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As part of an initiative to make generic drugs more widely available, the Food and Drug Administration (FDA) on June 18 issued final rules covering patent submissions required of companies filing a new drug application (NDA) and governing procedural aspects of filing an abbreviated new drug application (ANDA). An NDA is required for a compound not previously approved for use in humans, and requires the submission of safety and efficacy studies (clinical trials) of the new drug. An ANDA, on the other hand, is an application to market the generic equivalent of a drug that has already been found to be safe and effective. The final rules follow on proposed rules released last year, with certain changes in response to lengthy comments that the FDA received from interested parties, including generic and brand-name pharmaceutical companies, the Federal Trade Commission and the American Association of Retired Persons. The new rules attempt to eliminate manipulation of the provisions of the 1984 Hatch-Waxman Act. The goal of that act was to protect the interests of brand-name drug makers that invest millions in research development and testing, while encouraging generic pharmaceutical companies to bring low-cost drugs to the marketplace. Important aspects of the new rules, which alter certain portions of 21 C.F.R. Part 314, include the following: Only one 30-month stay per ANDA or � 505(b)(2) application is permitted (a 505(b)(2) application seeks approval of a new drug but in its report on the drug’s safety and efficacy, at least some of the data relied upon come from studies conducted by third parties, not by, or on behalf of, the applicant); Submission of patents claiming packaging, intermediates or metabolites is prohibited; and Patents claiming a different polymorphic form of the active ingredient described in the NDA must be submitted to the FDA. The rules also change the kinds of patent information that must be submitted to the FDA (and provide new forms for submission of the information), both with an initial NDA and after NDA approval. Only one 30-month stay is permitted per ANDA Perhaps most significantly, the final rules limit the number of 30-month stays to one per ANDA or � 505(b)(2) application. Under the Hatch-Waxman Act, when a generic company files an ANDA or 505(b)(2) application with a paragraph IV certification-which certifies that the patent covering the drug is either invalid or not infringed by the generic company’s activities or is otherwise unenforceable-notice is sent to the brand-name pharmaceutical company stating that an ANDA referencing the brand-name company’s patent has been filed. The brand-name company then has 45 days within which to file suit for patent infringement. If it files suit, the FDA automatically puts approval of the generic drug on hold for 30 months. Under the old regulatory scheme, it was possible for an NDA holder to obtain more than one 30-month stay by listing additional patents after the first stay had been triggered. Multiple stays are no longer available under the new rule. To avoid additional manipulation of the rule and to ensure that an NDA holder or patent owner has one full opportunity for a 30-month stay, the rule clarifies the circumstances under which notice is required when an ANDA or 505(b)(2) applicant changes its patent certification midstream. Under the old listing rules, the FDA required NDA applicants and holders or patent owners to submit information on specific types of patents for listing in the volume formally known as Approved Drug Products with Therapeutic Equivalence and informally known as the Orange Book. The Orange Book lists all U.S. patents covering the drug substance (ingredient), the drug product (formulation and composition) and method of use. Process patents were specifically prohibited. These basic requirements have not changed. Product-by-process patents, in which a claim is made to a drug that is made by a particular process, must be submitted for listing only if the product can be identified as novel. The proposed rule did not have this requirement, but, in response to numerous comments, the FDA modified its position and now requires novelty of the product for listing. The final rule also prohibits listing of patents claiming packaging, metabolites or intermediates. In the wake of several court rulings, the FDA clarified its position that a method-of-use patent should be submitted only if the use is described in the labeling for the drug product. Patents having claims to methods of use that do not appear in the labeling must not be listed. To protect against incorrect listings, additional data requirements have been added to the final rules, including the requirement that the specific method-of- use claim and the labeling language related to the method-of-use claim, be provided in the declaration forms. Although the FDA declined generally to require identification of each claim in each patent covering the drug product, method-of-use patents will require identification of the specific claim in the patent covering the method. One of the biggest changes to the new rules is the requirement that polymorph patents be listed. A drug substance that has the