THE CERTIFICATION PROCESS

At the time the antibiotic provisions were enacted in 1945, the only antibiotic prod-uct on the market was penicillin. In subsequent years, well over a hundred addi-tional antibiotic products were developed and approved by the FDA. Most of these approvals were under the 1945 regulatory scheme, which used a monograph system in conjunction with batch certification. To receive permission to market a product, the applicant was required to address a request for certification of a batch of an antibiotic drug to the commissioner of the FDA. The application was required to contain information describing the batch, including results of testing required by the regulations, and batch composition. Each batch shipped in interstate commerce was required to adhere to stated standards of identity, strength, quality, and purity.

Additionally, batches were required to have results for tests and methods of assay, including sterility tests, biological tests, microbiological assays, chemical tests, and tests for certain antibiotic dosage forms.

In its application, the manufacturer was required to submit actual samples of each batch of antibiotic which FDA would test in its own laboratories. Upon review and confirmation by the FDA that the batch met appropriate requirements, the FDA

would certify the batch as safe and effective, and fit for distribution in interstate commerce. These certifications were contained in an “Antibiotic Certificate” issued by the FDA to the applicant. Batches that were released prior to such FDA certifica-tion were deemed misbranded under seccertifica-tion 502 (1) of the FDCA, and were subject to seizure and other legal sanctions.

Certification was a creature of FDA discretion. FDA was authorized to with-hold certification of any batches, which it deemed required a further demonstration of safety and effectiveness. In this respect, FDA could require any additional test-ing or other information it deemed appropriate, and it did so in cases where new information or other changed circumstances indicated that the standard certifica-tion may no longer have been sufficient (12). Moreover, FDA had the power to sus-pend certification procedures for any person or company that was found to have used fraud, misrepresentation, or concealment in the application for certification, or had otherwise falsified records required by the regulations to be maintained by the company.

The 1962 Drug Amendments added a requirement that drugs demonstrate efficacy, in addition to safety, prior to distribution—a requirement that was equally applicable to antibiotics. Prior to these amendments, the FDA had been authorized to certify certain antibiotics as safe and effective: penicillin, streptomycin, chlorte-tracycline, chloramphenicol, and bacitracin. Other antibiotics available at the time were either classified as safe and effective or were generally recognized as safe, and therefore did not require a finding of effectiveness prior to marketing. As a result of the 1962 amendments, which now required proof of effectiveness, FDA determined that antibiotics marketed under a pre-1962 New Drug Application (NDA) would be certified or released from certification under the pre-1962 regulatory scheme, despite the fact that the pre-1962 regulatory scheme did not review drugs for effi-cacy. To address the new efficacy requirements, FDA determined to proceed under the rubric of its Drug Efficacy Study Implementation Program (DESI) to provide appropriate regulations for these antibiotics.

As a result of the 1962 amendments, FDA required the submission for sev-eral antibiotics of scientific evidence of “substantial well-controlled clinical studies”

demonstrating the effectiveness of the product. Products that failed to provide such evidence had their certifications revoked and the regulations under which they were marketed repealed by the FDA. Legal challenges to this action failed (13). In addi-tion, after review of submissions for other antibiotics, FDA withdrew certification and revoked approval of several antibiotic and antibiotic combination products that did not meet the FDA’s standards of substantial scientific evidence (14).

Exemptions from Certification Requirements

Under the FDCA, FDA was permitted to exempt certain products from certification as a requirement for proving safety and efficacy. Accordingly, the FDA exempted antibiotic drugs from the requirements of certification (15). Promulgated by the FDA to relieve the bottleneck in antibiotic approvals, this new regulation exempted from the certification requirements of the FDCA all antibiotic drugs provided there was an approved antibiotic application for each product.

The antibiotic approval process had previously been contained in the FDA’s Form FD-1675, rather than in a regulation. This form contained the information required to be submitted by the applicant for approval of the antibiotic, and was also referred to as a “Form 5” and “Form 6” application. Form 5 applications were

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for antibiotics for which no standards had previously been developed as shown in 21 CFR, Parts 440 to 455; Form 6 applications were for products for which such standards already existed and contained in the regulation.

