cause to waive the in vitro requirement; nor did the FDA have a basis to conclude that whatever good cause might have existed (although Bristol argues none was present) was compatible with the public interest. Bristol contends that the FDA did not offer "any reasoned explanation" why it was waiving the in vitro requirement. To buttress its case, Bristol chronicles the FDA's past practice of requiring either in vivo evidence of the bioequivalence of cholestyramine drug products or evidence of a correlation between in vitro and in vivo tests used to establish bioequivalence.
A variety of other agency regulations pertain to bioequivalence and under what circumstances the FDA may conclude that a showing of bioequivalence has been made. The FDA avers that in addition to 21 C.F.R. § 320.22(e), there are other regulations which provide independent bases for its decision. For instance, Section 320.24 provides that to determine whether bioequivalence has been established, the FDA may use any approach it deems adequate. 21 C.F.R. § 320.24(b)(6). The FDA also relies on certain specified "criteria and evidence to assess actual or potential bioequivalence problems" for guidance on factors used to determine whether in vivo and/or in vitro testing is necessary to establish bioequivalence. 21 C.F.R. § 320.33. In addition, 21 C.F.R. § 320.25(b)(5) lists "currently available in vitro tests acceptable to FDA" as a form of evidence available to establish bioequivalence. Consequently, there is no reason for the court: to conclude that 21 C.F.R. § 320.22(d)(3) is the only basis pursuant to which the FDA could approve Prevalite TM.
Section 355(j)(6)(A)(i)(III), affirmatively vests the FDA with the discretion to determine whether in vitro or in vivo bioequivalence studies, or both, are required for the approval of generic drugs under the abbreviated application process.
21 U.S.C. § 355; see also Schering Corp., 51 F.3d at 398. "Vesting the FDA with discretion to authorize in vitro tests to establish bioequivalence supports" the FDA's decision to approve a generic drug such as Prevalite TM, without requiring absorption testing. See Id., at 398. Moreover, although the Hatch-Waxman Amendments to the FFD&C Act, also known as Title I of the Drug Price Competition and Patent Term Restoration Act of 1984, Pub.L. No. 98-417, 98 Stat. 1585 (1984), mandate a showing of bioequivalence for approval of a generic drug, "there is no evidence that Congress intended to limit the discretion of the FDA in determining when drugs were bioequivalent for purposes of ANDA approval." 52 F.3d at 399. To the contrary, the expressed desire of Congress, through the 1984 amendments, was that the FDA retain "its historically wide discretion in defining showings of 'bioequivalence.'" Schering Corp. v. Sullivan, 782 F. Supp. 645, 648 (D.D.C. 1992), vacated as moot sub nom, Schering Corp. v. Shalala, 302 U.S. App. D.C. 35, 995 F.2d 1103 (D.C.Cir. 1993). "Congress did not intend to restrict the FDA's discretion to determine how the bioequivalence requirement is to be met..." 782 F. Supp. at 651; see also Fisons Corp. v. Shalala, 860 F. Supp. 859, 865 (D.D.C. 1994). Furthermore, the FDA has had a long practice of accepting alternative showings of bioequivalence and there is no evidence that Congress has intended to abridge that practice. Id. at 648.
Presently, the FDA is requiring a showing of bioequivalence for the Prevalite TM and Questran (R) drug products; however as part of its expertise and exercise of discretion, it may waive certain testing procedures. As a result, Bristol has not demonstrated that it has a substantial likelihood of succeeding on its claim that the FDA decision to require only in vitro testing to demonstrate bioequivalence is arbitrary and capricious.
Furthermore, Bristol is silent with respect to the FDA's argument that none of the examples the former uses for its position vis-a-vis the FDA's past practice, deal with an ANDA for a generic cholestyramine powder product, which is the form of cholestyramine at issue in this case. In addition, the FDA's position regarding nonsystematically absorbed drugs like cholestyramine was made clear in 1992. The FDA stated that ANDA applications for such drugs are not required "to submit evidence of in vivo bioavailability or in vivo bioequivalence in every case." Abbreviated New Drug Application Regulations, 57 Fed. Reg. 17,950, at 17,975 (1992) (preamble to final rules).
As the FDA points out, the cases relied upon by Bristol dealt with agency statutory interpretations.
In contrast, the present case involves the agency's scientific judgments concerning what testing methods are needed to establish bioequivalence. See Solite Corp. v. EPA, 293 U.S. App. D.C. 117, 952 F.2d 473, 490 (D.C.Cir. 1991) (according deference to the agency with respect to the testing methodology used). The administrative record as presently constituted demonstrates that the FDA made a comprehensive review of the scientific testing performed with respect to cholestyramine powders, such as Prevalite TM, and concluded that in vitro studies would be sufficient to establish bioequivalence.
