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Boehringer Ingelheim Pharma Gmbh & Co. KG v. United States Food and Drug Administration

United States District Court, District of Columbia

July 6, 2016



          COLLEEN KOLLAR-KOTELLY United States District Judge

         In this challenge to an action of the United States Food and Drug Administration ("FDA") under the Administrative Procedure Act, the underlying facts are complex, the related science even more so. But the legal issue before this Court is relatively narrow: the legal sufficiency of the FDA's interpretation of the statutory reference to "the date an application was initially submitted for such [approved] drug product" and the agency's implementation of that interpretation.[1] Before the Court are Plaintiffs' [23] Motion for Summary Judgment, and Defendants' [26] Motion to Dismiss, or in the Alternative Cross-Motion for Summary Judgment. Plaintiffs argue that the FDA's action violated the relevant statutory provisions, that the action violated the agency's own regulations, and the FDA acted arbitrarily and capriciously because this action was inconsistent with prior agency practice. Defendants respond that the agency's interpretation of the relevant statutory language is due deference, that its interpretation of that language was reasonable, that its action in this case was consistent with its regulations and the statutory language, and that it did not act arbitrarily or capriciously.

         Upon consideration of the pleadings, [2] the relevant legal authorities, and the record for purposes of this motion, the Court GRANTS Defendants' [26] Motion for Summary Judgment, DENIES Plaintiffs' [23] Motion for Summary Judgment, and DENIES AS MOOT Defendants' [26] Motion to Dismiss.[3] The Court concludes the agency's interpretation of the statutory language is due deference in the Chevron framework, that the interpretation is reasonable, that the agency reasonably applied that interpretation, and that the agency did not act arbitrarily or capriciously. The Court also concludes that Plaintiffs have identified no other legal shortcomings with the agency's application of that interpretation in this case. This case is dismissed in its entirety.

         I. BACKGROUND

         A. Statutory and Regulatory Framework

         Under the Food, Drug, and Cosmetic Act, approval of the Food and Drug Administration ("FDA") is required before a new drug can be distributed in interstate commerce. See AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1045 (Fed. Cir. 2010) (citing 21 U.S.C. § 355(a)). "To obtain approval for a new drug, an applicant may file a New Drug Application … that includes examples of the proposed label for the drug and clinical data demonstrating that the drug is safe and effective for use." Id. (citing 21 U.S.C. § 355(b)(1)(A), (b)(1)(F)). The statute requires that certain informational components be included in an application:

Such person shall submit to the Secretary as a part of the application (A) full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use; (B) a full list of the articles used as components of such drug; (C) a full statement of the composition of such drug; (D) a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug; (E) such samples of such drug and of the articles used as components thereof as the Secretary may require; (F) specimens of the labeling proposed to be used for such drug, and (G) any assessments required under section 355c of this title.

21 U.S.C. § 355(b)(1).

         To compensate patent holders for time lost regarding the use of their patents while a drug is undergoing FDA review, Congress has provided for certain extensions of patent duration associated with the FDA approval process. Congress promulgated these provisions in 1984 through what are often described as the Hatch-Waxman Amendments or the Hatch-Waxman Act. See Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. 98-417, 98 Stat. 1585 (1984). The Hatch-Waxman Amendments provide for an extension of a patent's term to account for a portion of the time consumed by regulatory review before the FDA. See Id. Under the statute, the "regulatory review period" for a new drug such as the one whose approval is at the center of this case consists of

(i) the period beginning on the date an exemption under subsection (i) of section 505 or subsection (d) of section 507 became effective for the approved product and ending on the date an application was initially submitted for such drug product under section 351, 505, or 507, and
(ii) the period beginning on the date the application was initially submitted for the approved product under section 351, subsection (b) of section 505, or section 507 and ending on the date such application was approved under such section.

35 U.S.C. § 156(g)(1)(B); see Astra v. Lehman, 71 F.3d 1578, 1579 (Fed. Cir. 1995). Only drug products submitted under section 505, codified at 21 U.S.C. § 355, are relevant to this case. In other words, the first phase of the "regulatory review period, " which is commonly referred to as the testing phase, ends when "an application was initially submitted for such drug product"; the second phase of the "regulatory review period, " known as the approval phase, begins on this same date and ends when the application is approved. For the reasons explained below, it is only the proper calculation of the "initially submitted date"-and thus the boundary between the testing and the approval phases-that is at issue in this case.

