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1 ZUCKERMAN SPAEDER 1900 M STREET, NW SUITE 1000 WASHINGTON, DC fax Kate C. Beardsley Partner (202) kbeardsley@zuckerman.com Division of Dockets Management Food and Drug Administration Department of Health and Human Services 5630 Fishers Lane Room 1061 Rockville, MD =) - TN) Re: Petition of Upsher-Smith Laboratories, Inc. Requesting that FDA Refrain Him Approving any Extended-release Topiramate Drug without Adequate and Well- Controlled, Safety and Efficacy Data on the Applicant's Formulation The undersigned submits this petition under 505 of the Food, Drug, and Cosmetic Act and 21 CFR requesting that FDA refrain from approving any application for extendedrelease topiramate that does not include suitable efficacy data on the applicant's formulation. ACTION REQUESTED Two applicants are known to be submitting NDAs for extended-release formulations of topiramate. One, Upsher-Smith Laboratories, Inc. (USL), is presently conducting an efficacy study of its formulation at the direction of FDA. The other, Supernus Pharmaceuticals, Inc. (Supernus), appears to have submitted its NDA without randomized, controlled studies demonstrating efficacy of its product. Rather, it has apparently submitted its application with only reports of studies on bioavailability and bioequivalence. It would be inequitable and inconsistent with FDA's policy to approve Supernus' NDA on the basis of only biostudies, especially when USL has been directed to conduct an adequate and well-controlled clinical study to demonstrate the safety and efficacy of its extended-release formulation. This petition therefore requests that FDA refrain from approving any application for extended-release topiramate, regardless of the indication, that does not include such a safety and efficacy study. D1)-(c790//./0, o 93/ op

2 pra ZUCKERMAN SPAEDER LLP Page 2 A. Factual Background 1. Topamax STATEMENT OF GROUNDS In December 1996, Ortho-McNeil-Janssen obtained approval of NDA for Topamax (topiramate) Tablets in multiple strengths, and, in 1998, obtained approval of NDA for Topamax Sprinlde, a capsule formulation of Topamax. Both formulations are immediate-release formulations, and there are currently no approved extended-release formulations of topiramate. Topamax is indicated for adjunctive therapy for adult and pediatric patients with partial onset seizures or primary generalized tonicclonic seizures, as adjunctive therapy for patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome, as initial monotherapy for patients 2 years of age or older with partial onset or primary generalized tonic-clonic seizures, and as therapy for prophylaxis of migraine headache for adult patients. The recommended adult dose of Topamax for epilepsy is mg/day in two divided doses. 2. USL's Extended-release Topiramate USL in recent years undertook the development of an extended-release formulation of topiramate. The USL product was developed for a once-daily dosing regimen. After spending significant time and resources developing the formulation and conducting preliminary testing, the company submitted an IND to FDA. USL hoped to obtain approval on the basis of pharmacokinetic studies, and proposed an approval pathway consisting largely of such studies. FDA did not agree to the proposed pathway. FDA informed USL that a clinical efficacy study would be needed unless USL could present a "compelling argument" that the relationship between the drug's pharmacokinetic and pharmacodynamic profiles was sufficiently well understood to justify approval based on pharmacokinetic equivalence. USL responded to FDA's request, and marshaled what it believed to be all available evidence that bioavailability and bioequivalence information alone could support approval of an extended-release topiramate. USL submitted the information to FDA, proposing to meet and discuss the scientific merits of a bioavailability/ bioequivalence approach with inclusion of information related to a pharmacokinetic/ pharmacodynamic relationship.

