Vaccines, Blood & Biologics

Summary Basis for Regulatory Action - Rotarix


From Laraine S. Henchal

Subject Summary Basis for Regulatory Action


Applicant GlaxoSmithKline Biologicals

Date of Submission June 4, 2007

PDUFA Goal Date April 3, 2008

Proprietary Name / Established (USAN) names Rotarix®/Rotavirus Vaccine, Live, Oral

Dosage forms Lyophilized vaccine with 1 ml liquid for oral administration

Proposed Indication(s) Prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (G3, G4 and G9)

Recommended Action: Approval

Signatory Authority(ies) Action
Offices Signatory Authority:
X I concur with the summary review
â–¡ I concur with the summary review and include a separate review or addendum to add further analysis
â–¡ I do not concur with the summary review and include a separate review or addendum

Material Reviewed/ Consulted List of specific documentation used in compiling SBRA
Clinical Review Paul Kitsutani, M.D., dated Feb 25, March 10, and March 14, 2008
Statistical Review Jingyee Kou, Ph.D., dated March 10, 2008
Pharmacology/ Toxicology Review Martin D. Green, Ph.D., dated March 19, 2008
Philip Snoy, D.V.M., dated March 5, 2008
CMC Review
Cell Substrate
Dino Feigelstock, Ph.D., dated March 13, 14, 28 and April 1 and 2, 2008
Laraine S. Henchal, dated April 1, 2008
EIR/Facilities/Inspection Jonathan Mcinnis
Pete Amin
Dino Feigelstock, see Inspection tab for inspection related documents
Bioresearch Monitoring Review Anthony Hawkins, dated March 3, 2008
Bioassay Reviews Sandra Menzies, dated February 25, 2008
Karen Meysick, dated February 27, 2008
Christian Lynch, March 10 and 11, 2008
Stephen Feinstone, March 13, 2008
Vladimir Chizikov, February 25, 2008
Lev Sirota, dated February 29, 2008
PNR review

Lisa Stockbridge, dated Feb 25, March 3, and Mar 4, 2008

Daphne Stewart, dated Feb 15, 2008

Pharmacovigilance Plan/Post-marketing Study Hector Izurieta, dated March 14 and 26, 2008
  1. Introduction

    ROTARIX®, Rotavirus Vaccine, Live, Oral is a vaccine indicated for the prevention of rotavirus gastroenteritis caused by rotavirus type G1 and non G1 types (G3, G4, and G9,) in infants and children. The vaccine is administered as a two dose series to infants between ages 6 weeks and 24 weeks, with at least 4 weeks between doses. The vaccine consists of a monovalent type G1 attenuated human rotavirus. The vaccine is presented as a lyophilized product in a glass vial. The diluent is packaged in a glass syringe with no needle accompanied by a plastic transfer device. The device is attached to the glass syringe and connected to the glass vial containing the vaccine. The diluent is then delivered into the vial and the lyophilized vaccine is resuspended. The resuspended vaccine is then drawn back into the syringe through the transfer device, the transfer device is removed and the vaccine is administered to the infant orally.

  2. Background

    The Biologics License Application (BLA) for Rotavirus Vaccine, Live, Oral (ROTARIX®) from GlaxoSmithKline Biologicals (GSK) was received by CBER on June 4, 2007. GSK had filed an Investigational New Drug Application (IND) under which an initial Phase 2 study had been conducted in the U.S. in June 2000. This trial was slow to accrue due to the withdrawal of another live, oral vaccine from the market two years previously, after an association with intussusception had been detected during the post-marketing period. GSK subsequently decided to conduct the pivotal trials outside the U.S., thus , the protocols for the Phase 3 studies were not submitted to the U.S. IND for FDA guidance. After the studies were completed, the applicant requested a meeting to assess whether the data obtained in these pivotal trials could be supportive for U.S. licensure. CBER agreed that the data appeared promising in regard to safety and efficacy, but requested that a study be conducted in the U.S. to assess the co-administration of ROTARIX® with U.S.- licensed vaccines that are administered in the first six months of life. These data would need to be included in the BLA. A Pre-BLA meeting was held in September of 2006.

    During the review of this file, two issues arose which created some discussion among the review team and supervisors. The first issue was the proposed release specification for the potency of each vaccine lot produced. GSK had proposed a potency release specification of ----------------------------------- CCID50 (cell culture infective dose) with ----------------- specified. The end-expiry titer was to be not less than 106.0 mean CCID50. The proposed dating period was ---------- months. This was identified as an issue by both the CMC reviewer and the clinical reviewer at the mid-cycle meeting. The main reason this is problematic is that the Phase 3 clinical studies were carried out with vaccine at a potency of 106.5 mean CCID50 This value, then, should be considered to be the maximum titer that the product should attain during it's shelf life as this was the titer that was demonstrated to be safe. The end-expiry titer as proposed by GSK is also problematic as there were no clinical studies conducted with vaccine at that level of potency (10 6.0 ccid50). Phase 2 trials were conducted with vaccine at lower potencies (105.3 mean CCID50 and 105.6 mean CCID50), but the studies had much smaller number of subjects and the confidence intervals for efficacy were very wide. This issue will be discussed in more detail in the CMC section.

    The other issue was in regard to the claimed indication for the vaccine. GSK proposed the indication to be for rotavirus type G1 and non-G1 types (G2, G3, G4 and G9). The vaccine contains an attenuated rotavirus type G1 human strain, and the efficacy for the non-G1 types is thought to be a result of cross protection. The types G3, G4, and G9 were encountered during the conduct of the pivotal clinical trials in sufficient number to attain statistical significance. The G2 type was not in the first year of follow-up in the pivotal trial. It was only when data from several studies were pooled and the follow-up continued into the second rotavirus season that the numbers for G2 became significant. FDA was disinclined to include this type in the indication for the vaccine. More discussion of this point appears in the Clinical section.

