Information Request Letter, October 8, 2013 - Ruconest

DEPARTMENT OF HEALTH & HUMAN SERVICES 
 Public Health Service

Food and Drug Administration
 1401 Rockville Pike
 Rockville, MD 20852-1448

Our Reference: BL 125495/0

Pharming Group N.V.
 Attention: Mr. Matthew Moran
 October 8, 2013
 Sent by email:

Dear Mr. Moran:

We are reviewing your April 15, 2013 biologics license application for C1 Esterase Inhibitor (Recombinant). We determined that the following information is necessary to continue our review:
1.Regarding AE Case Report for Site/Patient # 071/(b)(6) (Study 1304 OLE) & 204/(b)(6) (Study 1310), a 57-year old male who experienced a myocardial infarction 73 days after the first dose of rhC1INH in 1304 OLE; the AE was considered by the investigator to be “definitely not related” to the study treatment.a.FDA would like to confirm and/or clarify the reasons why the determination of “definitely not related” was made for this patient’s AE.

i.Was it solely due to the prolonged length of time from drug exposure to AE onset?
ii.Could a more prolonged thromboembolic response to rhC1INH have contributed to this AE?
iii.Did the patient have any additional cardiovascular or thrombotic risk factors not already noted in the case report?
2.Sequence 0003, Section 1.16 (Risk Management Plan), dated May 23, 2013a.Page 32, Populations Not Studied in the Pre-licensure Phase, Pediatric Patients: This section mentions a Pediatric Investigation Plan for the EU that involves a study that will evaluate the safety, immunogenicity, pharmacokinetics and efficacy of rhC1INH for the treatment of acute HAE attacks among patients 2-13 years of age (Study 1209).

i.Please provide a summary of the protocol for this study.
b.Page 53, Signal Detection
i.For additional clinical trials data, what specific methods will be used to assess:1.Whether the frequency or severity of an AE is significantly greater among those receiving rhC1INH vs. placebo?
2.Whether the temporal relationship between an exposure and an AE is significantly greater among those receiving rhC1INH vs. placebo?
3.Whether the frequency of an AE is increasing at a significantly greater degree with increasing dose of rhC1INH vs. placebo?

ii.What specific methods will be used in performing signal detection analyses among post-marketing HAE Registry data?
iii.What specific methods will be used in performing benefit-risk analyses among post-marketing data?
c.Page 56, US HAE Registry
i.Is this a new registry that will also include pdC1INH products already approved in the US?
ii.When did/will the registry begin to enroll patients?
iii.What specific information will be collected on each patient receiving rhC1INH treatment? (i.e., is there a protocol or protocol summary FDA can review for this registry? If so, please send it.)
d.Page 58, Table 24. Adverse Event Data Capture Aid Summary: This table lists the relevant MedDRA or Non-MedDRA verbatim terms that will be used to identify AEs using the Data Capture Aids; FDA notes that the Preferred Terms (PTs) for thromboembolic events (i.e., infarction, ischemia) are likely not specific enough to capture all potential AEs of interest (i.e., myocardial infarction, cerebral ischemia) and some PTs for hypersensitivity reactions (e.g., Type I hypersensitivity reaction) may be too specific to capture all potential allergic AEs of concern that may be reported by a patient or provider .
i.Please provide FDA with a more comprehensive list of MedDRA PTs that will ensure adequate capture of the following potential AEs of concern: allergic reactions, including anaphylaxis, shock, respiratory distress or difficulty breathing, angioedema, inspiratory stridor, bilateral wheezing, urticaria, serum sickness, and delayed hypersensitivity reactions, as well as all reports of thrombosis, including deep venous thrombosis, pulmonary embolism, ischemic colitis, myocardial infarction, stroke, transient ischemic attack, and cerebrovascular accidents (excluding device-related thrombosis).
e.Page 59, Data to be Collected (using the Data Capture Aids)
i.How timely will data collection be?
ii.Will multiple queries occur until all information about an AE is obtained for its specific category?

The review of this submission is on-going and issues may be added, expanded upon, or modified as we continue to review this submission.

Please submit your response to this information request as an amendment to this file by October 31, 2013 referencing the date of this request. If you anticipate you will not be able to respond by this date, please contact the Agency immediately so a new response date can be identified.

The action due date for this file is April 16, 2014.

If you have any questions, please contact me at (301) 827-6174.

Sincerely,

Nannette Cagungun, MS, PD, RAC
 Regulatory Project Manager
 FDA/CBER/OBRR/DBA
