Late Cycle Meeting Summary, January 16, 2014 - Ruconest

Application type and number:           STN BL 125495/0
Product name:                                   C1 Esterase Inhibitor (Recombinant)
Applicant:                                           Pharming Group, NV
Meeting category:                             Late-Cycle Meeting (LCM)
Meeting date & time:                       January 16, 2014, 2:30 p.m. to 3 p.m.
Meeting format:                               Face to Face
Meeting Chair/Leader:                     Howard Chazin, MD
Meeting Recorder:                            Nannette Cagungun

LCM package sent:                           January 3, 2014

FDA Participants:
 Abdu Alayash, PhD, Chief, Laboratory of Biochemistry and Vascular Biology, Division of Hematology, OBRR
 Jin Baek, PhD, Visiting Associate, Laboratory of Biochemistry and Vascular Biology, Division of Hematology, OBRR
 Nannette Cagungun, MS, PD, RAC, Regulatory Project Manager, Division of Blood Applications, OBRR
 Howard Chazin, MD, MBA, Deputy Director for Medical Affairs, Division of Hematology, OBRR 
 Alfred Del-Grosso, PhD, Team Lead,  Laboratory of Analytical Chemistry and Blood Related Products, Division of Biological Standards and Quality Control, OCBQ
 John Dennis, DVM, Director, Division of Veterinary Services, OM
 John Eltermann, RPh, MS, Director, Division of Manufacturing and Product Quality, OCBQ
 Mahmood Farshid, PhD, Deputy Director for CMC Policy and Review, Division of Hematology,  OBRR
 Basil Golding, MD, Director, Division of Hematology, OBRR
 Anthony Hawkins, MS, Consumer Safety Officer, Division of Inspections and Surveillance, OCBQ
 Wayne Hicks, PhD, Chemist, Laboratory of Biochemistry and Vascular Biology, Division of Hematology, OBRR
 Patricia Holobaugh, Chief, Bioresearch Monitoring Branch, Division of Inspections and Surveillance, OCBQ 
 Wei Hua, MD, PhD, MS, MHS, Acting Deputy Director, Division of Epidemiology, OBE
 Nisha Jain, MD, Chief, Clinical Review Branch, Division of Hematology, OBRR
 Elena Karnaukhova, PhD, Staff Scientist, Laboratory of Biochemistry and Vascular Biology, Division of Hematology, OBRR

Mark Levi, PhD, Interdisciplinary Scientist, Laboratory of Analytical Chemistry and Blood Related Products, Division of Biological Standards and Quality Control, OCBQ
 Yuqun Abigail Luo, PhD, Statistician, Therapeutics Evaluation Branch, OBE 
 Iftekhar Mahmood, PhD, Clinical Pharmacologist, Division of Hematology, OBRR
 Dominador Manalo, PhD, Staff Fellow, Laboratory of Biochemistry and Vascular Biology, Division of Hematology, OBRR
 Charles Maplethorpe, MD, PhD, Medical Officer, Clinical Review Branch, Division of Hematology, OBRR
 Thomas Maruna, MLS(ASCP), Regulatory Project Manager, Division of Blood Applications, OBRR
 Ginette Y. Michaud, MD, Deputy Director, OBRR
 Paul D. Mintz, MD, Deputy Director for Medical Affairs, Division of Hematology, OBRR
 Todd Mollan, PhD, JD, Staff Fellow, Laboratory of Biochemistry and Vascular Biology, Division of Hematology, OBRR
 L. Ross Pierce, MD, Medical Officer, Clinical Review Branch, Division of Hematology, OBRR
 Laura Polakowski, MD, MSPH, Analytic Epidemiology Branch, Division of Epidemiology, OBE
 Catherine Poole, MS, Regulatory Coordinator, Division of Biological Standards and Quality Control, OCBQ
 Pratibha Rana, MS, Regulatory Project Management Branch, Division of Blood Applications, OBRR   
 John Scott, PhD, Deputy Director, Division of Biostatistics, OBE
 Nancy Waites, Consumer Safety Officer, Division of Manufacturing and Product Quality, OCBQ
 Boguang Zhen, PhD, Chief, Therapeutics Evaluation Branch, OBE

Contractor Participant:
 Christopher Sese, Independent Assessor, Eastern Research Group, Inc.