  3. Chemistry Manufacturing and Controls (CMC)

    CMC Summary provided by Dino Feigelstock.

    Rotarix is a vaccine composed of a monovalent, live, attenuated rotavirus derived from the human 89-12 strain (isolated from a naturally infected child with rotavirus gastroenteritis). Rotarix is provided as a lyophilized cake contained in a glass vial and a liquid diluent (1mL) in a pre-filled oral glass applicator with a plunger stopper. The lyophilized vaccine contains live, attenuated rotavirus produced on Vero cells, amino acids, dextran, Dulbecco's Modified Eagle Medium (DMEM), sorbitol, and sucrose; the diluent contains calcium carbonate, sterile water, and xanthan. The vaccine is administered orally and contains no adjuvant.

    Rotarix is derived from a single human attenuated rotavirus strain. This is different from Merck's FDA approved vaccine (RotaTeq) which is a "pentavalent" vaccine, composed of five reassortants rotavirus strains derived from a bovine strain (each of which contains a gene encoding VP4 or VP7 from human origin). Rotarix vaccine also contrasts with the RotaShield vaccine (which was withdrawn from the market in 1999); RotaShiled is composed of 4 human-simian reassortants containing four serotypically distinct VP7 components.

    Rotarix has been approved for use in Mexico in 2004, and subsequently in other Latin American countries and Europe. Eight clinical trials performed in the USA, Latin America and Finland have shown that the vaccine is safe and protected children against rotavirus infection and against severe rotavirus gastroenteritis .

    The sponsor shows data ensuring that master cells banks, working cells banks, virus master seeds, and virus working seeds used in the production of the vaccine are sterile and free of extraneous agents.

    The sponsor shows data ensuring that end-of product cells are sterile and free of extraneous agents.

    The sponsor shows data ensuring safety from TSE concerns.

    The sponsor presents results showing that the elimination of --------------------- -------- throughout the process is consistently higher than -------------------- content in commercial bulks is ------------- dose.

    The vaccine manufacturing process is robust, and the titers achieved are highly consistent.

    The sponsor performs testing at different stages of production to ensure that the product meets specifications and is consistent. Testing for Lot Release of final containers (rotavirus) includes: Description, identity, sterility, moisture content, ----, potency and loss of potency after --- days at ----C. Testing for Lot Release of final containers (diluent) includes: Description, identity of -------------, identity --------------- volume, and calcium carbonate content.

    Extensive studies have shown that the vaccine is genetically stable; the markers for attenuation are not yet identified.

    The sponsor performed (and is performing) studies demonstrating the stability of the HRV lyophilized vaccine and the liquid diluent.

    Regarding the potency of the vaccine, the sponsor has set an ---------------- specification of ----- CCID50 ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

    Regarding the lower limit specification, the sponsor has set a lower limit specification of ----- CCID50. This titer, according to calculations made by CBER reviewers, will ensure a titer of 106.0 CCID50 at the end of expiry period of 24 months. This titer is not consistent with the phase 3 clinical studies that have shown efficacy of the product at a dose of 106.5 CCID50. According to CBER clinical reviewers, phase 2 clinical studies have shown that the vaccine protects at lower doses. However, it is not clear the level of protection at the end of expiry dose (106.0 CCID50); therefore, I strongly recommend to clearly state in the label that phase 3 clinical trials were performed at a dose of 106.5 CCID50. [Ed. note: This issue is futher discussed below. See heading DISCUSSION OF CMC ISSUE]

    Based on the above statements, I recommend approval of the product.


    The adventitious agent testing as described by GSK for Rotavirus Vaccine, Oral (Rotarix®) is adequate for U.S. licensure.

    Modern live viral vaccine production is well controlled. With assurance that the starting materials have been well-characterized, the testing plan for the virus vaccine can be kept to a basic set of general tests which will detect any unforeseen adventitious agents which may find their way into the production stream. I concur with the request for discontinuation of the ------------- test and the General Safety test (see CMC review for more detail on the latter).

    With regard to the virus seeds as established for Rotarix®, the data demonstrate that the virus seeds are extremely well-characterized. Firstly, an ----- treatment was carried out to avert any possible contamination with a ------------- contaminant that had been seen in the cell line --------------------------------------------------------------- under the original IND sponsored by the vaccine's developer. Next, in addition to the ----- treatment, GSK undertook to clone the virus in order to make the virus strain more homogeneous, but by so doing thereby also eliminated any possible carryover of a viral contaminating agent to which the vaccine virus may have been exposed to during development in the process. I had some concern regarding use of bovine derived materials ---------------------------------------------------------------------------
    ------------------------------------------------------------ to eliminate any exposure to additional bovine materials during manufacture. However, the vendor of the ------------- used for ---------------------------------------------------- conducted the appropriate testing for bovine viruses and was from a Transmissible Spongiform Encepahopathy (TSE)-free country, so thi sconcern was addressed. The testing conducted on both the master and working virus seeds is extensive and covers the testing as recommeded by CBER and the EMEA. This ----------- virus seed will be sufficient to supply the needs for rotavirus vaccine for the next -----------.

    The Vero cells were originally obtained from the ------ by GSK at level ---- in ----. Any material obtained 1980 and before are considered not at risk for TSE contamination. --------------------------------------------------------------------------------------------- used at that time was ------------------------------. The U.S. had its first case of BSE only a few years ago. However, due to concerns arising from the use of bovine derived ------------------------- -------------------------------------------------------
    ----------------------------------------- -----------------. ---------------- used for manufacture of this --------------------------------- was obtained from ---------, which remains a TSE-free country. The -------- was tested in ----- using tests considered to be necessary at that time. The end-of-production (EOP) cell bank was tested in ---------- with a slightly more extensive battery of tests, including many for ------------------------------------------------------------------------------------- testing on passage --- (reflects passage level of cells at end-of-production process) ---------------------------- ---------------------------------------. The data demonstrate that the Vero Cell Banks are adequately characterized for a live viral vaccine administered orally.