In 1985, the FDA published new regulations known as the “NDA Rewrite Regulations,” which entirely revamped the application procedures for drug prod-ucts. In these regulations, the FDA dispensed with the previous regulatory scheme of Form 5 and Form 6 for antibiotics, and replaced it with appellations that more closely mirrored those of nonantibiotic drugs. Accordingly, after May 23, 1985, antibiotic applications were classified as either “New Antibiotic Drug Applications”

or “Abbreviated Antibiotic Drug Applications” (16). Consonant with the new regu-latory framework, applicants, and manufacturers could now make certain changes in their products, without requiring prior FDA approval (17).

FDAMA

In 1997, President Clinton signed into law the Food and Drug Administration Mod-ernization Act of 1997 (FDAMA). This act, which was designed in part to intro-duce legal mechanisms to permit the speedier and broader introduction of phar-maceutical products to consumers, also addressed a number of prevailing historical anomalies in the FDA’s review and approval process. Among those anomalies was the approval mechanism for antibiotics, whose distinction from the general class of pharmaceuticals had long lost any scientific rationale. Accordingly, section 125 of Title I of the Act repealed section 507 of the FDCA, which contained the separate application scheme for antibiotics. Essentially, the import of the repeal is that antibi-otics would, with certain exceptions, be reviewed and approved on the same basis as any other pharmaceutical product.

The act specifically provided, moreover, that any full applications (NDA’s) approved under FDCA section 597 before the signing into law of FDAMA would be deemed to have been submitted and filed under the general pharmaceutical provi-sions, section 505(b) of the FDCA, and approved for safety and effectiveness under section 505(c) thereof. In addition, all abbreviated applications (ANDAs) approved under section 507 would be deemed to have been filed and approved under section 505(j) of the act, applicable to ANDAs for general pharmaceutical products.

One consequence of the effective dating of the repeal, however, was that antibiotic applications submitted to the FDA before the date of FDAMA were not subject to the patent listing and notification requirements, as well as the exclusiv-ity attendant thereto.^∗The inevitable result was that post-FDAMA applications for pre-FDAMA (“old”) antibiotics were not required to include patent information and

∗Under Section 505 of the FDCA, abbreviated new drug applications are required to certify the status of their product in relation to the patents claimed by the “listed” product in the Orange Book. These certifications indicate whether the product infringes the listed product, whether the applicant claims no patents of the listed product apply to the applicant’s product, whether listed patents apply, or whether listed patents apply but the patents are invalid. The application itself is deemed a legal infringement of any patents, and therefore may precipitate a patent infringement lawsuit by the owner of the listed drug against the applicant who certifies that listed patents apply, but are invalid. The statute provides a period of exclusivity to the first to file such a certification, in the event of a patent infringement lawsuit by the listed product owner.

were not eligible for the exclusivities of sections 505(c) or 505 (j) of the FD&C Act.

This included applications for a new dosage form or new indication for an “old”

antibiotic.

FDA’s Proposed Rule

In the Federal Registers of May 12, 1998, (18) and January 5, 1999, (19) the FDA issued conforming amendments to its regulations to remove provisions that were made obsolete by FDAMA, specifically the provisions that governed certification of antibiotic drugs (20).

Under section 125(d) (1), drugs that had been approved pursuant to section 507 of the act were now to be deemed approved under the standard new drug provisions of the act, and would be considered as NDA drugs. These drugs, hav-ing been approved under the previous regulatory scheme, had not been subject to the patent and exclusivity provisions of the act that were enacted under the Drug Price Competition and Patent Restoration Law (“Waxman-Hatch”), enacted in 1984, which were contained in section 505 of the act. Accordingly, FDAMA also exempted antibiotic-related drug applications from the drug exclusivity and patent listing pro-visions of Waxman-Hatch. As a result, section 125 of FDAMA exempted from the exclusivity and patent listing requirements all applications that contained an antibi-otic drug that was the subject of a marketing application received by the FDA under former section 507 of the act and received by the FDA prior to the enactment of FDAMA on November 21, 1997. This included applications that were withdrawn, not filed, or even refused approval under section 507.

In 2000, the FDA published a proposed rulemaking notice in the Federal Regis-ter, wherein it fleshed out its approach to its regulatory stance on marketing exclu-sivity and patents for antibiotic drugs (21).

