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Vaccines, Blood & Biologics

Record of Telephone Conversation - Cervarix, September 16, 2009

System Info - 105475  SHONE, DEANNA   21-Sep-2009 15:27:12  SHONEDE


Submission Type: Original Application   Submission ID:  125259/0    Office: OVRR 


Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant


GlaxoSmithKline Biologicals          

Telecon Date/Time:  16-SEP-2009 03:00 PM     Initiated by FDA?  Yes

Telephone Number:   

Communication Categorie(s):



Telecon Summary:

Telecon regarding FDA's position with regards to requiring GSK to submit a PMR as a condition of approval for Cervarix

FDA Participants:  

Non-FDA Participants:   

Trans-BLA Group: No

Related STNs:  None

Related PMCs:  None

Telecon Body:

Teleconference Memorandum

Date:        Wednesday, September 16, 2009

Time:        3:00 – 4:00 PM EDT

Sponsor:   GlaxoSmithKline Biologicals (GSK)

Product:   Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant

Subject:    FDA’s letter to GSK regarding a PMR

FDA (CBER/OBE) Attendees

Rickey Wilson, MD, JD, MS, Director, DE/OBE

Hector Izurieta, MD, Branch Chief, AEB/DE/OBE

LCDR Michael Nguyen, MD, Epidemiology Reviewer, VSB/DE/OBE

Martha Lee, Ph.D., Statistical Reviewer, VEB/DB/OBE

CDR Lori Austin-Hansberry, Regulatory Project Manager, DE/OBE

Cervarix Attendees

Dr. Tom Verstraeten
Dr. Gary Dubin
Dr. Len Friedland
Dr. Claudia Galindo
Dr. Clare Kahn
Mr. Matt Whitman
Mr. Nicholas Perombelon

Cynthia D'Ambrosio


This teleconference was held to discuss FDA’s position with regards to requiring GSK to submit a

PMR as a condition of approval for Cervarix. The teleconference was requested by FDA in an effort

to clarify the email sent to Cervarix on Tuesday, September 15, 2009.


The following is a summary of the FDA’s review sent to GSK by email, followed by a letter:

Following the anticipated approval of GSK’s Cervarix vaccine, FDA has determined that GSK is required, pursuant to section 505(o)(3) of FDAAA, criterion 3 that a postmarketing study is required, “to identify an unexpected serious risk when available data indicate the potential for a serious risk.”

FDA is concerned that the current concept protocol for the US Phase IV trial, as submitted, would not be sufficient to address the potential risk posed by Cervarix vaccination on fetuses with a normal karyotype.  Also, given heightened public awareness of the safety concerns related to pregnancy outcomes, subject accrual may not be sufficient under the current study protocol.

In order to better approximate the at risk period and inform the phase IV study design, FDA requests that GSK provide further information on spontaneous abortions occurring in clinical trials.


The meeting was opened with FDA stating that the purpose for the meeting was to further clarify the letter and to discuss the next steps for GSK to meet FDA’s requirements for a possible approval.

GSK’s concern was regarding the feasibility of the study and the speed at which they can complete the study. GSK is not sure that karotype testing can be accomplished due to the possibility that they may lose many cases and that in more than half of the cases the karotyping can not be done.

However, GSK will consult their statisticians to determine if this is feasible.  GSK noted that only two studies used this methodology.

FDA acknowledged that the study will be complex and clarified the purpose for requesting the karotyping, stating that this would more clearly clarify the true effect of Cervarix vaccination on viable concepti.  Given that the majority of naturally occurring spontaneous abortions are due to chromosomal abnormalities, the primary question of the vaccine’s effect on rates of spontaneous abortions is better delineated if the study population is restricted to normal karyotypic spontaneous abortions.  FDA understands that this study methodology poses additional logistical challenges; however, FDA must require a PMR in light of the safety signal identified in the clinical trial and to meet its regulatory obligations pursuant to FDAAA.

FDA offered the following as possible guidelines: because this was a postmarketing requirement, some elements of the study were less negotiable than others.  To be most efficient and avoid multiple rounds of discussions, FDA stated that the items that had less room for negotiation consisted of: (a) detection of a relative risk for spontaneous abortion of 2.0 with a power of 80; (b) restriction of study population to normal karyotypes;(c) analysis of pregnant women whose estimated date of conception was between 0 to 90 days of the nearest vaccination; (d) interim reports every 6 months and the final report no longer than 6 months after study completion.  Items which were still negotiable were timeline for protocol submission date, appropriate control group, rather the study was population based, location of study (US or foreign), whether to study only first vs. second trimester miscarriages.


After discussion, GSK agreed to start the study to assess the risk of spontaneous abortion with the understanding that GSK will not be able to launch the study immediately upon a possible approval letter due to Lot release considerations. They would not be able to launch the study until sometime in November. GSK further stated that if the study is done in the U.S. then the uptake of the vaccine will determine their ability to launch the study. However, FDA indicated that there is no requirement

for the study to occur in the U.S.

FDA requested to see data that provides both the data for women who had spontaneous abortions which occurred after 90 days of receiving the vaccine and in women who became pregnant 90 days after



Within 48 hours of this meeting, GSK agreed to FDA’s request to send FDA proposed dates for finalizing the protocol and starting the study.  FDA emphasized this information would be a requirement for an approval letter, if one is issued. OBE director further emphasized that the decision for an approval was not under his purview.

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