Moreover, bioequivalence may be established with in vitro data that is not correlated with in vivo data. Sullivan, 782 F. Supp. at 649-650. Bristol does not point to any legislative history that would require the FDA to adhere to a specific testing methodology; and Congress' silence on this issue further buttresses the FDA's position that its regulations and interpretations thereof are consistent with legislative intent. Id. The FDA has had a continuing practice of allowing in vivo testing or in vitro testing uncorrelated to in vivo data to establish bioequivalence. Id. There is nothing before the court which would lead it to conclude that this latitude is limited to only certain drug products. "While the 1984 amendments did make the bioequivalence requirement mandatory...there is nothing in the legislative history to indicate that Congress intended to restrict FDA's historical discretion to decide how that requirement would be met." Id. Accordingly, Bristol has not demonstrated a substantial likelihood of success on the merits on its claim that the FDA exceeded its authority by permitting Upsher to establish the bioequivalence of Prevalite TM and Questran (R) through in vitro testing that was not correlated with in vivo testing data.
3. Scientific Basis for Agency's Decision
Although the FDA has wide discretion to determine how the bioequivalence requirement is met, its discretion must be based on a "reasonable and scientifically supported criterion, whether it chooses to do so on a case-by-case basis or through more general inferences about a category of drugs..." Sullivan, 782 F. Supp. at 782. The FDA properly states that it has the discretion to accept in vitro bioequivalence data for particular drugs on a case-by-case basis. In this case, the FDA states that the scientific basis for its decision to allow in vitro testing to establish the bioequivalence of cholestyramine products, as articulated in the Guidance, is sufficient to establish the reasonableness of the agency's decision. In addition, the FDA submits its Response to Bristol's Citizen Petition to further support the legality of its decision. The FDA maintains that a reasonable scientific basis exists upon which to conclude that Prevalite TM is bioequivalent to Questran (R). Conversely, Bristol asserts that the FDA's decision to allow in vitro testing to establish the bioequivalence of cholestyramine drug products was arbitrary and capricious because it was unsupported by reliable scientific evidence.
At this juncture and based on the administrative record before the court, the court concludes that the FDA through the Guidance and its Response to Bristol's Citizen Petition has presented a reasonable scientific basis for its decision to allow in vitro testing data to establish the bioequivalence of the cholestyramine used in Questran (R) and Prevalite TM. In the Guidance, the FDA's Division of Bioequivalence concluded that in vivo studies are not necessary to document the bioequivalence of cholestyramine resin formulations. This judgment is based on over seven years of laboratory research and technical analysis by FDA scientists and consultants. The Guidance sets forth, in considerable detail, the kinds of in vitro studies and testing methods that the FDA finds acceptable to establish the bioequivalence of cholestyramine drug products. Therefore, the scientific basis for the agency's determination is that it found in vitro studies sufficient to establish bioequivalence and consequently it determined that the submission of the same would suffice. Moreover, the administrative record establishes, contrary to Bristol's intimation, that the FDA's judgment, as reflected in the Guidance, was based on evidence and analysis the agency used at the time its decision was made; not post hoc rationalizations for the FDA's determination.
The agency has submitted internal documents dating back to April 1989 which chronicle the history of its decision-making process which resulted in its decision, including a summary of the Prevalite approval. In that document the FDA concludes that Prevalite is bioequivalent to Questran (R) because the generic firm conducted the requisite tests which, in the FDA's view, yielded satisfactory results. The administrative record, at this juncture, establishes the scientific bases upon which the agency relied, including the raw data utilized.
In the Response, the FDA further articulates a rational basis upon which it relied in reaching its decision. It based its decision on "facts developed through its evaluation of information contained in NDA's and ANDA's, independent scientific research, and on experiments conducted by the Office of Generic Drugs, Center for Drug Evaluation and Research. FDA's decision was also, to a lesser degree, based on published literature." Response to Citizen Petition at 2. Although the FDA could have more fully responded at an earlier juncture to Bristol's Petition, Bristol has not pointed to and the court has found nothing in the FD&C Act that would require the FDA to first respond to a Petition before approving an ANDA.
Moreover, the FDA responds to all the substantive challenges raised by Bristol regarding its decision and provides an explanation as to its decision to allow in vitro studies alone to establish bioequivalence. Compare A.L. Pharma, Inc. v. Shalala, 314 U.S. App. D.C. 152, 62 F.3d 1484, 1490 (D.C.Cir. 1995) (directing the FDA to provide an adequate explanation of its determination that a particular study established bioequivalency). The agency, in its response, systematically addresses Bristol's concerns.