Notwithstanding the relatively bright-line distinctions contained in FDAMA, an issue that was reminiscent of the original enactment of the Waxman-Hatch Amendments, i.e., the definition of the type of drug product included in its stric-tures, still remained. In the case of FDAMA’s section 125 exemption, therefore, it remained unclear what constituted an “antibiotic” exempt from the requirements and benefits of drug exclusivities and patent listing.^∗

Accordingly, in the Federal Register of January 24, 2000, FDA proposed regu-lations governing the exemption of antibiotic applications from regulatory provi-sions governing marketing exclusivity and patents (22). In its notice, the FDA noted that under the former section 507 of the act antibiotic drugs were not subject to the patent listing and exclusivity provisions of section 505. Under section 125 of the Modernization Act, however, this distinction is preserved “with an expansive line” (23). Under section 125, applications are exempted which contain an antibiotic drug which was the subject of a marketing application received by FDA under for-mer section 507 prior to the enactment of FDAMA on November 21, 1997. Drugs

∗The effect of “drug listing” in the Orange Book, for example, is to grant the owner of the Reference Listed Drug (“RLD”) an automatic 30-month stay of approval in the event the RLD owner sued a generic applicant for patent infringement following certification by the generic applicant that its product did not infringe the patent of the RLD.

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approved and marketed under former section 507 as well as drugs that were the subject of applications, “which may have been withdrawn, not filed, or refused approval under section 507 of the act” were similarly excluded from the patent list-ing and exclusivity provisions of section 505 (24).

The term “antibiotic drug,” the FDA recounted, is defined in section 125 of FDAMA as

[a]ny drug (except for drugs for use in animals other than humans) composed wholly or partly of any kind of penicillin, streptomycin, chlortetracycline, chloramphenicol, bacitracin, or any other drug intended for human use con-taining any quantity of any chemical substance which is produced by a micro-organism and which has the capacity to inhibit or destroy micro-micro-organisms in dilute solution (including a chemically synthesized equivalent of any such substance) or any derivative thereof.

21. USC 321(jj) From this definition, the FDA concluded that the term “antibiotic drug” refers not only to the active chemical substance but also to any derivative of the substance, such as a salt or ester of the substance. Accordingly, FDA determined that section 125’s applicability applied to any drug that is the subject of a marketing application containing an “active moiety,” which could be found in a drug applica-tion submitted to the agency prior to the enactment of FDAMA.^∗ In defending its position, FDA noted that it had previously taken the same position for nonantibiotic drugs with regard to patent listing and exclusivity.

In interpreting the exclusivity provisions in the Hatch-Waxman Amendments, the agency concluded that Congress did not intend to confer significant periods of exclusivity on minor variations of previously approved chemical compounds.

Therefore, the agency determined that it is appropriate to assess whether the drug seeking exclusivity is a new chemical entity, that is, a drug that does not contain any previously approved active moiety (25).

Having established that the congressional intent was to exempt from patent listing and exclusivity any applications for the same “active moiety” of a prerepeal antibiotic drug, FDA went on to propose a mechanism “[t]o help interested persons determine which drug products [are] exempt from the marketing exclusivity and patent provisions” by maintaining in the Code of Federal Regulations a list of the names of each prerepeal active moiety, in section 314.109(b) of the CFR This list, FDA indicated, is intended to be comprehensive and to provide interested persons a means of determining whether a marketing application would be for a drug that contains a prerepeal antibiotic.^† Included with its proposed rule was a list of these active moieties of prerepeal antibiotics, which the FDA considered exempt from patent listing and exclusivity provisions of section 505 of the act (26).

∗FDA defined an “active moiety” as the “molecule or ion responsible for physiological or pharma-cological action, excluding appended portions that would cause the drug to be an ester, salt, or other noncolvalent derivative of the molecule.” 65FR at 3625.

†Although intended to be comprehensive, FDA notably stressed its use as an aid to interested parties, but without legal effect. Thus, if any products were inadvertently omitted from the list, such omissions would not affect the regulatory status of the application; the application would still be exempt from patent listing and exclusivity, notwithstanding inadvertent omission from the list. 65FR at 3625.