced without pre-marketing clearance by the FDA. The issue is an important one on which there is vehement difference of opinion. I do not believe that the FDA should be bound irretrievably to it until its full ramifications have been explored. That will take further "percolation" in the courts.
Third, the FDA, charged as it is with the responsibility of safeguarding the public interest in the matter of drug marketing, has taken the position that no new drug products should be introduced without pre-marketing clearance.
Without such clearance, I believe that substantial public danger from the introduction of new drug products exists. This is exactly the position of the FDA the agency charged with the Act's administration and enforcement, and an agency possessed of extensive expertise in the field. I have some doubt that the Lannett court appreciated, on the record before it, the fact that safety and efficacy of drugs is inextricably intertwined with things other than recognition of active ingredients. Since this is a matter of most important public interest, I believe that a wise exercise of discretion requires denial of preliminary injunctive relief until the issue can be explored in more depth than it has.
Following completion of the foregoing opinion but before it was filed, the FDA requested an evidentiary hearing. The request was granted. It originated in the following fashion. Hoechst, the manufacturer of Lasix, obtained a sample of Pharmadyne furosemide tablets and ran some tests on them. The results of these tests were made available to the FDA which desired to present them and related information to the court.
On January 8, 1979, testimony was taken from Victor J. Bauer, Ph.D. and vice-president of Hoechst. In addition, the FDA filed its direct testimony of several other witnesses by affidavit, and was ordered to have these affiants available for cross-examination by plaintiff at plaintiff's demand. Counsel for plaintiff conducted some cross-examination of Dr. Bauer, but on January 9, 1979 placed on the record his waiver of the right to cross-examine the FDA's affiants.
After qualifying as an organic chemist, Dr. Bauer testified as to the tests run under his supervision and the results thereof. The principal finding was that dicalcium phosphate is used as an excipient in Pharmadyne's furosemide while lactose is used in Lasix.
Bernard E. Cabana holds a Ph.D. in Pharmacology and is employed by the FDA. Among other things, his affidavit stresses that changes in such things as particle size, identity of inert ingredients, etc. may have definite effects upon bioavailability and bioequivalence. Such changes may lead to toxicity and therapeutic failure. Dr. Cabana believes that the substitution of dicalcium phosphate for lactose in Pharmadyne's furosemide product makes plaintiff's product a potential hazard in the marketplace in the absence of further proof of In vivo bioavailability. Dr. Cabana opines that plaintiff's excipient is "very likely to interfere with the dissolution of the product in the intestine thereby rendering the product ineffective at the prescribed dosage of Lasix." Dr. Cabana points out that Lasix is used for chronic illnesses E.g., congestive heart failure, the edema secondary to cirrhosis and highlights the problems that would result if a patient titrated to Lasix is switched to a supposedly identical drug which, however, is not a therapeutic equivalent. Dr. Cabana also refers to the dangers of "dumping" of the contents of a sustained release medication.
The FDA has also supplied the affidavit of J. Richard Crout, M. D., a board certified internist with a special interest in hypertension. Among other things, Dr. Crout mentions state generic substitution laws1a and opines that the purpose of these laws may be impaired if all generic drugs supposedly identical to each other do not bear the FDA approval implicit in pre-marketing clearance.
There is no point in reciting the contents of these affidavits in detail. To some extent they present legal argument that parallels the opinion. Their factual assertions, however, only strengthen my determination that the Lannett dictum raises serious issues concerning the public safety. I am more convinced than ever that the Lannett dictum is incorrect, and I still believe that before it becomes the uniform law of the nation it should be reexamined and subjected to the most intense scrutiny.