    In summary, I recommend the approval of this application. My review is dated April 1, 2008.


    Inspection Summary provided by Jonathan McInnis, Pete Amin and Dino Feigelstock

    The manufacture, fill and finishing sites for this vaccine are located in --------, Belgium and all of these facilities were inspected by the FDA. Buildings ---------- (new --- filling line for Rotarix® filling and lyophilization) in ---------- and Building ----- (Building -------------- for Rotarix diluent formulation and Building ------ for diluent filling) in Rixensart are recommended by the inspection team to be approved as part of the license for Rotavirus Vaccine, Live, Oral.

    CBER LOT RELEASE, provided by Bill McCormick

    Due to the lack of a production and testing track record in the U.S., CBER will require Lot Release of this vaccine. Review of results from tests performed by the manufacturer at various stages of manufacture of the product (submitted in the protocols) and confirmatory testing of lyophilized final container vaccine is the mode of CBER regulation of this vaccine.


    A categorical exclusion from filing an environmental assessment was requested by GSK and granted. See memo from Jonathan McInnis in the Inspection Tab.

    Discussion of CMC Review Issue: Potency Release Specification

    GSK responded to questions about their proposed potency release specification on Feb 11, 2008 (rec'd Feb 13, 2008). CBER discussed the issue in two separate meetings with GSK representatives on February 29, 2008 and March 17, 2008. In these two meetings, the group discussed how the potency release specification was set by GSK. It appeared that the -----------------------------------------------------------------------" had not been followed for the stability evaluation of the product, the variability of the potency assay had not been sufficiently considered, ---------------------------
    -----------------------------------------------------------------------------------------------------------------------------------------------------------. After additional data was submitted to the BLA on March 21, 2008 and CBER review of this data, it was agreed (see meeting summary dated March 27, 2008) that the potency release specification should be ---------------------------- CCID50 per dose. Because the stability regression line -------------- a 24 month dating period was granted rather than the -- month dating period requested by GSK. The end-expiry titer is to be not less than 106.0 CCID50/dose. See also review from Drs. Phil Krause ane Lev Sirota for the details of the regression analysis. The clinical efficacy of a dose at end-expiry is supported in a memo to the file from Drs. Paul Kitsutani and Steve Rosenthal (March 14, 2008) after careful consideration of all the clinical data submitted to the BLA. This issue was then resolved.

    Novel Issues:

    CBER received a consult review from the Center for Devices and Radiological Health for the plastic transfer device. The consult reviewer, Dr. Sajjad Syed found that the plastic used for the device was of a satisfactory material and the appropriate testing had been conducted by the applicant. Initial questions from the consult reviewer had been communicated to the applicant in November of 2007. The applicant responded in January 2008. Dr. Syed's complete review is dated January 17, 2008, in which he states that the applicant had satisfactorily responded to his questions. He did express some concern regarding the transfer device and it not being sterile. Since this was a consult review, CBER has the final decision regarding the adequacy of the device for use in a biologic product. Dr. Syed's supervisor, Mr. Anthony Watson stated this in his e-mail memo dated March 4, 2008. Since this is an oral vaccine and the vaccine diluent is sterile, and the contact time for the vaccine and the transfer device is minimal, the review team does not consider this to be an issue.

  4. Nonclinical Pharmacology/Toxicology

    Executive Summary for Submitted Toxicity Study, by M. David Green:

    One single dose combination repeat dose toxicity study was submitted in support of the BLA. The validity of the animal model was established in the study titled "Preliminary study of human rotavirus strains in rats ------------." In this study, 5-day and 21-day old ------- ---- rats were given two different human rotavirus strains (Wa and RIX 4414) intragastrically on days 0 and 14 of the study. Although no specific antibody response was detected to human rotavirus in 5-day old rats, a specific antibody response was found in 21-day rats.

    In the repeat dose GLP toxicity study, 21-day old ---------------- rats were given 4 doses of rotavirus vaccine orally (intragastic administration). The four doses used in the repeat dose toxicity study exceed the number of injections that are intended for use in the clinic. The dosing interval was 2-weeks; thus, dosing occurred on days 0, 14, 28, and 42. The full human dose of vaccine of 0.5 ml was used in the toxicity study. The study was design with the following 4 groups: saline (group 1); antacid alone, --- mg of CaCO3 (group 2); RIX 4414, 106.7 ffu and ---- mg of CaCO3 (group 3); or RIX 4414, 106.1(group 4). Groups were composed of N = 15/sex with animals killed on days 5, 47 and 70 of the study.

    No treatment-related effects were observed on the following endpoints: clinical signs, mortality, body weight, food intake, ophthalmology, body temperature, coagulation, macroscopic findings upon necropsy, histopathology and clinical chemistry. Of note, no histopathological changes were found in the intestinal villi such as epithelial syncytia and no intracytoplasmic eosinophilic inclusions in the ileum.

    Low seroconversion rates 10% and 20% were observed in the study population.

    In terms of viral shedding, no positive response was found in the control groups and waning and variable response was observed for the rats given the test article.

    When a combined virology and serology analysis was used, it demonstrated an 80% response in rats given RIX4414 and CaCO3 (--- mg) and 40% in rats given the vaccine alone. The vaccine take was defined as the percentage of rats that either seroconverted and/or shed virus in their stool.

