Then and Now
A RETURN TO THE DEFINITION OF ANTIBIOTIC
This chapter began with a definition of the term “antibiotic”; however, in light of the critical economic consequences of this designation for any particular product as discussed above, it is perhaps not surprising that the courts would have the last word on the subject of what constitutes an antibiotic. This issue came up in the case of Allergan v. Crawford (30) litigated in the District Court of Washington, D.C., under the following circumstances.
A product known as “RestasisR” marketed by Allergan, Inc., is a topical oph-thalmic emulsion of cyclosporine used to treat an eye condition known as kerato-conjunctivities (or dry eye disease). This product was submitted to the FDA in a New Drug Application in 1999 and was approved by the FDA in December 2002.
As noted by the court, the issue is that “[t]he distinction between drugs entitled to market exclusivity/patent protection and those not so entitled, depends on whether the drug is classified as an ‘antibiotic’ that was subject to FDA review prior to 1997.”
In this case, the FDA classified Restasis as an antibiotic and accordingly denied it Waxman-Hatch exclusivity; Allergan argued that its mechanism of action proved otherwise, i.e., it was not an antibiotic, but rather an immunosuppressive drug and accordingly entitled to exclusivity.
In the course of its application process, Allergan submitted its application to the FDA in 1999 as a nonantibiotic, and it was so approved by the FDA in 2002.
FDA’s Antibiotic Regulatory Scheme 139
However, in March of the following year, the FDA informed the company that the active ingredient, cyclosporine, was an antibiotic previously approved by the FDA prior to the enactment of FDAMA and its repeal of section 507. Accordingly, it was therefore not eligible for the Waxman-Hatch protections under section 125(d) (2). Interestingly—and crucially, in the eyes of Allergan—Restasis is not approved for any antibiotic use. In fact, the company pointed out the FDA-approved label-ing for the product specifically contraindicates its use where an eye infection is present.
It turns out that the issue of the antibiotic status of cyclosporine was itself a prior controversy at the FDA earlier in connection with the drug applications of its innovator, Sandoz Pharmaceuticals, for approval of its SandimmuneR drug prod-uct. This product, developed and indicated to suppress organ rejection in transplant patients, was approved by the FDA in 1983 and classified as an antibiotic under sec-tion 507. Follow-on applicasec-tions using the same active ingredient were approved as nonantibiotics in 1994, but then were reversed and reclassified as antibiotics. San-doz strongly objected to the reclassification, and in fact, the record shows that the decision was itself highly controversial within the FDA. As the court noted, the record showed that “many members in Pilot Drug [FDA] did not agree nor under-stand why Sandimmune is classified [as] an antibiotic.” The company pointed to the statutory language for antibiotics and argued in effect that mere antibiotic activity in vitro, which did not correlate with antibiotic activity in vivo except at unsafely high concentrations, did not cause the product to be classified as an antibiotic given that such antibiotic activity was not relevant to its therapeutic use in humans notwith-standing the existence of such activity.
The FDA effectively agreed with Sandoz, but nevertheless held to its position on narrower grounds. Noting that it agreed that “no credible evidence or rationale was identified that would support the conclusion that cyclosporine has any clini-cally relevant antibacterial activity,” the FDA nevertheless found that “cyclosporine has been shown to possess antifungal activity against 2 relevant human pathogens”
in in vitro and animal studies and therefore should remain classified as an antibi-otic drug. The FDA applied this antibiantibi-otic classification to three approved NDAs and two pending NDAs of Sandoz in 1995.
Allergan cited this and subsequent similar FDA controversies in its attempt to classify its product as a nonantibiotic. At bottom, Allergan argued that its drug was approved for no antibiotic indications and that the FDA as a matter of statutory interpretation should have construed the term “antibiotic drug” in section 125(d) (2) of FDAMA “to mean antibiotic drug product rather than antibiotic active moiety.”
The former, “product,” was dependent on the product as a whole in the context of its indication, whereas the latter, “moiety,” related solely to the active drug sub-stance in any of its forms and indications. The FDA determined that the statutory definition related to the drug substance “the definition does not reference a par-ticular quantity of the drug substance, nor a parpar-ticular indication.” Reviewing the scientific study, the FDA noted that cyclosporine in fact has antimicrobial activity against two fungal pathogens at concentrations that are found in plasma following administration of the drug to patients at its recommended doses. Accordingly, it was properly classified as an antibiotic.
The court, noting the plausibility of Allergan’s view of the law, nevertheless found that the FDA’s action was more consistent with the language of FDAMA.
