Information Request, September 25, 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
 September 25, 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:
•Protocol C1 1310 requires periodic monitoring of study sites, as described in section 16.2 of the protocol. Please submit information in the form of a table that describes the extent to which each study site was monitored. The table should have a record for each study site, with fields that provide the following information:1.the dates that a study monitor contacted/ visited the study site,
2.the name of the person making the contact/visit,
3.the name of the organization responsible for the study site monitoring contact/visit, and
4.a list of any actions that resulted from the contact/visit to ensure that all data are reliable and have been processed correctly.

•STN125495 describes the death of a subject from “laryngeal edema” twenty-five days after completing participation in the routine prophylaxis study 1207 at a Romanian study site, as follows:

“Laryngeal edema” (laryngeal edema)
 This 50-year-old female Caucasian patient (patient (b)(6), centre No. 22) with hereditary C1INH deficiency experienced laryngeal edema while enrolled in study C1 1207. The patient's medical history included mild, moderate and severe attacks of angioedema for approximately 30 years (abdominal, genito-urinary, oro-facial-pharyngeal, laryngeal and subcutaneous/peripheral). The patient had a family history of hereditary angioedema. Previously, the patient also experienced moderate anemia (23 Jan 2010), endocervical polyp (04 Feb 2010) and exocervicitis (04 Feb 2010-10 Feb 2010).

On 18 December 2009, the patient was enrolled into the study. ECG (electrocardiogram) and clinical examinations were normal on all occasions. Before the first administration of study drug, mild anemia was detected. This did not worsen during the study.

On ------(b)(6)------, the patient received the first dose of study medication (50 U/Kg, once a week) for the treatment of hereditary angioedema. The last dose of study medication administered prior to the event was on ----(b)(6)----- (8 weeks’ treatment was received prior to the event). No side effects of the study drug were reported. The patient did not receive any concomitant medications.

The patient called the investigator on -----(b)(6)------ at around 14.30 hours reporting dysphonia, malaise and progressive swelling of the neck (externally). On the same day, the patient was taken to the local hospital by ambulance and admitted to the hospital at around 17.00 hours. The investigator called the patient at 20.30 hours and the patient's husband informed the investigator that the patient had died one hour before. The patient had not received any treatment. No laboratory data were requested. Autopsy was performed on -----(b)(6)------. The cause of death was reported as laryngeal edema.

Macroscopic diagnosis from the hospital pathology department was received; the diagnosis made on -----(b)(6)------ was slight to moderate laryngeal edema, acute pulmonary edema and hemopericardicum. Acute pulmonary edema and hemopericardicum were considered to be post mortem findings caused by the resuscitation.

The event met seriousness criteria since it involved hospitalisation of the patient and the patient died.

No action was taken with the study medication at the time of this event. The investigator considered the relationship between the rhC1INH and the event as not related. According to the investigator, the last dose of study drug was given 4 weeks before. The study drug has a very short half life and consequently it cannot be suspected as the cause of the event. The sponsor agrees with the investigator’s assessment.

This death is remarkable in that a patient known to have a diagnosis of hereditary angioedema and who experienced laryngeal edema and was transported to a hospital, did not receive any C1-INH containing product.

Please submit the following:
1.a statement from the investigator, Dr. Moldovan, stating to what extent this patient, or the hospital in which she died, had access to C1-INH containing products at the time of her death, including the investigational drug rhC1-INH, and
2.documentation of the disposition of all vials of the investigational drug rhC1-INH that had been distributed to sites in Romania up to the time of her death.
•The June 14, 2013, FDA File-with-Deficiencies letter noted that the pivotal study 1310 did not demonstrate efficacy in the pre-specified subgroups female subjects (63% of enrollment) and U.S. subjects (half of the enrollment).

 In the July 26, 2013, response to this letter, you said both outcomes can be explained by the rapid response shown by U.S. female subjects in the placebo arm, who accounted for all U.S. placebo subjects. You stated as follows:

On average, female patients and patients enrolled in the US tended to have longer times between attack onset and presentation for evaluation than male patients and patients enrolled in the Rest of World… We believe it is these differences in the time between attack onset and presentation for evaluation between placebo rhC1INH patients that has led to a lack of numerical superiority for rhC1INH for female and US patients.
1.Please calculate the time interval from HAE attack onset to the time of treatment for all subjects in study 1310, and exclude from the analysis all subjects for whom this time interval is more than two standard deviations from the average of the time intervals for all subjects (i.e. the outliers). Please calculate the average and standard deviation of this time-to treatment time interval for the following groups and submit the results to this BLA: 
a.U.S. males in rhC1-INH arm
b.U.S. females in rhC1-INH arm
c.U.S. males in placebo arm
d.U.S. females in placebo arm
e.European males in rhC1-INH arm
f.European females in rhC1-INH arm
g.European males in placebo arm
h.European females in placebo arm
2.Using this new database in which the time-to-treatment-outliers are excluded, please calculate the statistical parameters of the primary endpoint and submit the results to this BLA. 
•Validation report VAL-R-03-135, titled “Validation of a method for the determination of neutralizing anti-C1-INH antibodies in human citrate plasma samples,” summarizes the process for measuring neutralizing antibodies as follows:

The neutralising power of the isolated antibodies was assessed in the ----(b)(4)----- C11NH assay. ----------------------------------------------------------------------------------------------------------------------------(b)(4)--------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

This assay is designed to detect neutralizing antibodies against native C1-INH in plasma, but it is not designed to detect antibodies that may neutralize rhC1-INH. It is important to know if antibodies against rhC1-INH also neutralize the rhC1-INH activity because there may be situations in which the appropriate choice of a C1-INH containing product could be life-saving.

Please submit data obtained using the serum or plasma samples from subjects who were positive for antibodies against rhC1-INH that can determine whether the observed antibodies are neutralizing for rhC1-INH.

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 25, 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/RPMB