3 ZUCKERMAN SPAEDER LLP Page 3 FDA nonetheless rejected USL's rationale and affirmed that "a clinical efficacy trial is necessary," noting that FDA generally has "required such trials in all recent applications like this," and that the decision was based on the lack of "adequate proof that [ER topiramate] will have the same efficacy as the immediate release formulation." The Division noted that the mechanism of action for some antiepileptic drugs remains theoretical, and that there is not enough well-documented comparative data between various immediate-release and extended-release anticonvulsant formulations to generalize from one chemical entity to another. Therefore, USL subsequently designed and submitted a protocol for a randomized, placebo-controlled safety and efficacy study of its extended-release formulation. FDA reviewed the protocol and approved a Special Protocol Assessment. USL is still conducting the worldwide study, which involves approximately 300 subjects at greater than 70 sites, and it is expected that the full cost of development will exceed $75 million. Assuming positive results, USL intends to submit a 505(b)(2) application when the study is concluded. 3. Supernus' Extended-release Topiramate Supernus has also been developing an extended-release formulation of topiramate. In December 2010, Supernus filed a Form S-1 with the Securities and Exchange Commission, in which the company stated its intention to submit an NDA for extendedrelease topiramate. 1 On February 8, 2011, Supernus filed with the SEC an amended S-1, in which it stated that it had submitted a 505(b)(2) NDA in January 2011 for an extendedrelease topiramate drug product.2 In the S-1, Supernus stated that it had conducted ten clinical studies of its formulation, including bioequivalence studies. Supernus explained that its studies were "designed to select the best extended-release once-per-day formulation that delivers equivalent levels of topiramate compared to the immediate-release twice-per-day Topamax product, as well as to test the robustness and consistency of our technology in delivering the once-per-day formulation". 3 Supernus offered no details about its studies in its Form S-1. 1 Securities and Exchange Commission Form S-1, Supernus Pharmaceuticals, Inc. (December 23, 2010), P. 83 ("Supernus S-1). The relevant pages of the S-1 are attached at Tab 1. 2 Securities and Exchange Commission Form S-1, Pre-Effective Amendment No. 1 (February 8, 2011, pp. 2, 90). The relevant pages of the Form S-1 are attached at Tab 2. 3 Supernus S-1 at 83.

4 ZUCKERMAN SPAEDER LLP Page 4 More recently, Supernus presented information regarding its extended-release topiramate at the American Epilepsy Society (AES) Annual Meeting December 2-6, In both printed documents and a display at the Medical Affairs section of its corporate booth, Supernus reported that a New Drug Application (NDA) was "filed" for SPN-538 (extended-release topiramate) in The written statements were made on pages 3 and 6 of a brochure4 that was distributed at the AES meeting and appears to be dated August 11, 2011 on the last page. The statement regarding submission of a NDA in the February amendment to the S-1 has now been stated a second time by Supernus. In addition, as observed on December 27, 2011, a Supernus webpage entitled "Product Pipeline" ( indicates a status of "NDA" for its SPN-538 extended-release topiramate product. USL, despite diligent effort, has been unable to find any Supernus announcement or publication of the results of any adequate and well-controlled safety and efficacy studies. For example, there appear to be no entries on ClinicalTrials.gov suggesting that Supernus has initiated or conducted such an adequate and well-controlled safety and efficacy study. With respect to its development of an extended-release topiramate, Supernus has registered two studies on ClinicalTrials.gov. The first study, NCT , is entitled A Conversion Study of Immediate Release (IR) and Modified Release (MR) Forms of Topiramate (TPM). The primary endpoint identified by Supernus is the relative bioavailability at steady-state of topiramate modified release (MR) and topiramate immediate release (IR), as determined by topiramate levels in plasma after two weeks of drug. The secondary endpoint is also relative bioavailability, measured immediately following switch to the topiramate MR product. Overall, this study consists of a twoweek measurement of plasma concentrations while the subject is taking IR topiramate. The subject is then switched to an equal dose of Supernus' MR topiramate for two weeks with measurement of plasma concentrations. This study was not designed to measure safety and efficacy and does not meet the definition of an adequate and well-controlled study to demonstrate the safety and efficacy of an anti-epileptic drug as discussed above. Although this study was conducted in patients having epilepsy, the study was not designed to demonstrate reduction in seizure activity. The status of the study on ClinicalTrials.gov was changed to "completed" on June 6, Brochure entitled "Supernus XR Technologies Releasing More than Just Medicine" (August 11, 2011). Attached at Tab 3.