Pharming\Salix\Santarus Attendees:
 Enoch Bortey, VP, Clinical Operations and biostatistics – Salix Pharmaceuticals, Inc (Salix)
 Pam Golden, Executive Director, Nonclinical & Clinical Pharmacology– Salix
 Zohra Lomri, Director, Regulator – Salix
 Craig Paterson, Vice President, Medical & Clinical Development– Salix
 Bob Rolleri, Executive Director, Clinical Development– Salix
 Edwin van Amersfoort, Director, Regulatory & CMC – Pharming Group NV (Pharming)
 Anurag Relan, Medical Director – Pharming
 Bruno Giannetti, CEO – Pharming
 -------(b)(6)--------, Biostatistician – Consultant for Pharming
 Maria Bedoya-Toro, Vice President, Regulatory Affairs – Santarus, Inc, a wholly owned subsidiary of Salix Pharmaceuticals, Inc. (Santarus)
 Yun Hardiman, Biostatistician – Santarus
 Mark Totoritis, Senior Vice President, Clinical Research – Santarus

By phone:
 Bill Forbes, Executive Vice President, Medical, R&D & CDO – Salix
 Linda Young, Vice President, Regulatory – Salix
 Jody Lockhart, Associate Vice President, Pharma Development & Manufacturing – Salix
 Mike Williams, Executive Director, Manufacturing – Salix
 Adam Fowler – Santarus
 Grace Benedict – Santarus
 Jaco Koiter – Director, Manufacturing Development – Pharming
 Jos van der Lubbe – Sr. Director, Quality Assurance – Pharming
 Sander Mathot – Sr. Director, Supply Chain – Pharming

Background and Objectives: 
 FDA notified Pharming Group, NV on October 10, 2013, of the date for the late-cycle meeting.  The purpose of the meeting is to present substantive review issues and communicate our objectives for the review cycle of STN BL 125495/0 for C1 Esterase Inhibitor (Recombinant), which was submitted to FDA in April 2013 under the PDUFA V Program for the proposed indication of the treatment of acute attacks of hereditary angioedema in adult and adolescent patients.

FDA sent the Late-Cycle Meeting package to Pharming on January 3, 2014.  A few hours before the meeting, Pharming submitted slides that they planned to present at the meeting. 

Discussion:

FDA introduced the purpose of the meeting and proceeded to present the substantive CMC and clinical issues.

The BLA chairperson read the following CMC substantive review issue and made no further comment on the applicant’s presentation:

Chemistry, Manufacturing and Controls
 Section 5.3.1 that addresses the validation of the methods/assays for clinical studies is lacking a neutralizing assay for the rhC1INH, and is also lacking a method for the assay of rhC1INH antibodies that has been validated using a standard rhC1INH antibody with proven specificity to the recombinant form of the C1 esterase inhibitor.  In both cases Pharming uses antibodies that have been validated for C1INH and have been demonstrated to cross react with rhC1INH.  The antibodies used for validation are ----------------------------------------------------------(b)(4)-----------------------------------------------------------------------------------------.  This was previously the subject of an information request that was submitted on October 23, 2013, regarding validation report VAL-R-03-137.

Clinical
 The phase 3 study 1310 suggests a lack of efficacy in the primary endpoint of time to beginning of relief in the pre-specified subgroups of “US subjects” and “female subjects.”  FDA has communicated to you our concern over these study outcomes and reviewed your responses to these communications.  Your responses to our informational requests, including post hoc analyses have not alleviated our concerns regarding efficacy of rhC1INH in these subgroups.

Applicant’s Presentation
 Pharming provided their response to the substantive review issues with a slide presentation.

CMC Issues - Regarding the anti-rhC1INH neutralizing antibody assay, Pharming said assay development will be completed in January 2014 and assay validation has been initiated.  Analysis of samples from Study 1310 is planned in February-March 2014 and data will be available in March.  FDA said receipt of the amendment by February 16, 2014, would allow review of the information before the action due date.  Receipt of the data in March would be too close to the action due date.

Clinical Issues - Pharming reviewed information from the three studies (1310, 1205, and 1304), and additional summaries of rescue medication utilization.  Pharming said the FDA reviewers might have been confused by the use of medians in the representation of the data in the original submission; therefore, Pharming clarified the previously submitted data by presenting outcomes as relative risks utilizing point estimates and hazard ratios.  This “relative risk” format was used to present the efficacy results of the supportive studies 1205 and 1304, and the pivotal study 1310.  The results for the pre-specified subgroups “gender” and “geographic region” were also presented in the “relative risk” format.  Pharming said the point estimate of the treatment effect is consistent throughout favoring Ruconest regardless of gender and geography in the subgroup analyses.

FDA stated it could not comment on the slides given that these were provided to the Agency just a few hours before the meeting.  FDA asked for clarifications regarding the conduct and outcomes of the clinical trials.

Regarding time to beginning of relief, Pharming noted that overall, in all the studies and at all doses, all point estimates favor Ruconest.  Pharming said baseline imbalances may explain differences in magnitude of treatment effect (i.e., there were differences in how long subjects waited to present at the clinic).  Pharming said female subjects and U.S. subjects receiving placebo came in later in the course of the attack, and Pharming felt that this impacted the outcomes. 

Pharming said that the Ruconest treatment effect is greater for severe attacks (greater than 70 mm VAS) in both female subjects and U.S. subjects.  Pharming said U.S. subjects had less severe attacks than did subjects outside the U.S.

