DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockville, MD 20857
`
`w~ ©rEo w ~1M'
`!till OCT 0 4 2006 w
`
`By
`
`Biogen Idee, Inc.
`Attention: Nadine D. Cohen, Ph.D.
`Senior Vice President, Regulatory Affairs
`14 Cambridge Center
`Cambridge, MA 02142
`
`Dear Dr. Cohen:
`
`Please refer to your Investigational New Drug Application (IND) file for BG00012.
`
`We also refer to the End of Phase 2 meeting between representatives of your firm and the FDA
`on August 30, 2006. The purpose of the meeting was to discuss the continued development of
`BG00012.
`
`The official minutes of that meeting are enclosed. You are responsible for notifying us of any
`significant differences in understanding regarding the meeting outcomes.
`
`If you have any questions, call James H. Reese, Ph.D., Regulatory Project Manager, at
`(301) 796-1136.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Russell Katz, M.D.
`Director
`Division of Neurology Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Enclosure
`
`Page 1 of7
`
`Biogen Exhibit 2297
`Coalition v. Biogen
`IPR2015-01993
`
`

`
`MEMORANDUM OF MEETING MINUTES
`
`MEETING DATE:
`
`August 30, 2006
`
`TIME:
`
`3:00 - 4:30 PM
`
`LOCATION:
`
`White Oak, Building 22, Rm. 1309
`
`APPLICATION:
`
`PIND 73,061, BG00012
`
`TYPE OF MEETING:
`
`B: End of Phase 2
`
`MEETING CHAIR:
`
`Dr. Russell Katz
`
`FDA Attendees
`Russell Katz
`Kun Jin
`Eric Bastings
`Janeth Rouzer-Kammeyer
`Paul Roney
`Ta-Chen Wu
`James Reese
`
`Biogen Idee Attendees
`Nadine Cohen
`Tammy Samelli
`Katherine Dawson
`Michael Panzara
`Frances Lynn
`Lisa Beebe
`Chris TenHoor
`Khandan Baradaran
`Sophia Lee
`Minhua Yang
`Janet Clarke
`Ratna Lingamaneni
`Jason Brauner
`Carmen Bozic
`KahLay Goh
`
`The questions discussed below were submitted as part of the EoP2 package dated July 24, 2006.
`The Sponsor's questions are presented below in italics, followed by the preliminary FDA
`response (conveyed to the sponsor by e-mail just prior to the meeting), and then a summary of
`the discussion from the meeting.
`
`Page 1
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`Page 2 of 7
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`

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`Pharmacology/toxicology:
`
`I) Does the Agency concur that the preclinical plan is sufficient to support Phase 3 clinical
`studies and registration ofBG00012 (Section 5)?
`
`FDA Response:
`With the following exception, your nonclinical program appears to be acceptable for supporting
`Phase 3 clinical studies and registration ofBG00012:
`In Table 5-2 on page 34 of the briefing package, you state that the Pre- and Post-Natal
`Development Toxicity Study will be conducted using rabbits. We recommend that this study be
`conducted using rats.
`
`Meeting Discussion
`The Sponsor asked if they could begin their Phase 3 clinical trial prior to submitting the 12
`month repeat dose toxicity study in monkeys. The monkey study will be submitted within three
`months of the initiation of the clinical trial. The Sponsor has already submitted a nine month
`repeat dose toxicity study in dogs.
`The Division stated that this approach is acceptable.
`
`Clinical pharmacology:
`
`2) Does the Agency concur that the clinical pharmacology plan is sufficient to support Phase 3
`clinical studies and registration of BG00012 (Section 6)?
`
`FDA Response:
`1. We recommend that you conduct additional screening for drug interaction potential involving
`CYP2C8 or P-glycoprotein inhibition by BG00012. Though not a prerequisite before the
`initiation of Phase 3 clinical trials, you should consider conducting studies or providing
`justifications for not conducting such investigation to eventually support an NDA
`application.
`
`2. Your proposal for PK studies in subjects with hepatic or renal impairment seems reasonable.
`However, we recommend that you initiate the planned human mass-balance study at an
`earliest time, so that the results obtained will not only help in assessing the need for studies in
`patients with hepatic or renal impairment, but will also help guide the proper design for such
`studies.
`
`3. You should provide more details of the enteric coated (MR) formulation and the rationale for
`enteric coating. If dose-dumping (or degradation in acidic pH) is a likely concern, then we
`recommend that you investigate the potential dose-dumping effect as a result of interaction
`between the MR formulations and alcohol. This should be discussed in the future with the
`Agency.
`
`4. We also recommend you include a population PK program and collect sparse samples (in
`proposed Phase 3 trials) that may help detect the potential drug-drug interaction with
`concomitant medications and/or other factors, e.g., body weight, age, etc, that contribute to
`the variability. This will also help explore the exposure-response relationships for efficacy
`and safety, which is an important aspect of development program. Please be aware that it
`will be important to have adequate support for safety and efficacy across the range of patients
`
`Page 2
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`Page 3 of 7
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`