5 F ra ZUCKERMAN SPAEDER LLP Page 5 The second study, NCT , is entitled Evaluation of the Pharmacokinetics, Safety and Tolerability of TPM XR as Adjunctive Therapy in Pediatric Subjects with Epilepsy. The primary endpoint identified by Supernus is the steady-state pharmacokinetics of extended-release topiramate, and the study also assesses the safety and tolerability relating to repeated oral dosing. This study does not identify a baseline period, but it does identify the duration of dosing as days. This study was not designed to measure safety and efficacy, and does not meet the definition of an adequate and well-controlled study to demonstrate the safety and efficacy of an anti-epileptic drug as discussed above. Although this study is being conducted in pediatric patients having epilepsy, the study was not designed to demonstrate reduction in seizure activity. USL does not know whether Supernus reached agreement with FDA regarding the content of its NDA prior to submitting the NDA, or whether FDA has in fact filed the NDA that was reportedly submitted. Given FDA's policy that an adequate and wellcontrolled safety and efficacy study is needed to support an extended-release formulation of an antiepileptic drug, it seems unlikely that FDA has either agreed to a Supernus development program that includes only bioequivalence or bioavailability studies, or that it has filed the Supernus NDA. Nevertheless, USL is submitting this petition to ensure that no inequity occurs. B. Approving an Application for an Extended-release Version of Topiramate Without an Adequate and Well-controlled Safety and Efficacy Study Would Result in Disparate and Inconsistent Treatment of Similarly Situated Parties Both USL and Supernus have been developing an extended-release version of Topiramate. It is expected that both applications will be handled by the same Division at CDER. While there may be some differences in the extended-release technology used in manufacturing the two drugs, the same standards of proof of safety and efficacy should be required. To do otherwise would be unfair to USL, which has incurred significant expense in reliance on FDA's direction that an adequate and well-controlled safety and efficacy study is required. This matter is not just one of equity, but also of law. Any agency policy that results in disparate treatment of similarly situated person is likely to be invalid as arbitrary and capricious. This basic principle of administrative law has been applied to many federal agencies. In the FDA context, there are cases enunciating the principle from

6 ZUCKERMAN SPAEDER LLP Page to One such case in the drug and device context is Bracco Diagnostics v. Shalala,6 in which applicants for approval of competing contrast agents sought to prevent FDA from treating some contrast agents as devices and others as drugs. There, the court concluded that FDA was not free to treat the two sets of products dissimilarly "and to permit two sets of similar products to run down two separate tracks, one more treacherous than the other, for no apparent reason." That principle applies here as well. It would be unacceptable to permit the USL and Supernus applications to run down two separate tracks for approval, one requiring adequate and well-controlled safety and efficacy studies, and the other having no such requirement, when there is no apparent material difference in the proposed products that would justify the disparate treatment. As stated in Bracco, "The disparate treatment of functionally indistinguishable products is the essence of the meaning of arbitrary and capricious."' Further, to avoid disparate treatment, the studies conducted by any applicant should include an adequate and well-controlled study to demonstrate safety and efficacy. A suitable study should be a randomized, double-blind study comparing the proposed extended-release formulation to placebo in subjects with the disease to be treated, and include a standard eight-week baseline period and at least eleven to twelve weeks of administration of the drug. Because there is no accepted surrogate endpoint for measuring seizure activity, the only acceptable endpoint is a reduction in seizures. These criteria match widely accepted safety and efficacy protocols conducted for approval of antiepileptic drugs. C. FDA's Policy and Precedent Requires a Suitable Efficacy Study for an Extended-release Version of an Immediate-release Anti-Epileptic Drug Willapoint Oysters v. Ewing, 174 F.2d 676,697 (9thCir. 1949)(striking down an FDA labeling regulation that required Western oyster canners to label their product specifically, while allowing Eastern and Southern canners to label their nearly identical product generically; Independent Turtle Farmers of Louisiana, Inc. v. United States,703 F. Supp. 2d 604, 607 (W.D. La. 2010) (citing United States v. Diapulse Corp. of Am.,748 F.2d 56, 62 (2d Cir. 1984)("[W]e must insist that the FDA apply its scientific conclusions evenhandedly and that it not `gyant to one person the right to do that which it denies to another similarly situated'... Deference to administrative discretion or expertise is not a license to a regulatory agency to treat like cases differently.") F. Supp. 20, (D.D.C. 1997) 7 Id at 28, citing Independent Petroleum Assoc. of America v. Babbitt, 92 F.3d 1248, 1260 (D.C. Cir. 1996).

