System Info - 110079 SHONE, DEANNA 06-Nov-2009 12:27:42 SHONEDE
RECORD OF TELEPHONE CONVERSATION
Submission Type: Original Application Submission ID: 125259/0 Office: OVRR
Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant
Telecon Date/Time: 15-SEP-2009 02:21 PM Initiated by FDA? Yes
Author: HELEN GEMIGNANI
Trans-BLA Group: No
Related STNs: None
Related PMCs: None
From: Gemignani, Helen S
Sent: Tuesday, September 15, 2009 2:21 PM
Cc: firstname.lastname@example.org; Cynthia.A.D'Ambrosio@gsk.com
Subject: Cervarix - Postmarketing
Please see the CBER document and supporting articles. CBER/OBE would like to speak with your team, not today, but Wednesday, September 16, between 3:00 - 5:00pm EST. Please let me know your availability to discuss this Postmarketing Requirement.
Helen Sullivan Gemignani
Regulatory Project Manager
Division of Vaccines and Related Products Applications
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research
Food and Drug Administration
phone: (301) 827-3070
GSK Notification Letter Regarding Postmarketing Study Requirement
Following the anticipated approval of GSK’s Cervarix vaccine, FDA has determined that GSK is required, pursuant to section 505(o)(3) of FDAAA to conduct a postmarketing study.
(A) In general. For any or all of the purposes specified in subparagraph (B), the Secretary may, subject to subparagraph (D), require a responsible person for a drug to conduct a postapproval study or studies of the drug, or a postapproval clinical trial or trials of the drug, on the basis of scientific data deemed appropriate by the Secretary, including information regarding chemically-related or pharmacologically-related drugs.
(B) Purposes of study or clinical trial. The purposes referred to in this subparagraph with respect to a postapproval study or postapproval clinical trial are the following:
(i) To assess a known serious risk related to the use of the drug involved.
(ii) To assess signals of serious risk related to the use of the drug.
(iii) To identify an unexpected serious risk when available data indicates the potential for a serious risk.
We are requiring a postmarketing study pursuant to (B)(iii). This postmarketing requirement is based upon clinical trial data that identified higher rates of spontaneous abortion among Cervarix recipients whose pregnancies occurred around the time of vaccination (defined as last menstrual period 30 days before until 45 days after vaccination), compared to control subjects. The findings were strengthened by exploratory analyses conducted by the National Cancer Institute (NCI). In these analyses, NCI identified higher rates of spontaneous abortion among 15–25 year olds who received Cervarix around the time of conception (–30 to 90 days), identified a possible increased risk of spontaneous abortion in women within 90 days after vaccination.
In light of this postmarketing requirement, FDA requests that GSK design a population-based study to assess the risk of first trimester spontaneous abortion within 90 days of Cervarix administration. Fetal viability is complex and the majority of spontaneous abortions result from chromosomal abnormalities. To better determine the true effect of Cervarix administration on fetal viability, we request that subject recruitment be restricted to fetuses with a normal karyotype. Data collection should be inclusive of factors that are thought to influence fetal viability including but not limited to age, smoking status (using plasma cotinine), number of previous pregnancies, history of spontaneous abortion, and alcohol consumption. The target population should be females aged 15–25 years, corresponding to the subgroup where the imbalance was noted in clinical trials. For analysis, the comparison group should be female controls (or the cohort from which cases were derived) who did not have a spontaneous abortion. As previously mentioned in GSK’s concept protocol, the sample size should be sufficient to detect a relative risk of 2.0 for spontaneous abortions with 80% power.
The required postmarketing study does not need to be completed in the United States (US), but the study findings should be generalizable to females in the US. Additionally, we request that GSK propose a timeline for completion of the draft and final versions of the study protocol. Key elements to incorporate into the study protocol include progress reports to OBE every 6 months for the duration of the study, as well as a timeline for the final report no later than 6 months after study completion. For information, we have attached two articles on the subject of risk factor assessment for spontaneous abortions.
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.
Finally, 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. FDA requests all available data on the gestational ages of spontaneous abortions occurring within 90 days after administration of any Cervarix vaccination and of any controls, accompanied by a table or graph showing the intervals between onset of pregnancy and abortion.
To facilitate communication regarding the postmarketing study requirement, we propose a teleconference with GSK. OBE has the following availability:
- Wednesday, September 16 — Between 3 pm and 5 pm