    Although no treatment related deaths occurred during the course of the study, 4 animals died (one in group 1, one in group 2 and two in group 3) after blood sampling on day 70 and were necropsied shortly after their deaths. The cause of death was thought to be associated with the blood sampling procedure.

    The vaccine did not exhibit evidence of toxicity as measured by a number of endpoints including histopathology data of the gut including the intestinal villi of ileum as measured by epithelial syncytia or intracytoplasmic eosinophilic inclusions. Reproductive and developmental toxicity studies were not performed because the target population does not include women of child bearing potential or involve male fertility as the clinical population is composed of infants. Although the toxicity study did not reveal evidence of intussusception, the validity of the model is uncertain and should not be used as a tool in assessing the risk.

    Neurovirulence Testing, provided by Dr. Philip Snoy

    Neurovirulence testing was performed by the applicant on --------------------------, including the -----------------. ----------------- monkeys were inoculated with 0.5 ml of virus into the left and right side of the thalamus and then observed for 21 days for neurologic signs. The monkeys were then humanely killed and their brains and spinal cords examined histologically for inflammatory lesions. No excessive neurologic signs were seen clinically and most of the inflammatory lesions seen in the brain were associated with the inoculation tracks near the thalamus. There was no evidence of viral spread to any areas of the spinal cord. There is no indication of neurovirulence in ------------------------------------- lots of rotavirus vaccine tested.

  5. Clinical Pharmacology

    N/A see clinical summary

  6. Clinical/Statistical-Efficacy

    Executive Summary - ROTARIX®, as provided by Dr. Paul Kitsutani

    This Biologics License Application (BLA) contains efficacy, immunogenicity, and safety data provided by GlaxoSmithKline to support approval of Rotarix, a live, oral, monovalent rotavirus (RV) vaccine indicated for the prevention of RV gastroenteritis (GE) caused by G1 and non-G1 types. Rotarix is to be administered as a 2-dose series to healthy infants 6 to 24 weeks of age, with doses separated by a minimum interval of 4 weeks. The proposed release specification potency is ------- median Cell Culture Infective Dose (CCID50) ------------ CCID50 per dose of live, attenuated human RV, with an end-of-shelf-life potency of ≥ 106.0 CCID50 per dose.

    The Biologics Licensing Application (BLA) contains six Phase II trials and five Phase III trials. Two of the Phase III trials are considered pivotal efficacy studies: Rota-023, conducted in 11 Latin American countries, and Rota-036, conducted in six European countries. Rota-023 was also specifically designed and powered to evaluate the risk of definite intussusception (IS), with over 63,000 infants from 11 Latin American countries plus Finland receiving either Rotarix or placebo. Rota-033 was a Phase III lot-to-lot consistency study of 3 lots conducted in three Latin American countries. Rota-060, a Phase III trial evaluating the immunogenicity of routine childhood vaccines when co-administered with Rotarix, was conducted in the U.S.


    Two Phase III studies, Rota-023 and Rota-036, are considered pivotal to the efficacy claims in this BLA. The primary objective of Rota-036 was to assess vaccine efficacy (VE) against any RV GE during the first efficacy follow-up period from 2 weeks post-Dose 2 until the end of the first RV epidemic season. The primary objective of Rota-023 was to assess VE against severe RV GE during the first efficacy follow-up period from 2 weeks post-Dose 2 until 12 months of age. Both studies were prospective, randomized, double-blinded, placebo-controlled trials. In each study, the According to Protocol (ATP) efficacy cohort was used for the primary efficacy analyses, and consisted of 17,867 subjects (Rotarix: 9009, placebo: 8858) in Rota-023 and 3874 subjects (Rotarix: 2572, placebo: 1302) in Rota-036. VE for each endpoint was calculated using the following formula: 1 - (attack rate in the Rotarix group ÷ attack rate in the placebo group).

    In Rota-036, RV GE was defined as an episode of GE in which RV other than the vaccine strain was identified in a stool sample collected no later than 7 days after GE symptom onset, while severe RV GE was defined as an episode of RV GE with a score of ≥ 11 points using the Vesikari scale. In Rota-023, the primary case definition of severe RV GE was defined as an episode of RV GE requiring hospitalization and/or rehydration therapy (equivalent to WHO plan B or C) in a medical facility.

    The applicant demonstrated that Rotarix, at 106.5 CCID50 per dose, was effective in preventing naturally occurring RV GE of any grade of severity and severe RV GE during the first year of life. VE was 87.1% (95% CI: 79.6, 92.1%) against any RV GE in Rota-036. VE against severe RV GE was 95.8% (95% CI: 89.6, 98.7%) in Rota-036 compared to 84.7% (95% CI: 71.7, 92.4%) in Rota-023, suggesting geographical and/or ethnic differences in efficacy. Protection was also demonstrated against any and severe RV GE caused by circulating G1 and certain non-G1 types, as well as other clinical endpoints during the first-year, second-year, and combined (first- and second-year) efficacy follow-up periods.


    Immunogenicity to Rotarix was assessed by measuring serum anti-RV IgA antibodies, considered a standard measure of immunity in most field studies and vaccine trials, at pre- and post-vaccination time points. Definitions of seropositivity and seroconversion were uniform across studies. Seropositivity was defined as an anti-RV IgA concentration ≥ 20 U/mL. Seroconversion was defined as an anti-RV IgA concentration ≥ 20 U/mL in a subject seronegative for RV pre-Dose 1. Stool samples were also collected to evaluate vaccine take, defined as anti-RV IgA seropositivity in any post-vaccination blood sample or detection of RV antigen in any post-vaccination stool sample in a RV-uninfected subject pre-vaccination. Anti-RV IgA seroconversion rates and geometric mean concentrations (GMCs) were measured in all or a pre-defined subset of subjects from all BLA studies, while vaccine take was estimated in 7 studies, including Rota-033. In each study, the ATP immunogenicity cohort was used for the primary immunogenicity analyses.