Pharming said, unlike other studies, Study 1310 allowed patients to be rescued.  Open-label product was given if a subject had a life-threatening condition or if after 4 hours, symptoms were not alleviated.  Pharming said, after rescue the median time to relief was approximately 50 minutes.  They found that most (5/6) of U.S. placebo subjects rescued were female and most (6/7) Rest of the World (ROW) placebo patients rescued were male.

After the slide presentation, FDA noted that any substantial data submitted in an amendment to the BLA at this point in the review cycle may extend the review clock beyond the April 2014 due date. 

FDA commented there did not seem to be a significant improvement in subjects because the confidence intervals did not exclude lack of effect for some subgroups.  FDA also pointed out the large placebo effect and that the p values were not statistically significant in many cases.  In addition, these analyses were done post hoc.  Pharming acknowledged that these are post hoc analyses.  They would like to understand the FDA-stated concerns about a lack of efficacy in female subjects in the U.S.; Pharming questioned whether this concern arose from their original presentation of the outcomes using medians.  FDA reviewed the data on its totality; concerns over the Study 1310 outcome in the U.S. and the female subjects were not based on any particular statistical analysis or summary.  FDA acknowledged that Study 1310 was not powered for the pre-specified subgroup analyses.  Pharming said that the placebo group in the U.S. responded quickly, and hence it was difficult to demonstrate efficacy of rhC1INH in the U.S.  FDA and Pharming reaffirmed that Study 1310 was the confirmatory study, and Studies 1205 and 1304 were supportive.  FDA did acknowledge that efficacy may be more easily demonstrated in the subgroup of patients with the higher baseline attack severity.

Pharming asked if there were other analyses that the FDA would like them to conduct.

FDA suggested some considerations to allow more efficient FDA review of the BLA, if Pharming were to submit another amendment.  Pharming did not need to resubmit information already submitted and reviewed.  Instead, they may provide a brief recapitulation and refer to information in the previous submissions.  Pharming may submit new information on the U.S. versus ROW subgroups without those on the female versus male subgroups, because the lack of efficacy for the U.S. subjects is of more concern to FDA and results in these two subgroups are confounded due to chance imbalance.  Pharming may submit information on the TEQ without those on the VAS, because these two PROs provide similar results for the U.S. subjects.

FDA asked how time of attack was recorded.  Pharming explained subjects were asked when the attacks began when they arrived at the study center.  Information was limited to subject recall. 

FDA asked why subjects came to the treatment centers so late.  Pharming said no one really came in late.  Some subjects had symptoms in multiple anatomic locations.  The protocol allowed enrollment of subjects with another anatomic location of symptom provided they presented within a 5-hour window. 

FDA asked if the analysis based on severity was predefined in the protocol as severity of attack may have clinical relevance related to efficacy of Ruconest.  Pharming clarified 75 mm was selected because it was the median of the 50 mm to 100 mm interval.  Pharming said 88% of U.S. subjects had less severe attacks of hereditary angioedema. 

FDA asked Pharming to present data for use of rescue medication in an amendment to the BLA, e.g., outcomes after rescue medication.

FDA asked about Pharming’s statement that there were more than 1,500 treatments in the EU.  Pharming indicated it would be difficult to track the number of subjects treated; however, they know the number of vials sold in the market.  FDA asked if the product is tracked in the EU under an active pharmacovigilance plan.  Pharming replied no.

Additional Information - Ruconest is currently marketed in the EU.  During the most recent reporting period (October 28, 2010 – April 28, 2013), (b)(4) vials of Ruconest were distributed in 16 countries.  A post-approval HAE Registry is currently being conducted in the EU.  In brief, the study design is a non-interventional treatment registry of HAE patients in the EU treated with a C1 esterase inhibitor, either pdC1INH or rhC1INH.  As of February 21, 2013, 36 patients with HAE were screened, and 4 of these patients received 12 rhC1INH treatments.  The Registry will remain open until the target number of 300 doses in the rhC1INH arm is reached, consisting of 100 patients followed up for at least three exposures to rhC1INH each.

FDA said the available safety and efficacy outcomes from the registry study may be submitted to the BLA.  FDA said that Pharming should attempt to obtain additional efficacy data by obtaining information on subjects treated at the centers in Europe.  Pharming will try to address these substantive issues as soon as possible.

Decisions made and/or agreements reached:
1.Pharming will provide a draft of items for inclusion in the BLA amendment for FDA review.
2.Pharming will submit an amendment to the BLA that will include the result of the subgroup analysis.
3.Pharming will provide data for the neutralizing antibody assay validation by February 16, 2014.
4.Pharming was notified that substantial data submitted in the BLA amendment may extend the review clock beyond the April 16, 2014 due date.