For instance, the agency states that its decision was based on experiments it conducted which showed that in vitro studies could establish the bioequivalence of cholestyramine powder products. The agency specifies what those experiments entailed. The agency also addresses the studies relied upon by Bristol in challenging the FDA's decision. It explains why those studies do not support Bristol's position. Additionally, the FDA outlines its reasons for concluding that the in vitro tests specified in the Guidance are scientifically sound.
The FDA has, at this point, examined the relevant data and "articulated a satisfactory explanation for its action including 'a rational connection between the facts found and the choice made.'" Motor Vehicle Manufacturers Ass'n v. State Farm Mut. Ins. Co., 463 U.S. 29, 43, 77 L. Ed. 2d 443, 103 S. Ct. 2856 (1983). The parties' dispute is fundamentally a scientific one over which the court lacks expertise and over which the FDA is the expert. The court therefore cannot conclude, at this stage, that the agency's decision was arbitrary and capricious. See Zotos Intern., Inc. v. Young, 265 U.S. App. D.C. 202, 830 F.2d 350, 353 (D.C.Cir. 1987) (stating that "given [the court's] hopeless ignorance of the subject matter, it would be most difficult for [it] to find the FDA's rejection of [plaintiff's scientifically based] arguments arbitrary") (internal citations omitted). The court cannot presently conclude that the agency has not evaluated the relevant factors or that it has made a clear error of judgment. As other courts have observed, "the FDA is the agency charged with implementing the Food, Drug and Cosmetic Act as amended. Its judgments as to what is required to ascertain the safety and efficacy of drugs fall squarely within the ambit of the FDA's expertise and merit deference from" the courts. Schering Corp., 51 F.3d at 399.
B. Irreparable Harm
"Irreparability of injury is a very high standard." American Coastal Line Joint Venture, Inc. v. United States Lines, Inc., 580 F. Supp. 932, 936 (D.D.C. 1983). Bristol's irreparable harm argument is premised on the alleged economic injury it will suffer as a result of the competition that will be engendered by Prevalite TM, as well as any possible injury to its reputation that could result if a health risk ensues from Prevalite TM approval, which in turn might be imputed to Bristol by the using public. The first prong of the argument is insufficient to establish irreparable harm and the second is based solely upon conjecture.
Bristol's sales in 1995 reached a total of $ 13.767 billion. See "US Company 1995 Results," SCRIP No. 2099, Feb. 2, 1996 at 8. According to Bristol, in 1995 net sales of Questran (R) and Questran (R) Light were approximately $ 97 million. Sales of these two products thus accounted for only .7% of Bristol's total sales. "It is well settled that economic loss does not, in and of itself, constitute irreparable harm... 'The key word in this consideration is irreparable. Mere injuries, however, substantial, in terms of money, time and energy necessarily expended in the absence of a stay are not enough.'" Wisconsin Gas, Co. v. FERC, 244 U.S. App. D.C. 349, 758 F.2d 669, 674 (D.C.Cir. 1985) (quoting Virginia Petroleum Jobbers Ass'n v. FPC, 104 U.S. App. D.C. 106, 259 F.2d 921, 925 (D.C.Cir. 1958)).
Moreover, demanding scrutiny must be applied to claims of irreparable injury. For instance, in CityFed Fin. Corp. v. OTS, 313 U.S. App. D.C. 178, 58 F.3d 738 (D.C.Cir. 1995), the Office of Thrift Supervision froze the assets of CityFed. CityFed sought to enjoin enforcement of that order, relying on affidavits from its officers stating that it would be driven into bankruptcy absent a stay. 58 F.3d at 746-747. The Court of Appeals, based on its own analysis of the order and CityFed's financial position, rejected CityFed's claim because the order provided a narrow escape valve that permitted the bank to apply for "hardship" relief from the order. Id. Thus, because the bank had a means by which it could keep itself from going into bankruptcy, the Court concluded that irreparable injury had not been established.