    In studies that evaluated Rotarix at 106.5 CCID50 to 106.8 CCID50 per dose (total number of Rotarix subjects at these potencies in the ATP immunogenicity cohorts = 2642), 2 doses of Rotarix appeared immunogenic in infants, as demonstrated by post-Dose 2 anti-RV IgA seroconversion rates, GMCs, and vaccine take rates. At 1-2 months post-Dose 2, the anti-RV IgA seroconversion rate was 86.5% (95% CI: 83.9, 88.8%) in Rota-036 compared to 76.8% (95% CI: 72.4, 80.9%) in Rota-023. Similarly, 1-2 month post-Dose 2 GMC was higher in Rota-036 (197.2 U/mL; 95% CI: 175.2, 222.0 U/mL) than in Rota-023 (102.6 U/mL; 95% CI: 86.3, 122.0 U/mL). These results suggest that geographical and/or ethnic factors may impact the anti-RV IgA immune response to Rotarix.


    Intussusception (IS)

    In Rota-023, the primary safety objective was to determine the safety of Rotarix with respect to IS occurring within 31 days (Days 0-30) after each dose. The safety database consisted of the Total Vaccinated Cohort (Rotarix: 31,673, placebo: 31,552) that was followed from Dose 1 to 1-2 months post-Dose 2. Definite IS was defined as a diagnosis of IS confirmed by intestinal invagination at surgery or autopsy, or by radiologic techniques (gas/liquid contrast enema or abdominal ultrasound). The primary safety objective was achieved if the following two criteria were met: upper limit of the 95% confidence interval (CI) of the risk difference (Rotarix minus placebo) for definite IS was <6/10,000 and lower limit of the 95% CI of the risk difference was < 0. An increased risk of definite IS following Rotarix vaccination was not observed within 31 days after any dose when the date of IS diagnosis was used to categorize cases (risk difference/10,000 = -0.32; 95% CI: -2.91, 2.18/10,000). An increased risk within 31 days was also not demonstrated in an FDA analysis that used the date of IS onset to categorize cases (risk difference = -8.48/107; 95% CI: -2.63, 2.61/10,000). Increased risk was not observed after Dose 1 or Dose 2. Temporal clustering after either dose was also not observed.

    When pooled safety data from 8 BLA studies of subjects who received Rotarix at the proposed licensure potency (≥ 106.0 CCID50 per dose; n = 36,755) were analyzed (Core Integrated Safety Summary [ISS] analysis), a statistically significant increased risk of IS within 31 days after Rotarix was not observed (Rotarix: 9 [0.024%], placebo: 7 [0.020%]; RR=1.23, 95% CI: 0.41, 3.90). Pooled safety data from 5 BLA studies of subjects who received Rotarix at the less-than licensure potency (< 106.0 CCID50 per dose; n = 3076) (Supplementary ISS analysis) also did not demonstrate a significantly increased risk of IS within 31 days after Rotarix (Rotarix: 1 [0.033%], placebo: 0 [0%]; LL 95% CI: 0.01).

    Serious adverse events - deaths

    A total of 118 deaths (0.158% of all study subjects) were reported throughout the course of the studies. Overall death rates were 0.184% (68/36,755) in the Rotarix (≥ 106.0 CCID50 potency) group, 0.163% (5/3076) in the Rotarix (< 106.0 CCID50 potency) group, and 0.158% (55/34,739) in the placebo group. In the Core and Supplementary ISS analyses for deaths, there were no significant imbalances between treatment groups in the rates of fatalities during the 31 days post-vaccination or entire study follow-up periods. For either follow-up period, there were no significant imbalances in fatalities between groups for any Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term (PT).

    Pneumonia deaths - Rota-023

    In Rota-023, an FDA analysis revealed statistically significant difference between treatment groups in the rate of subjects with pneumonia-rselated deaths between Dose 1 and Visit 3 (1-2 months post-Dose 2 or 2-4 months post-Dose 1) (Rotarix: 0.051%, placebo: 0.019%; p = 0.0354). The applicant provided a p-value of 0.054. Pneumonia-related death rates within 31 days post-vaccination were still higher in Rotarix compared to placebo recipients (0.022% [7/31,673] vs. 0.010% [3/31,552]). However, there were no differences between the treatment groups in rates of non-fatal pneumonia events and pneumonia hospitalizations (Dose 1 to Visit 3, within 31 days and beyond 31 days post-vaccination).

    Serious adverse events

    In the Core and Supplementary ISS analyses for severe adverse events (SAEs), there were no significant imbalances between treatment groups in the rates of subjects with at least 1 SAE during the 31 days post-vaccination or during the entire study follow-up period. In the Core ISS analysis, PTs Diarrhea, Gastroenteritis, Dehydration, and Ileus were reported significantly less during the entire study follow-up periods in the Rotarix group than in the placebo group. There were no significant imbalances for any other specific PT except Foreign body trauma (Rotarix: 11/36,755 [0.035%], placebo: 1/34,739 [0.003%]; RR = 9.11, 95% CI: 1.31, 394.8). However, all cases involved swallowing a foreign body between 48-483 days post-dose, and were assessed by the applicant as not related to vaccination.