The statute, the court noted, defined “antibiotic” as “any other drug intended for
human use containing any quantity of any chemical substance which is produced by a microorganism and which has the capacity to inhibit or destroy microorganisms in dilute solution. . .” 21 USC section 321(jj). Thus, the court found that the language was quite explicit in including in the definition any ingredient in any quantity that destroys microorganisms in dilute solution. Its “intended use” under the statutory language referred, the court held, merely to the fact that it is intended for use in humans, not necessarily for “antimicrobial” use per se, as Allergan argued. Under these criteria, the court found that cyclosporine was clearly included in the class of products defined by the statute as “antibiotic.”
Turning to the term “dilute solution,” Allergan argued that it clearly referred to the use of the drug and its activity at the levels found in its own product, Restasis, rather than its concentration in the predecessor product, Sandimmune, where it was present in far higher concentrations. The court, adopting the view of the FDA, rejected this contention, by noting that the statutory language did not define “dilute solution” further, and consequently, did not determine what evidence the FDA should consider in determining the antimicrobial character of the ingredient. That it was antimicrobial in concentrations found in Sandimmune, therefore, settled the matter notwithstanding that the amounts in Restasis were not antimicrobial. In other words, its approval at the higher dose in Sandimmune rendered the ingre-dient an antibiotic, irrespective of the fact that Restasis itself was not antibiotic in effect. At bottom, the FDA’s scientific expertise was given great—and decided—
deference by the court.
As this case shows, the stakes involved in the classification of a product as antibiotic are quite high, and, as it turns out, a definition believed long-settled has again, in light of the intense economic consequences, come up for renewed debate.
The court’s decision, however, in so firmly supporting the FDA’s scientific expertise and granting it the deference intended by Congress, has in all likelihood settled this issue—at least until another economically weighty set of facts presents yet another angle for intellectual attack.
CONCLUSION
The history and development of antibiotic regulation represents a process of increasing evolution of a particular legislative scheme that had, over time, increas-ingly outstripped the historical circumstances and needs that were its provenance.
Revised by the FDA to take account both of changing scientific standards and regu-latory and marketplace realities, the scheme was finally abandoned entirely by the Congress and folded into the standard drug regulations, thereby putting an end to its unique approval mechanism and separate status.
REFERENCES
1. FDCA§507(a), 21 USC 357(a).
2. Pub. L. No. 77–366, 55 Stat 851 (1941); Pub. L. No. 79–139, 59 Stat 463 (1945); codified at 21 USC§356.
3. FDCA§507(a), 21 USC 357.
4. John D. Harrision. Antibiotic Application Requirements. Clin Res Practices & Drug Reg Affairs 1986; 4(4);265, 267.
FDA’s Antibiotic Regulatory Scheme 141
5. Id. at 267.
6. 21 USC§357(a).
7. Harrison. Id. at 267.
8. See FDA Proposal, 47FR 19957. May 5, 1982; see also former 21 CFR 314.50, 314.55.
9. Harrison. Id. at 269.
10. Id.
11. FDA Order, 47 FR 39155. September 7, 1982.
12. See Barr Laboratories, Inc. v. Harris, 482 F. Supp. 1183 (DDC 1980).
13. See Pfizer, Inc. v. Richardson, 434 F2 d 536 (2 d Cir 1970).
14. See In the Matter of Antibiotic Antifungal Drugs (FDA 1988). 1988–1989n FDC LRept Dev Trans Bind at 38070.
15. 21 CFR 433.1(a) (repealed).
16. See former 21 CFR 314.
17. See former 21 CFR 314.70.
18. 63 FR 26066.
19. 64 FR 396, 64 FR 26657 (May 17, 1999).
20. 21 CFR parts 430–460
21. Marketing Exclusivity and Patent Provisions for Certain Antibiotic Drugs. 65 FR 3623 (Jan. 24, 2000).
22. 65 FR 3623 (Jan. 24, 2000).
23. Id. at 3624.
24. Id.
25. Id.
26. 65 FR at 3625.
27. Guidance for Industry and Reviewers: Repeal of Section 507 of the Federal Food, Drug and Cosmetic Act. FDA Center for Drug Evaluation and Research (“CDER”). May 1998.
28. Section 201(jj) of the FDCA.
29. Guidance for Industry: Drug Master Files for Bulk Antibiotic Drug Substances.FDA Cen-ter for Drug Evaluation and Research (“CDER”). November, 1999.
30. Civil Action No. 03–2236 (RMC). U.S. District Court. District of Columbia. (Jan. 19, 2005).