Archived Content

The content on this page is provided for reference purposes only. This content has not been altered or updated since it was archived.

Vaccines, Blood & Biologics

Clinical Support for the Efficacy of Rotarix - Potency

Date: March 14, 2008

From: Paul Kitsutani, OVRR, DVRPA

Subject: Clinical support for the efficacy of Rotarix (STN 125265/0) at a potency of less than 106.5 CCID50 per dose against rotavirus gastroenteritis

To: Norman Baylor, OVRR, DVRPA

Through: Steve Rosenthal, OVRR, DVRPA

Cc: Laraine Henchal, OVRR, DVRPA; Douglas Pratt, OVRR, DVRPA

During internal CBER discussions involving the release potency of Rotarix, concerns were raised over the requirement that the sponsor release vaccine lots at 106.5 CCID50 per dose. By factoring in the variability of the potency assay and the stability of the product, a lot released at 106.5 CCID50 could potentially have a potency as low as 106.1 CCID50. The efficacy of vaccine doses below 106.5 CCID50 was not evaluated in the large randomized controlled pivotal efficacy trials Rota-023 and Rota-036. However, the available clinical efficacy and immunogenicity data from Phase 2 clinical trials in the BLA provide evidence that a potency as low as 106.1 CCID50 would likely be protective among infants in the United States (Tables 1 and 2).

Clinical Efficacy

Study Rota-004, conducted in Finland, demonstrated a vaccine efficacy of 90.0% (95% CI:10.3, 99.8) against severe RV GE at a potency of 105.3 CCID50 per dose (Table 1). Although the 95% CI was wide due to the relatively small sample size (N=368), this estimate was higher than the point estimates for the corresponding 105.3 CCID50 group (65.8%; 95% CI: 32.2, 83.9) and the 106.6 CCID50 group (85.6%; 95% CI: 63.0, 95.6) in Rota-006, conducted in Latin America. The efficacy point estimate in Rota-004 was also higher than in Rota-023 (84.8%; 95% CI: 71.1, 92.7) (Latin America) and similar to Rota-036 (95.8%; 95% CI: 89.6, 98.7) (Europe).

In Rota-004, the efficacy point estimate against RV GE of any severity at a potency of 105.3 CCID50 was also higher than both the 105.3 CCID50 and 106.6 CCID50 groups in Rota-006 (Table 1).

Although the efficacy estimates from Rota-004 have wide 95% CIs due to the relatively small sample size, these data provide evidence that at a potency well below 106.5 CCID50, Rotarix protects against RV GE; additionally, efficacy is consistently higher in a developed country compared to a developing country. Similarly, higher efficacy against severe RV GE was observed in the European pivotal trial (Rota-036) compared to the Latin America pivotal trial (Rota-023) (Table 1). This is consistent with what is observed with other enteric vaccines, such as OPV, which have higher efficacy in developed countries compared with developing countries.

While clinical trials at potencies of 106.1 CCID50 have not been conducted in Finland or elsewhere in Europe, it is likely that efficacy against RV GE would be higher than estimates obtained at potency of 105.3 CCID50 in Rota-004. Due to socioeconomic and demographic similarities between Europe and the US, the degree of efficacy would very likely be similar in both geographic regions.

Immune Response

Presently, there is no immune correlate of protection for RV GE. However, anti-RV IgA has generally been considered the standard measure of immunity in most field studies and vaccine trials. In Rota-006, the anti-RV IgA GMC was higher in the 106.6 CCID50 group compared to the 105.6 CCID50 group (Table 2). In Rota-005 (US, Canada), the anti-RV IgA GMC was also higher in the 106.6 CCID50 group compared to the 105.6 CCID50 group. However, the point estimate for the 105.6 CCID50 group in Rota-005 was higher than the 106.6 CCID50 group in Rota-006 (Table 2). In Rota-007 (Singapore), the point estimate for the 105.6 CCID50 group was not only higher than the 106.6 CCID50 group in Rota-006, but was also higher than the 106.6 CCID50 group in the same study (Rota-007).

These immunogenicity comparisons between studies parallel efficacy comparisons described above. The lower potency groups in Rota-005 and Rota-007, conducted in developed countries, demonstrated better anti-RV IgA immunogenicity than the higher potency group in Rota-006, conducted in less developed countries in Latin America. In Rota-007, the GMC point estimate for the lower potency group was even higher than the high potency group. Although immunogenicity at potencies of 106.1 CCID50 or 106.2 CCID50 were not evaluated in the US/Canada or Singapore, it is likely that anti-RV IgA GMC would be both higher than estimates obtained at 105.6 CCID50 and similar to estimates obtained at 106.5 CCID50 during the trials.


Based on adequate and well controlled clinical trials of Rotarix at a potency of 106.5 CCID50 (Rota-023 and Rota-036) and supplementary data from Phase 2 trials (Rota-004 and Rota-006) the clinical reviewers are confident to conclude that a Rotarix lot potency of 106.1 CCID50 would provide significant and meaningful protection against RV GE in the U.S.

Table 1: ATP efficacy summary (%, 95% CI)

Year 1

Endpoint -

10 6.5 CCID50

10 6.5 CCID50

10 5.3 CCID50

Rota-006 (2-dose subset)

10 5.3 CCID50

10 5.6 CCID50

10 6.6 CCID50

Any   87.1 (79.6, 92.1) 73.0 (27.1, 90.9) 58.4 (29.4, 76.3) 55.7 (25.3, 74.5) 70.0 (45.7, 84.4)
Severe 84.8 (71.1, 92.7) 95.8 (89.6, 98.7) 90.0 (10.3, 99.8) 65.8 (32.2, 83.9) 71.0 (39.9, 87.2) 85.6 (63.0, 95.6)

Table 2: ATP immunogenicity summary


( Latin America)

(US, Canada)

( Singapore)

10 5.6 CCID50

10 6.6 CCID50

10 5.6 CCID50

10 6.8 CCID50

10 5.6 CCID50

10 6.6 CCID50

Seroconversion rate– % (95% CI)
2 months post-Dose 2 62.4 (53.3, 70.9) 65.3 (56.3, 73.6) 67.4 (58.9, 75.1) 78.2 (70.2-84.9)

87.3 (80.9, 92.2)

85.0 (78.5-90.1)

GMC – U/mL (95% CI)
2 months post-Dose 2 52.1 (39.7, 68.3) 70.7 (51.9, 96.3) 80.1 (59.5, 107.0) 117.0 (88.3-154.9)

139.6 (112.0, 174.0)

112.1 (89.0-141.1)

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

Page Last Updated: 11/23/2015
Note: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players.