         Subject to other exceptions not relevant here, the patent term extension is equal to half of the length of the testing period plus the entire length of the approval period. See 35 U.S.C. § 156(c) (explaining that the extension equals the regulatory review period with a reduction for half of the length of the period under section 156(g)(1)(B)(i), the testing period applicable in this case).[4] Under regulations promulgated by the FDA regarding the determination of a patent term extension, an application "is initially submitted on the date it contains sufficient information to allow FDA to commence review of the application." 21 C.F.R. § 60.22. Plaintiffs agree that this definition is consistent with Congress's intent in passing the Hatch-Waxman Amendments. Pls.' Mot. at 4.

         To receive a patent term extension, a patent holder must submit a timely application to the Director of the United States Patent and Trademark Office. 35 U.S.C. § 156(d)(1); see also Astra, 71 F.3d at 1580. For drugs such as the one at issue in this case, the Director of the Patent and Trademark Office refers the application to the Secretary of Health and Human Services who "determine[s] the applicable regulatory review period." 35 U.S.C. § 156(d)(2)(A)). The Secretary of Health and Human Services has the sole authority to determine the length of the regulatory review period and, concomitantly, the patent term extension. Astra, 73 F.3d at 1581. The Secretary of Health and Human Services must then communicate this information to the Patent and Trademark Office. 35 U.S.C. § 156(d)(2)(A). Under the applicable regulations, these responsibilities of the Secretary of Health and Human Services are delegated to the FDA. See 21 C.F.R. § 60.20; Patent Term Restoration Regulations, 53 Fed. Reg. 7, 298, 7, 298 (Mar. 7, 1988).

         After the FDA determines the regulatory review period, it publishes that determination in the Federal Register. 21 C.F.R. § 60.20(c). "Any person may request a revision of the regulatory review period determination within 60 days after its initial publication in the Federal Register." Id. § 60.24(a). The FDA then considers such a request and makes a definitive determination of the regulatory review period.

         B. Factual Background

         Plaintiff Boehringer holds all rights in U.S. Patent No. 6, 087, 380 ("the'380 patent"), which covers the active ingredient in Pradaxa. On August 6, 2003, the FDA granted Boehringer an exemption under 21 U.S.C. § 355(i) to begin clinical trials on Pradaxa. See AR 5404; see also Determination of Regulatory Review Period for Purposes of Patent Extension; PRADAXA, 77 Fed. Reg. 26, 289, 26, 289 (May 3, 2012). There is no dispute that this date-August 6, 2003- marks the beginning of the testing phase in this case.

         On August 17, 2009, the FDA officials participated in a meeting with representatives of Boehringer regarding the development of Pradaxa. AR 5636. Certain proposed drugs are eligible for priority review by the FDA.[5] AR 8192. For drugs under priority review, the agency sets a target of approving a drug within six months rather than within 10 months. AR 8192. At the August 2009 meeting, Boehringer indicated that it intended to request priority review for the drug in development. AR 5637. In response, the FDA representatives indicated that they "believe[d] it likely" the application for Pradaxa would receive priority review if Boehringer requested one. Id. The FDA further indicated that its "ability to complete [its] review within six months is critically dependent on the quality of your application." Id. The agency further indicated that "[i]n order for us to complete our review of your [New Drug Application] in a timely fashion, we request that you submit each module as you complete it." Id. Finally, the agency indicated that, "[a]t the time the last module of the [New Drug Application] is received, the decision will be made regarding a priority review, and the review clock will start." Id.

         In the aftermath of that meeting, Boehringer submitted portions of its applications on a rolling basis throughout the Fall of 2009, as agreed, with the first submission on September 17, AR 5645-46; the second and third submissions on September 30, AR 5682-83, 5685-86; the fourth submission on October 13, AR 5699-5700; the fifth on October 27, AR 5705-06; the sixth on November 4 and November 9, AR 5707-08[6], 5711-12; the seventh on November 13, AR 5716-17; the ninth on November 30, AR 5735-46; and the tenth on December 8, AR 5752-53. On December 15, 2009, Boehringer submitted its eleventh submission. AR 5770. In the letter accompanying the eleventh submission, Boehringer represented that "[t]his submission provides the final documents to complete the original new drug application for dabigatran etexilate (NDA 22-512) for the prevention of stroke and systemic embolism in patients with atrial fibrillation." AR 5769. Through that letter, Boehringer also requested priority designation for its application. Id. On January 5, 2010, the FDA sent Boehringer a letter in response, acknowledging that it had received the application denominated as NDA 22-512 on December 15, 2009, and that the application was dated December 15, 2009.[7] AR 5794-96. That letter noted that, "[u]nless we notify you within 60 days of the receipt date that the application is not sufficiently complete to permit a substantive review, we will file the application on February 13, 2010 in accordance with 21 CFR 314.101(a)."[8] AR 5694.

