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Vaccines, Blood & Biologics

Executive Summary Pharmacovigilance Review - Rotarix

STN: BL 125122

MARCH 14, 2008


TO: Laraine Henchal, PhD, Division of Vaccines and Related Products Applications (DVRPA), Office of Vaccines Research and Review (OVRR), Chair, BLA 125122 Committee

FROM: Hector s. Izurieta, MD, MPH, Vaccine Safety Branch (VSB), Division of Epidemiology (DE), Office of Biostatistics and Epidemiology (OBE)

THROUGH: Robert Ball, MD, MPH, ScM, Chief, VSB, DE, OBE
Miles Braun, MD, MPH, Director, DE, OBE

DATE: March 26, 2008

SUBJECT: Executive summary pharmacovigilance review, BLA Submission, 125122 Glaxo

Reference: STN: BL 125122

Sponsor: Glaxo SmithKline, Inc.

This memorandum is to provide you with a summary of my reviews regarding post-marketing commitments for Glaxo's Biologics License Application (BLA) for the HRV vaccine (Rotarix®).

(A) In December, 2007, Midcycle Review comments regarding the postmarketing clinical commitments outlined in Glaxo's submission to the BLA of April, 2007.

CBER's main comments can be summarized as follows:

A.1 Safety specification:

Kawasaki disease: Kawasaki disease was not discussed in the safety specification. Based on the preliminary clinical review analysis, for all studies combined (including also those not under the original BLA), for the 30-day period after vaccination, there were 2 Kawasaki cases among vaccine recipients and one among placebo recipients. Although the difference found was not statistically significant, the sample size was not sufficiently large to study this important subject.

Moreover, based on the preliminary clinical review, the total number of Kawasaki disease cases occurring at any time interval for all the studies in the original BLA for all doses utilized was 4 for the vaccine recipients vs. 0 for placebo recipients. Of these 4 cases, two (with onset intervals of 91 and 213 days) complied with the case definitions for Kawasaki disease.

Therefore, CBER believes Kawasaki disease should be discussed in the safety specification and should also be included among the outcomes to be studied in any potential post-licensure observational or active surveillance study.

Convulsions: This subject is not discussed in any detail in the safety specification. Nonetheless, in study 023, a significant difference was found for the MedDRA PT (preferred term) convulsion throughout the whole study period between vaccine and placebo groups (16 cases vs. 6, Clinical Study report, Table 25). Moreover, when a secondary analysis included other pooled codes for convulsion (table 27) the magnitude and direction of the imbalance was maintained (20 vs. 12) although, according to your analysis, the difference was no longer significant. Therefore, we believe your statement that there was "no imbalance" regarding convulsion to be not accurate. If a statement regarding statistical significance is needed, it would be advisable to use more precise wording less subject to erroneous interpretation.

Therefore, CBER believes that convulsion should be discussed in detail in the safety specification and should also be included among the outcomes to be studied in any potential post-licensure observational or active surveillance study.

Pneumonia SAEs: In study 036, the PT Pneumonia was reported significantly more in the Rotarix group compared to the placebo group from Dose 1 to Visit 7 (24 vs. 4, p=0.029). Of the 28 cases, only one case (Rotarix group) was reported within 31 days after vaccination. CBER's analysis showed that 3 cases in the Rotarix group compared to 0 in the placebo group reported PT Pneumonia within 43 days after vaccination. Furthermore, when the CBER reviewer combined the pneumonia-related PTs (Pneumonia, Bronchopneumonia, Lobar pneumonia, Pneumonia viral), an imbalance was still seen from Dose 1 to Visit 7 (Rotarix - 31, placebo - 7), within 31 days post-vaccination (Rotarix - 2, placebo - 0) and within 43 days post-vaccination (Rotarix - 5, placebo - 0).

Based on these findings, combined with pneumonia deaths as described above in section 1.5, CBER believes that pneumonia and pneumonia fatalities within the first 43 days after vaccination (which includes days 0-42) should be examined further in any post-licensure study.