7 ZUCKERMAN SPAEDER LLP Page 7 USL is aware of two relatively recent approvals of extended-release versions of anti-epileptic drugs the 2007 approval of UCB's Keppra (levetiracetam) XR in 2007 (NDA ) and the approval of GlaxoSmithKline's Lamictal (lamotrigine) XR in 2009 (NDA ). Both of those approvals relied on clinical effectiveness data submitted in the application. On April 25, 2011, FDA approved a separate indication for Lamictal XR, also on the basis of an efficacy study. Prior to that approval, FDA convened an advisory committee meeting in March 2011 to consider the study design and results of the safety and efficacy study supporting the application for a new indication for Lamictal XR. During the meeting, Dr. Russell Katz, director of CDER's Division of Neurology Products, publicly confirmed that it is the Division's policy to require at least one controlled trial demonstrating the effectiveness of a controlled release preparation when an immediate-release preparation is already approved for the same indication. 8 Dr. Katz explained that the Division requires such a study even when the total exposure [AUC] for the two products may be essentially identical "because we are not certain whether any particular pattern of absorption is critical to effectiveness."9 As noted above, this is precisely the reason that Dr. Katz gave USL when he conveyed the agency's policy and explained that the company needed to conduct an effectiveness study to obtain approval of its extended-release topiramate product. In the 1990s, FDA apparently had a slightly different policy, although not one that would affect the outcome here. In 1996, FDA approved Ciba Geigy's application for an extended-release version of Tegretol based on biostudies in addition to an animal study, and, in 1997, FDA approved Abbott's NDA for an extended-release version of Depakote based on biostudies. These approvals appear to have been based on a policy that FDA would approve extended-release versions of previously approved immediate-release drugs formulation on the basis of biostudies for products with well-established efficacy and safety profiles. 1 In both cases, the approvals for the immediate-release version of the drug were held by the same company and both products had been marketed in immediaterelease formulations for some time. Even if this policy were still in place, which is doubtful based on the standards set for the Keppra XR and Lamictal XR approvals, 8 Lamictal XR (lamotrigine) Extended-Release Tablets Background Package, Peripheral and Central Nervous System Drugs Advisory Committee Meeting, March 10, 2011 at 2. The package is attached at Tab 3; see Meeting Transcript at 23. Dr. Katz also made the same statement at the Antiepileptic Drug Trials X Meeting in Lamictal XR Background Package at 2. 1 See letter from Abbott submitting its New Drug Application in Approval Package for NDA The letter is attached at Tab 4.

8 F ri ZUCKERMAN SPAEDER LLP Page 8 Supernus has no approval for an immediate-release version of topiramate and no history of marketing a topiramate product. In short, FDA's policy and practice in this situation appear to be very clear, and FDA has expressed its policy recently approximately eight months ago. Agencies are, of course permitted to depart from prior policy, but an agency may not depart from a prior policy "sub silentio." In this case, USL is not aware that FDA has announced any change in policy. If the agency were to depart from its previous policy, the agency would have to show that there are good reasons for the new policy, particularly when its prior policy has "engendered serious reliance interests that must be taken into account." 12 USL has relied on FDA's expressed policy, and is conducting a development and clinical program for its extended-release formulation that is expected to cost some $ million or more by the time it is completed. Further, USL is not aware of any reason why the Division would depart from its previous policy. USL keeps abreast of developments in anti-epileptic medicine and believes that it is aware of all relevant literature. USL is not aware of any new scientific finding that would justify a departure from FDA's policy. It is as true today as it was two years ago that, as Dr. Katz explained as recently as March of this year, variations in a drug's rate of absorption could affect its clinical profile. D. Conclusion For all of these reasons, FDA should not ignore its publicly stated policy and approve an extended-release topiramate drug without requiring a suitable adequate and well-controlled clinical study of the formulation's safety and efficacy. ENVIRONMENTAL IMPACT USL claims a categorical exclusion under 21 C.F.R (a) because the grant of this petition would have no effect on the environment. 11 United States v. Nixon,418 U.S. 1800, 1811 (2009). 12 FCC v. Fox Television Stations, 735, 742 (1996). 683, 696 (1974), referenced in FCC v. Inc.,129 U.S. at 1811, citing Smiley v. Fox Television Stations, Inc.,129 S. Ct. Citibank (South Dakota),N.A., 517 U.S.

9 ra ZUCKERMAN SPAEDER LLP F Page 9 ECONOMIC IMPACT Information on the economic impact of the action requested by this petition will be submitted if requested by the Commissioner. CERTIFICATION The undersigned certify that, to the best of their knowledge and belief, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner that are unfavorable to the petition. I certify that, to the best of my knowledge and belief: (a) this petition includes all information and views upon which the petition relies; (b) this petition includes representative data and/or information known to the petitioner which are unfavorable to the petition; and (c) I have taken reasonable steps to ensure that any representative data and/or information which are unfavorable to the petition were disclosed to me. I further certify that the information upon which I have based the action requested herein first became known to the party on whose behalf this petition is submitted on or about the following date: January 11, 2011 and December 2-6, If I received or expect to receive payments, including cash and other forms of consideration, to file this information or its contents, I received or expect to receive those payments from the following persons or organizations: Upsher-Smith Laboratories, Inc. I verify under penalty of perjury that the foregoing is true and correct as of the date of the submission of this petition. Sincerely, 44-e- Sp:I-Axle Kate C. Beardsley cc: Jack A. Khattan President and Chief Executive Officer