Presently, Bristol will undoubtably survive as a going business concern absent injunctive relief. Further, its ability to survive is not theoretical; its total sales picture will not be greatly affected by any loss of market share that will result from Prevalite's TM competition-- a loss of less than 1 percent of total sales is not irreparable harm. Moreover, Bristol's claim that it will loose between 50 and 70 percent of its market share of the cholestyramine market, is supported by mere speculation concerning the encroachment of Prevalite TM into its market share. See Mead Johnson Pharmaceutical Group v. Bowen, 655 F. Supp. 53 (D.D.C. 1986) (holding that plaintiff's contention that if an ANDA was approved it would loose twenty to thirty percent of its market share was inadequate to establish irreparable harm). Additionally, Bristol's argument that if it prevails on the merits it will be unable to recover damages is inconsequential. See General Textile Printing v. Expromtorg Intern., 862 F. Supp. 1070, 1075 (S.D.N.Y. 1994) (denying an injunctive request which was based on a defendant's potential inability to satisfy a money judgement). If it ultimately prevails on the merits, Bristol's total sales will be insignificantly affected over the duration of the litigation. Even assuming that Bristol's projections are correct, as a result of Prevalite's competition, the effect of Bristol's total sales would be minuscule.
"The mere existence of competition is not irreparable harm, in the absence of substantiation of severe economic impact." Holiday Tours, 559 F.2d at 843 n. 3.
Similarly, Bristol's claim that its reputation will suffer if there is any adverse health effect that ensues from the use of Prevalite TM is insufficient to establish the requisite harm. There is nothing before the court which would lead it to conclude that Prevalite TM will cause any harmful health effects. See Sullivan, 782 F. Supp. at 652. Finally, the court notes that if the injunction is granted, Bristol would substantially receive the ultimate relief it requests, before there has been a trial of the issues and on a record which fails to show Bristol's substantial likelihood of succeeding on the merits. See Triebwasser & Katz v. AT&T, 535 F.2d 1356, 1360 (2d Cir. 1976).
C. Balance of Harms
Presently, the balance of harms decidedly weighs in favor of denying a preliminary injunction. The resulting harm to Upsher would be significantly greater than the harm that will be visited upon Bristol if its request for injunctive relief is denied. The approval of Prevalite TM has entailed a significant investment of economic and other resources on the part of Upsher. Upsher has endured a seven year process to obtain FDA approval and has satisfied the FDA's testing protocol and established, to the FDA's satisfaction, the bioequivalence of Prevalite TM and Questran (R). Moreover, the effect of an injunction on Upsher would be dramatically greater than the harm to Bristol, considering that its total sales in 1995 amounted to $ 33 million and both companies expect the sale of Upsher's Prevalite TM to be upwards of $ 20 million or more in the first year on the market.
D. Public Interest
Bristol has not established that the public interest will be better served if an injunction is issued by the court. The Hatch-Waxman Amendments to the FFD&C Act aimed to increase competition in the drug industry by creating an administrative regime pursuant to which the approval of generic drugs would be facilitated. Mead Johnson Pharmaceutical Group, 838 F.2d at 1333. This new, abbreviated process was encompassed in the ANDA application process. This process has made the manufacture of generic drugs more practical. Id. To balance the interests of generic drug manufacturers and those of pioneer drug manufacturers, Congress provided the latter with varying periods of exclusivity prior to FDA approval of a competing generic drug. Id. Presently, Bristol has benefitted from the period of exclusivity to which it was entitled. The using public will therefore now benefit from increased competition and the concomitant decrease in cholestyramine drug products.
A delay in the approval, without the showing of a substantial likelihood on the merits would not further the public interest. See Sullivan, 782 F. Supp. at 652.
Lastly, there is no reason for the court to conclude that there may exist a possible health risk posed by the approval of Prevalite TM. See id. at 652. Bristol maintains that because Prevalite TM contains aspartame, also know as Nutrasweet TM, a potential public health risk exists. This is so because some individuals do not metabolize phenylalanine, a component of aspartame. However, this danger is negated by the fact that Prevalite TM, as does Questran (R) Light, contains a clear warning label specifying that the drug product contains phenylalanine. The product box also states that it contains aspartame. A treating physician who has a patient who could not metabolize phenylalanine would be on notice, as with other drugs which may have an adverse effect on his or her patients, not to prescribe the drug to phenylketonurics. Bristol further argues that because in certain situations a pharmacist would be required to substitute the generic drug Prevalite TM for Questran (R), a potential health risks exists. However, in such situations physicians would presumably require that a particular brand be dispensed; as the FDA has counseled them to do. See FDA, Approved Drug Products with Therapeutic Evaluations, at viii.
Finally, the FDA has, in its scientific judgment, concluded that Prevalite TM is safe for its intended use and responded to each of Bristol's concerns relating to the public health.
Accordingly, since Bristol has failed to establish that it is entitled to injunctive relief, it is this day 25 of March 1996,
ORDERED that plaintiff's motion for a preliminary injunction be and is hereby denied.
Ricardo M. Urbina
United States District Judge