    Convulsions - Rota-023

    In Rota-023, a statistically significant difference between treatment groups was observed in the rate of PT Convulsions between Dose 1 and Visit 3 (Rotarix: 16/31,673 [0.051%], placebo: 6/31,552 [0.019%]; p = 0.034). However, when convulsion-related PTs (Convulsions, Epilepsy, Grand mal convulsion, Status epilepticus, and Tonic convulsion) were pooled in a post-hoc analysis, a statistically significant difference between groups was not demonstrated (Rotarix: 20/31,673 [0.063%], placebo: 12/31,552 [0.038%]; p = 0.219). Furthermore, convulsion-related episodes within 31 days after any dose occurred less in Rotarix recipients than placebo recipients. Among subjects who experienced a convulsion-related event within 31 days after any dose, 7 (0.022%) were Rotarix and 9 (0.029%) were placebo recipients. Within 43 days post-vaccination, 12 (0.04%) Rotarix and 9 (0.03%) placebo recipients reported a convulsion-related event.

    Imbalances between groups in convulsion-related PTs within 31 or 43 days post-vaccination were not observed in Rota-036.

    Pneumonia - Rota-036

    In Rota-036, rates of PT Pneumonia were significantly higher in the Rotarix compared to the placebo group from Dose 1 to Visit 7 (end of the second RV epidemic season) (24 vs. 4, p = 0.029). Of the 28 cases, only one (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).

    Imbalances between groups in pneumonia-related PTs within 31 or 43 days post-vaccination were not observed in Rota-023.

    Unsolicited adverse events (non-SAEs)

    In the Core and Supplementary ISS analyses for unsolicited AEs 31 days post-vaccination, there were no significant imbalances between groups in the rates of subjects with at least 1 AE of any intensity or Grade 3 intensity after any dose. In the Core ISS analysis, there were small but statistically significant increases in Rotarix compared to placebo recipients in rates of PTs Irritability (11.4% vs. 8.7%) and Flatulence (2.2% vs. 1.3%). However, no significant imbalances in Grade 3 Irritability and Flatulence were observed. In the Supplementary ISS analysis, there was a statistically significant increase in rates of PT Bronchitis in Rotarix compared to placebo recipients (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 applicant stated that this imbalance was driven by an imbalance of Bronchitis in Rota-006. FDA calculated a total of 44 (3.9%) Rotarix recipients (< 106.0 CCID50 groups) compared to 10 (1.8%) placebo recipients in Rota-006 who reported PT Bronchitis during Days 0 to 30 post-vaccination. Grade 3 Bronchitis occurred in 1 Rotarix compared to 0 placebo recipients. In Rota-006, the rate of any Bronchitis in the Rotarix group receiving the licensure potency was higher than in the placebo group during this same interval (3.7% vs. 1.8%); no Grade 3 Bronchitis was reported in this Rotarix group. In the Core ISS analysis, when PTs Bronchitis and Bronchitis acute were combined, 116 (2.3%) Rotarix recipients compared to 45 (1.6%) placebo subjects reported an AE. Grade 3 AE rates were comparable (Rotarix: 0.16%, placebo: 0.14%).

    Solicited adverse events

    In the Core and Supplementary ISS analyses for solicited symptoms 8 days (Days 0-7) post-vaccination, there were no significant imbalances in rates of fever, irritability, loss of appetite, vomiting, or diarrhea, of any severity or Grade 3 severity, between the Rotarix and placebo groups after any dose. The exception was Grade 3 cough/runny nose after any dose in the Core ISS analysis (Rotarix: 3.6%, placebo: 3.2%, RR=1.41, 95% CI: 1.01, 1.99). However, imbalances in rates of cough/runny nose after each dose were not observed.

    Shedding and Transmission

    Post-vaccination RV antigen shedding in stools was evaluated in all or a subset of subjects from 7 BLA studies. In all studies (total number of Rotarix subjects in the ATP immunogenicity cohorts = 1086), samples were collected on Day 7 after each dose, while in 4 studies, samples were also collected on Day 15 post-dose. In addition, 4 studies collected samples at 30 days post-Dose 1 (pre-Dose 2), while 4 studies collected samples at 60 days post-Dose 1 (pre-Dose 2).

    Among Rotarix treatment groups from studies that administered vaccine at 106.5 CCID50 to 106.8 CCID50 per dose, post-Dose 1 RV antigen shedding ranged from 50.0% to 80.0% of subjects at Day 7, 19.2% to 64.1% at Day 15, 0% to 24.3% at Day 30, and 0% to 2.6% at Day 60. The highest rates of post-Dose 1 shedding at Days 7, 15, and 30 occurred in subjects from Rota-007, a Phase II study conducted in Singapore. The applicant stated that these results may be due to a population effect or older age at Dose 1 (median = 13 weeks) when maternal antibodies known to have an impact on RV immune response have already declined. Among the same Rotarix treatment groups, post-Dose 2 shedding ranged from 4.2% to 18.4% at Day 7, 0% to 16.2% at Day 15, and 0% to 1.2% at Day 30. Shedding at Day 45 post-Dose 2, monitored only in Rota-033, was 0%. Highest post-Dose 2 shedding rates at Days 7 and 15 were also in subjects from Rota-007.

    In 2 BLA studies that administered Rotarix at 106.5 CCID50 per dose, an estimated 25.6% to 26.5% of subjects shed live RV at Day 7 post-Dose 1. In addition, data from 4 other studies combined demonstrated that among RV antigen-positive samples, live RV was detected in fewer samples from Rotarix vaccinated subjects than samples from wild-type RV GE episodes (14.6% vs. 68.6%)

    Transmission of Rotarix was not formally evaluated in any of the BLA studies.

    Co-Administration with Other Childhood Vaccines

    Concomitant administration of other routine childhood vaccines with Rotarix or placebo was allowed in 10 of the 12 BLA studies. Only one study (Rota-014, Phase II, South Africa; n = 447) allowed concomitant administration of oral poliovirus vaccine.