         On February 12, 2010, the agency sent Boehringer a follow-up letter stating that, "[a]fter a preliminary review, we find that your application is not sufficiently complete to permit a substantive review." AR 5961 (emphasis added). Therefore, the agency refused to file the application. Id. (citing 21 C.F.R. 314.101(d)). The agency explained why it deemed the application insufficient as follows:

In support of the proposed indication, you conducted a single phase 3 trial titled "Randomized Evaluation of Long term anticoagulant therapy comparing the efficacy and safety of two blinded doses of dabigatran etexilate with open label warfarin for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: prospective, multi-centre, parallel-group, non-inferiority trial (RE-LY) . " The primary objective of RE-LY was to demonstrate the efficacy and safety of dabigatran etexilate in subjects with non-valvular atrial fibrillation for the prevention of stroke and systemic embolism.
We note that you claim an overall data error rate of 0.1% or less for primary outcome data and 0.25% or less for all other data. However, we found data errors in five out of six subjects in our initial analysis of your INR.xpt data. These errors are described in Tables 1 and 2. These errors include transcription errors, transposition errors, and auditing errors.
[Data tables omitted]
We note that you closed site 6; therefore, we do not comment on problems evident in the data from that site.
We recognize that that there may be occasional inaccuracies in a large trial database; however, the frequency of errors in the data sets impedes our ability to perform an adequate review, and undermines our confidence in your data.
In recognition of the importance of this priority application, we proposed a rolling review. We will, of course, continue our review of parts of your application that are complete and reviewable, such as the chemistry and pharmacology toxicology sections. In addition, the clinical reviewers will work with you to evaluate further data integrity issues and to provide comment on your plans to respond to these issues. Please note that the above comments are only a partial listing of deficiencies, and that there may be additional deficiencies with your submission that are not included in this letter.

AR 5961-62. The letter also noted that the agency would refund 75% of the total user fee associated with the application. AR 5962. Finally, the letter informed Boehringer of its ability to seek review of the agency's "refusal to file" decision. Id.

         After the "refusal to file" decision, Boehringer and the FDA continued to exchange emails regarding the materials that had already been submitted. AR 5970-71, 5982-83. In addition, agency representatives met with Boehringer representatives regarding steps for moving forward on February 18, 2010. AR 5984-86. The internal meeting notes from that meeting summarized the shortcomings with Boehringer's application as follows:

Preliminary review revealed a number of errors in the blood transfusion dataset and the INR dataset. These errors included transcription errors, transposition errors, and auditing errors. Though the Agency recognizes that that there will be some errors in the datasets of large trials, the errors found by relatively unsophisticated means in clinically important datasets during preliminary review called into question the overall quality of those datasets.

AR 5985 (emphasis added). The agency and company representatives discussed the issues with the data and the other materials submitted and set out a roadmap to resolve those issues. AR 5985-5986. Boehringer did not seek to have the agency file its December 15, 2009, application over protest. See 21 C.F.R. § 314.101(a)(3) ("If, following the informal conference, the applicant requests that FDA file the application (with or without amendments to correct the deficiencies), the agency will file the application over protest …, notify the applicant in writing, and review it as filed."). Accordingly, Boehringer accepted the refund of 75% of the filing fees that it had paid for the earlier filings. See AR 5624-5632, 5962.

         Following the February, 2010, meeting between Boehringer and the agency, Boehringer provided additional materials on February 19, 2010, which had been requested by the agency. AR 5988-90 ("Reference is made to the communication from the Division to the Sponsor on February 16, 2010 requesting the 85 case report forms (CRFs) from RE-LY that have been identified in review of the transfusion page … . This submission provides the 7 additional [case report forms] that have not been previously submitted."). That same day, by a separate submission, Boehringer provided additional information that responded to the agency's request for information in light of the deficiencies in the materials previously submitted. AR 5998-6000 ("Reference is made to the communication from the Division to the Sponsor on February 16, 2010 requesting documentation on what would trigger the investigator to complete the RE-LY [case report form] 122. The medical reviewer has requested details surrounding what the investigators were told and how they were told to fill this out. Additionally, it was requested that this documentation be provided for all the outcome events."). One week later, on February 26, 2010, Boehringer provided additional materials again responding to deficiencies in its earlier submissions. AR 5998-99 ("Reference is made to the February 23, 2010 telephone conversation from Sharon Gershon (Division of Scientific Investigations) identifying Site 0006 - Patrick Simpson, M.D. and Site 0351 - Initially Melvin Tonkon, M.D. replaced by Charles Morcos, M.D. ...

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