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`who would be in the indicated population (e.g., the range in body weight). We will be happy
`to review the protocol when submitted.
`
`Clinical:
`
`3) Are the Phase 3 study designs appropriate to support registration of BGOOO 12 in relapsing
`forms ofMS? (Section I)? Specifically:
`
`a. Is the patient population described in the clinical development plan appropriate? (Section
`8.2)?
`
`FDA response:
`You are excluding patients with progressive-relapsing MS, yet your indication is for "relapsing
`forms ofMS". The indication for the population as defined in the study protocols would likely be
`"relapsing-remitting MS".
`
`Meeting Discussion
`The sponsor stated that he is excluding patients with slow progressive MS and that historically,
`patients with a substantial number of relapses would be included. FDA stated that excluding
`people with secondary progressive (non relapsing) MS is acceptable, but that the definition of
`"relapsing forms ofMS" includes progressive-relapsing.
`
`b. Does the Agency concur that the primary endpoint of proportion relapsing is appropriate to
`.
`support registration? (Section 8.6)?
`
`FDA response:
`According to your proposed analysis plan, your endpoint is actually time to first relapse (survival
`curve distribution). That endpoint will not give adequate information regarding the maintenance
`of efficacy in the second year of treatment. You should instead analyze an endpoint that will not
`be sensitive to only shifting the time of occurrence of relapses (e.g., the proportion of patients
`relapsing or relapse-free). You should also carefully design your studies to address the issue of
`maintenance of efficacy in the second year (see also below).
`
`Meeting Discussion
`These are actually two separate issues.
`1. The proportion of patients who are relapse free is an acceptable endpoint. However, the time
`to event is problematic. Your approach to imputation should be explained.
`2. You should provide sufficient data to support chronic treatment in MS. We will need to see
`consistent efficacy for two years. Your design gives little data for year two in the case of an
`early dropout. Your expected dropout rate of 25% makes this a problem. The Agency is
`open to other designs intended to provide more data from the second year. An interim
`analysis at 18 months may not be needed.
`
`c. Is the selection of dose appropriate for the Phase 3 studies? (Section 8. 4)?
`
`FDA response:
`We agree that tolerability issues appear to limit the maximum dose to be tested to 240 mg t.i.d.
`You should however consider testing intermediate doses in the Phase 3 study, e.g. 240 mg b.i.d.
`
`Page 3
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`or 120 mg t.i.d .. Such a dose might improve patient compliance and/or minimize dropouts from
`adverse effects during the study.
`
`We note that you hypothesize that BG00012 at 240mg t.i.d. might develop the efficacy effect
`over a period of several months, and that your phase 2 study was limited to 6 months of
`assessment. You have no data that a dose less than 240 mg t.i.d. might provide equivalent
`efficacy in the longer period (i.e., longer than 6 months) and have lesser adverse effects. For a
`chronic disease such as MS, the longer term efficacy is more important than small differences in
`the rapidity of effect.
`
`In addition, if the lower dose was observed to be less efficacious in an adequate and well
`controlled study, this evidence of dose superiority could strengthen the totality of evidence
`supporting marketing of your product.
`
`Meeting Discussion
`Biogen Idee indicated that the 240 mg t.i.d. group has shown continued efficacy, and proposed
`that dose as the best choice.
`
`d. Does the Agency concur that if a superiority analysis of the primary endpoint at the specified
`alpha level after an average of 18 months and after all subjects have had a minimum of I year of
`treatment demonstrates statistical significance, then the blinded portion of the Phase 3 trials
`could be terminated and these data would be sufficient to file the NDA (Section 8.5)?
`
`FDA response:
`No. Considering the potentially large number of patient dropouts or early escapes, it is difficult
`to predict how many patients will have data approaching 2 years of treatment if the studies, as
`currently proposed, were carried out without eady termination. In the event of early termination
`as proposed, it is likely that a very limited number of patients would reach that 2 year timepoint.
`You may have only a fraction of patients left to analyze sustained efficacy and safety during the
`second year of treatment, in particular in the last 6 months. Early termination of the trial may
`provide inadequate evidence of efficacy during the second year.
`
`As discussed above, we are concerned about having insufficient information on the maintenance
`of efficacy in the second year of treatment. This concern applies to the studies as proposed, with
`or without early termination. It will be necessary for you to supply adequate evidence of
`efficacy during the second year of treatment. We are also interested in getting sufficient 2-year
`safety data, to adequately assess the risk of delayed infectious, neoplastic, and cardiac adverse
`events.
`
`We are also concerned about your plan to offer a switch to open-label study drug for patients
`who have a relapse during the study. Given the intended therapeutic equipoise, the drug proposed
`for patients relapsing during the study should be one of the approved MS drugs, and not your
`investigational drug, for which efficacy and safety have not been established.
`
`In order to improve the retention of patients in the trial and maintenance of study treatment, we
`suggest that you modify your proposed active comparator study by transforming it into an add-on
`trial, where a combination of your study drug and copaxone could be compared to copaxone and
`placebo. This trial design may have improved likelihood to provide adequate second year safety
`and efficacy data.
`
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`Page 5 of 7
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`e. Assuming the Phase 3 trials terminate at I 8 months, does the Agency concur that the overall
`patient safety database is adequate for registration? (Section 8. 7)?
`
`FDA response:
`No. We are concerned that the safety database will be inadequate due to expected dropout of
`patients due to relapse or adverse events. As discussed above, we are concerned about obtaining
`sufficient long-term safety data in the second year of treatment, to obtain adequate information
`on possible delayed infectious and neoplastic toxicities, and have an adequate assessment of the
`cardiac risk in the MS population.
`
`4) Is the overall clinical development plan for BGOOOI 2 adequate to support registration of
`BGOOOJ2for relapsingforms ofMS? (Section 8)?
`
`FDA response:
`See above.
`
`5) Does the Agency concur that a pediatric waiver is appropriate for BGOOOJ 2? (Section 8.8)?
`
`FDA response:
`Yes.
`
`Page 5
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`Page 6 of 7
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`

`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/s/
`
`Russell Katz
`9/29/2006 08:48:58 AM
`
`Page 7 of 7