    Only Rota-060 was specifically designed to evaluate non-inferiority of immune responses to diphtheria, tetanus, pertussis, hepatitis B, poliovirus, Haemophilus influenza type b (Hib), or S. pneumoniae antigens when these routine vaccines were co-administered with Rotarix. All study subjects received 3 doses each of Pediarix® (DTaP-HepB-IPV), Prevnar® (pneumococcal 7-valent conjugate vaccine), and ActHIB®. In the co-administration group, Rotarix was administered with the first two routine vaccine doses, while in the separate administration group, Rotarix was administered one month after routine vaccine Doses 1 and 2. Antibody responses to diphtheria, tetanus, pertussis (PRN, FHA, PT), hepatitis B (HBs), poliovirus (types 1, 2, 3), Hib (PRP), and S. pneumoniae (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) antigens were measured one month after Dose 3 of routine vaccinations. Non-inferiority criteria were based on comparisons of seroprotection rates (diphtheria, tetanus, hep B, Hib, polio) and GMCs (pertussis, S. pneumoniae) between treatment groups. Non-inferiority criteria were met for all antigens, indicating that co-administration of Rotarix with routine childhood vaccines did not impair the immune responses to any of these vaccine antigens.


    Rotarix at a potency of 106.5 CCID50 per dose was effective in preventing RV GE of any grade of severity and in preventing severe RV GE caused by naturally-occurring RV strains during the first year of life across heterogeneous geographical populations. Protection against any and severe RV GE was also demonstrated against circulating G1 and certain non-G1 types that are similar in distribution in the U.S. Co-administration of Rotarix with other routine vaccines in the U.S. did not cause interference of the immune response to each of these vaccine antigens. Rotarix had no increased risk of intussusception. However, increases in pneumonia-related deaths and convulsion-related SAEs were observed in Rotarix compared to placebo recipients from Dose 1 to Visit 3 in Rota-023, although the difference in pneumonia-related deaths occurring within 31 days post-vaccination was smaller. Rates of bronchitis within 31 days post-vaccination were also generally higher in Rotarix recipients, most notably in Rota-006.


    The reviewer recommends that Rotarix be approved for use in infants 6 to 24 weeks of age.

    As part of the pre-BLA agreement, the applicant will conduct a prospective US post-licensure observational safety study that will be adequately powered to evaluate the risk of intussusception. Other measured outcomes will include deaths from all causes, hospitalizations due to acute lower respiratory tract infections (including pneumonia), convulsions, and Kawasaki disease.


    The concomitant administration study (060) was conducted in order to determine whether ROTARIX interfered with other vaccines licensed in the US that would likely be administered to the birth cohort who would be receiving ROTARIX. For details on the study, please see the Clinical Review. The assays that were used by GSK to assess the effect of coadministration were reviewed by a large number of individuals within the Center, based on their expertise. The pertussis assays were reviewed by Sandra Menzies (dated Feb 25, 2008). The polio assays were reviewed by Vladimir Chizikov (dated Feb 25, 2008). The diphtheria and tetanus assays were reviewed by Karen Meysick (dated Feb 27, 2008). The Hepatitis B assays were reviewed by Steve Feinstone (dated March 13, 2008). The Hemophilus influenza type b, Streptococcus pneumoniae, and Neisseria meningitidis assays were reviewed by Chritian Lynch (dated March 10, 2008 and March 11, 2008, respectively). In regard to the Neisseria assays, in a telecon dated March 10, 2008, it was decided that since there are no currently licensed meningococcal vaccines that are routinely recommended for use in the US and since this vaccine was not included in the 060 study, it would not be necessary to review this assay. All of these reviews found that the assays as included in the BLA were satisfactory for use in evaluating the concomitant vaccine study.

    BIOSTATISTICAL REVIEW, summary provided by Dr. Jingyee Kou

    1. All three phase 3 studies, Study Rota-023, Study Rota-036, and Study Rota-033, were not conducted under US/FDA IND regulation. Therefore, none of the protocols and amendments were concurred upon by CBER before or during the trial.
    2. By the reviewer's relative risk calculation based on the onset day of the IS symptoms, the applicant has reached the revised primary safety objective.
    3. The efficacy results based on the Cox proportional-hazard model were confirmed by the reviewer for Study Rota-023. The reviewer considers the Cox model to be a more appropriate method for estimating the efficacy of this vaccine, compared to the applicant's method, due to large variations in the follow-up times of the subjects. The Cox model results from Study Rota-036 are similar to the ones from the larger study, Rota-023, are considered acceptable.
    4. For individual serotypes in the circulating wild-types, statistically significantly fewer cases were found in G1, G3, G4, and G9 in the HRV group than in the placebo group in separate studies. However, there were no properly formed hypotheses or power estimates before the trial was conducted. Hence, the observed results are more appropriate for hypothesis forming for future studies than for vaccine label claims. [Ed. note: See further discussion of vaccine efficacy for specific serotypes under the heading Discussion of Clinical Issue]
    5. Lot consistency based on three lots was demonstrated, with upper limits of both the 90% and 95% confidence intervals being under 2.

    From the study results shown above, the reviewer concludes that the applicant has fulfilled the primary objective of each of the studies reviewed here. Therefore, the reviewer concludes that this product may be approved, unless there are other considerations beyond those reviewed here that would warrant otherwise.

    BIORESEARCH MONITORING REVIEW, provided by Anthony Hawkins


    The bioresearch monitoring inspections of six clinical sites did not reveal problems that impact the data submitted in the application.


    Six clinical investigator inspections were performed in support of this Biologics License Application (BLA). Study subject population, geographic distribution, and field resource considerations were among the factors used to select the inspected sites. Information from the BLA was compared to source documents, during the inspections.