same active ingredient, but in a different physical form, such as a different crystalline structure or hydration state, is called a polymorph. Under the new rule, drug companies will be required to submit patents claiming a polymorph of the drug substance if the polymorph performs the same as the drug product described in the NDA in terms of dissolution, solubility and bioavailability. In spite of the fact that many comments submitted to the FDA during the rule-making process argued that requiring polymorph patents to be listed would make it more difficult for generic companies to design around existing patents, the FDA declined to modify the position taken in the proposed rule. However, to ensure that the submitted patents claim the same active ingredient, additional information is required on the part of the NDA applicant or holder. The final rule and declaration forms require certification that test data exist demonstrating that the drug containing the polymorph will perform the same as the drug described in the NDA. The test data required are similar to those required by the FDA for generic applicants, which must submit information on physical and chemical characteristics, stability, manufacturing methods and components, and bioequivalence. If a patent claims more than one polymorph, each polymorph for which the required test data are available must be identified by claim or description in the declaration forms. The final rule does not require the tests to be submitted to the FDA at the time of patent submission, nor does it require the NDA applicant or holder to conduct the testing itself. The declarations required for patent submission have also been changed. As noted above, claim-by-claim declaration for each patent is not required except in the case of method-of-use patents. The existing declaration is replaced with a more detailed one, which is now mandatory and requires attestation statements. The forms also include a warning statement to alert the submitter that a willfully and knowingly false statement is a criminal offense under 18 U.S.C. 1001. The final rules do not address the issue of listing of patents that could be considered double patenting without the filing of a terminal disclaimer, i.e., the promise to the patent office that the two patents will remain owned by the same entity. Many comments were submitted during the rule-making period urging the FDA to prohibit listing of patents for which a terminal disclaimer had been filed. The FDA’s position is that, because there is no opportunity for multiple 30-month stays if patents with terminal disclaimers are listed, there is no need to prohibit the listing of this category of patents. The FDA declined to create an additional administrative process for challenging patent listings beyond that already established in the existing rules, nor did the FDA create an administrative mechanism to ensure timely patent infringement litigation if no statutory notice is provided to the NDA holder. The FDA also declined to amend the proposed rule to exempt ANDA applicants from submitting patent certifications if the patent was listed after the ANDA was filed. Two obstacles to savings from generic drugs remain In an FDA white paper released simultaneously with the new regulations, the FDA emphasized its mission to ensure that generic drugs are available and are as safe and effective as brand-name versions of the drugs. While the new regulations promise to lead to billions of dollars in lower drug costs each year, the FDA cited two other obstacles to helping consumers get greater savings from generic drugs: long approval times for generic drugs and lack of consumer knowledge and safe use of generic drugs. On average, it takes more than 20 months for a new generic drug to be approved by the FDA, mainly because the applications require multiple “review cycles” for approval. In addition, health care practitioners and patients do not always know when generic drug alternatives are available, or that the generic alternatives are just as safe and effective as the brand-name drug. As a result, the FDA estimates that many additional billions of dollars in potential savings are likely to go unrealized each year. As part of the federal government’s efforts to improve access to generic drugs, the FDA has been promised an increase in resources to the tune of $13 million, which it will use to provide more staff to review generic drug applications on a timely basis and facilitate communications with generic manufacturers. Part of the money will also be used to develop additional methods, other than comparative clinical trials, to determine therapeutic equivalents of branded and generic drugs. Finally, the FDA promises greater efforts to inform consumers about the safety, effectiveness and value of generic drug options. The final rules became effective on Aug. 18, and there will be a compliance date of Dec. 18 for patent information submitted on patents claiming a polymorph of the same active ingredient of the product described in the NDA. Debra Z. Anderson is an associate at Pittsburgh’s Eckert Seamans Cherin & Mellott specializing in chemistry, pharmaceuticals and biotechnology, and in FDA law.

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