Bronchitis AE: In the supplementary ISS analysis, there was a statistically significant increase for Rotarix compared to placebo recipients in the rates of the PT Bronchitis of any severity within 31 days post-vaccination (1.85% vs. 0.74%, RR=2.39, 95% CI=1.27-4.90). Grade 3 bronchitis occurred in 6 Rotarix compared to 0 placebo recipients. The sponsor stated that this imbalance was driven by an imbalance of bronchitis in Rota-006. The CBER reviewer calculated a total of 41 (3.8%) Rotarix recipients (administered the less-than licensure dose) compared to 9 (1.7%) placebo recipients in Rota-006 who reported PT Bronchitis. Grade 3 bronchitis occurred in 5 Rotarix compared to 0 placebo recipients. In the core ISS analysis, when PTs Bronchitis and Bronchitis acute were combined, 116 (2.3%) Rotarix recipients and 45 (1.6%) placebo subjects reported them. Grade 3 bronchitis rates were comparable (0.16% versus 0.14%). In Rota-006, the rate of any bronchitis in the Rotarix group receiving the licensure potency dose was higher than in the placebo group (3.3% vs. 1.7%); no Grade 3 bronchitis was reported in this Rotarix group.

Therefore, CBER believes that bronchitis should be included among the outcomes to be studied in any potential post-licensure observational or active surveillance study.

A.2 Pharmacovigilance plan:

As proposed, besides passive surveillance in the U.S. and abroad, the pharmacovigilance plan includes an active surveillance component to be implemented in Germany and the United Kingdom, and a self-controlled case-series analysis based at the Mexico Social Security network (PASS).

Limitations of the proposed studies, lack of U.S. data: (1) The population of Mexico is not necessarily representative of that in the U.S.; (2) The studies proposed in the U.K. and Germany, although from populations apparently socio-economically similar to the U.S., are not necessarily representative of the U.S. population either (e.g. these populations might be les heterogeneous than the U.S.), and the two studies are described not as prospective observational cohort studies but as active surveillance studies. As such, they might be subject to biases and limitations common to other active surveillance studies. These may include any of the following: (a) unverifiable completeness of reporting, (b) unknown degree of under-ascertainment even despite a high response rate for questionnaires and cards, and (c) lack of confirmation of case ascertainment by review of hospital discharge diagnosis.

Also, all epidemiological post-licensure studies proposed by the Sponsor are outside the U.S, and a large majority of patients studied during the clinical trials were also outside the U.S.

As a reminder, concerns regarding the almost total absence of U.S. data were expressed by CBER to the Sponsor both at the November 9, 2005 meeting and at the July 17, 2006 meeting. During the July 17, 2006 pre-BLA meeting, CBER stated the following: "as discussed at the meeting on November 9, 2005, we have stated that a post-marketing study conducted in Mexico will not be satisfactory for post-marketing evaluation in the U.S. A post-marketing study must be conducted in the U.S. It will need to be of sufficient size to capture intussusception events and for overall safety, should be equivalent in scale to that being conducted by Merck for Rotateq®." CBER would like these comments to be considered by the Sponsor.

Because there is so far practically no U.S. experience with this vaccine, CBER considers important to include a U.S. post-licensure study. It would be beneficial if the U.S. study were an observational cohort study of sufficient size to address concerns regarding intussusception. Therefore, the study should be designed to detect an increased risk of intussusception due to vaccine of 2.5 or greater with 80% probability. Other outcomes for this study should include Kawasaki disease, pneumonia, pneumonia hospitalizations, pneumonia deaths, bronchitis, and convulsions (within 60 days following vaccination). Also, it would be beneficial if, prior to implementation, there is coordination between the sponsors, the CDC and FDA to: (a) avoid duplication of efforts with CDC's Vaccine Safety Datalink study (in the initial planning stages), and (b) get sure that case definitions are compatible among studies.

Because of the safety signals described above, CBER proposes that the Mexico study should include the Kawasaki disease and pneumonia and bronchitis hospitalizations.

(B) Based on the positive response from the Sponsor to the comments outlined above, CBER accepted the revised post-marketing commitments as described in Glaxo's Submission of the risk management plan dated February 29, 2008.

The revised PostMarketing Commitments include their agreement on an action plan to implement safety surveillance activities, including also a large U.S. post-marketing study, to address mainly the following potential safety concerns: Intussusception, lower respiratory tract infections, Kawasaki disease and convulsions. CBER will negotiate specific timelines for finalization of study protocols, study reports, and completion and submission of final study reports with the manufacturer.

Contact FDA

(800) 835-4709
(240) 402-8010
Consumer Affairs Branch (CBER)

Division of Communication and Consumer Affairs

Office of Communication, Outreach and Development

Food and Drug Administration

10903 New Hampshire Avenue

Building 71 Room 3103

Silver Spring, MD 20993-0002

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