    Site # #Subjects 483 Inspection Classification
    Dr. Alexandre Linhares
    Instituto Evandro Chagas
    Belém - Pará, Brazil
    Dra. Maribel Rivera
    Hospital Escuela
    Tegucigalpa, Honduras
    Dra. Mercedes Macias-Parra
    Instituto Nacional de Pediatria
    Mexico City, Mexico


    A phase III, double-blind, randomized, placebo-controlled, multi-country and multi-center study to assess the efficacy, safety and immunogenicity of two doses of GSK Biologicals' oral live attenuated human rotavirus (HRV) vaccine in healthy infants. (Study Rota-023)

      Site # #Subjects 483 Inspection Classification
    Dr. Tiina Korhonen
    Tampere rokotusklinikka
    Tampere, Finland
    Dr. Niklas Lindblad
    Turku Rokotetutkimukset
    Turku, Finland
    Dr. Anna-Maija Hanni
    Oulun Rokotetutkimusklinikka
    Oulu, Finland

    STUDY TITLE: A phase IIIb, double-blind, randomized, placebo-controlled, multi-country and multi-center study to assess the efficacy, safety and immunogenicity of two doses of GSK Biologicals' oral live attenuated human rotavirus (HRV) vaccine in healthy infants in co-administration with specific childhood vaccines. (Study Rota-036)

    No sponsor or monitoring issues were noted.


    Part of one subject's electronic case report form (CRF) was deleted to include a serious adverse event (SAE), intussuseption, which occurred after the study subject was enrolled but before treatment with the study vaccine. The sponsor acknowledged that, at the time of the study, there was no clear instruction for completion of a CRF in case a subject was enrolled and randomized but did not receive the study vaccine (Dra. Rivera).


    We issued closeout letters to Drs. Linhares, Rivera, Macias-Parra, Korhonen, Lindblad and Hanni. All investigator issues were resolved.

    Discussion of Clinical Issue

    Vaccine efficacy (VE) against severe RV GE by the main RV serotypes during Year 1 was demonstrated for G1, G3, G4, and G9 types, which were associated with P[8] type contained in the vaccine. Vaccine efficacy for the G2 serotypes, associated with the P[4] type, did not reach statistical significance against severe G2 RV GE during the first efficasy follow-up period (Year 1) in either pivotal study, Rota-023 or Rota-036. This period defined the primary efficacy endpoint for each study (Rota-023: severe RV GE; Rota-036; any RV GE). Statistically significant efficacy against any and severe G2 RV GE was observed during the second efficacy follow-up period (Year 2) and combined efficacy follow-up period (Year 1 and Year 2) in Rota-036. In addition, when data from all four efficacy studies (Phase II studies: Rota-004 and Rota-006; Phase III studies: Rota-023 and Rota-036) were pooled and analyzed, statistically significant efficacy against any and severe G2 RV GE during Year 1 was demonstrated.

    After review of the clinical data and subsequent discussions between the clinical and biostatistical reviewers, CBER did not accept efficacy results from the sponsor's post-hoc G2 integrated (pooled) analysis as justification for inclusion of G2 type in the INDICATIONS AND USAGE section of the label due to inherent statistical problems that may arise from such methodology. CBER also did not accept statistically significant efficacy results against G2 RV GE from either Year 2 or the combined efficacy periods as justifications for inclusion of G2 type in the INDICATIONS AND USAGE section of the label, because statistically significant efficacy against G2 RV GE was not demonstrated during Year 1, the period that defined primary efficacy objectives and endpoints for both pivotal studies.

    The issue was resolved by including the efficacy estimates against any and severe G2 RV GE during the Year 1 and combined efficacy follow-up periods in Rota-036 in the CLINICAL STUDIES section of the label.

  7. Safety

    N/A See Clinical Section

  8. Advisory Committee Meeting

    The Vaccines and Related Biological Products Advisory Committee meeting took place on February 20, 2008. The committee voted unanimously regarding the adequacy of the efficacy of the vaccine and all except one member voted in favor of the adequacy of the safety data to support the licensure of ROTARIX.

  9. Pediatric

    Under the Pediatric Research Equity Act of 2007 (21 U.S.C. 355c), all applications for new active ingredients, new dosage forms, new indications, new routes of administration, and new dosing regimens are required to contain an assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is waived or deferred. ROTARIX was presented to the Pediatric Research Committee Review Panel on March 12, 2008. Dr. Paul Kitsutani presented CBER's review of the pediatric assessment contianed in the BLA. The pediatric study requirement for children from 6-24 weeks of age for this application has been fulfilled. We wish to waive the pediatric study requirement for children from 0-5 weeks of age because it is highly impracticable to enroll subjects 0-5 weeks of age because of the potential limitations of the neonatal immune response. We wish to waive the pediatric study requirement for children from 25 weeks to 18 years of age because necessary studies are impossible or highly impracticable because it is likely that children in this age group would have already received a rotavirus vaccine or would have acquired a natural infection with rotavirus. The panel agreed with the waivers recommrnded by CBER for ages 0-5 weeks and 25 weeks to 18 years.

  10. Other Relevant Regulatory Issues

    No other relevant regulatory issues were identified.

  11. Labeling

    No special labeling issues other than the G2 indication and this is discussed in the Clinical section. Labeling was jointly agreed upon with input from APLB, clinical and other labeling experts in OVRR.

  12. Recommendations/Risk Benefit Assessment

    CBER's comments regarding the Phamacovigilance Plan as submitted in the original application can be summarized as follows courtesy of Dr. Hector Izurieta:

    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. 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 post-marketing 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 has negotiated specific timelines for finalization of study protocols, study reports, and completion and submission of final study reports with the manufacturer, which were submitted to the BLA on April 2, 2008.


Contact FDA

(800) 835-4709
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