Summary Basis of Decision for Rotarix ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
RotarixTM
Human rotavirus, live, attenuated, oral vaccine
106.0 CCID50/mL, Powder for suspension, Oral
GlaxoSmithKline Inc.
Submission control no: 109624
Date issued: 2008-07-23
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), ROTARIXMD, vaccin à rotavirus humain, vivant, atténué, 106.0 CCID50/mL, poudre pour suspension, GlaxoSmithKline Inc., No de contrôle de la présentation 109624
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02300591
Therapeutic Classification:
Non-medicinal ingredients:
Diluent: calcium carbonate, sterile water, xanthan gum
Submission type and control no:
Control No. 109624
Date of Submission:
Date of authorization:
™ ROTARIX used under license by GlaxoSmithKline Inc.
2 Notice of decision
On October 9, 2007, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the vaccine Rotarix™.
Rotarix™ contains live, attenuated, human rotavirus (strain RIX4414). Rotarix™ is an active immunizing agent.
Rotarix™ is indicated for active immunization of infants from the age of 6 weeks for the prevention of gastroenteritis caused by rotavirus types G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]. Rotavirus infection is the leading cause of severe acute gastroenteritis in infants and young children throughout the world. The immunologic mechanism by which Rotarix™ protects against rotavirus gastroenteritis is not completely understood. A relationship between antibody responses to rotavirus vaccination and protection against rotavirus gastroenteritis has not been established.
The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from non-clinical and clinical studies. Approximately 80,000 doses of Rotarix™ were administered to over 40,000 infants. The clinical development program for Rotarix™ consisted of 14 clinical studies (and 4 supportive studies): 2 Phase I studies, 8 Phase II studies, and 4 Phase III studies. Four of the clinical studies were conducted to evaluate the protective efficacy of Rotarix™ against any and severe gastroenteritis. No conclusions could be drawn from a fifth study, due to the small number of rotavirus gastroenteritis cases documented in this Phase II study. Rotarix™ was shown to be effective during both the first and second year of life. The safety profile of Rotarix™ is acceptable.
Rotarix™ (106.0 CCID50/mL, human rotavirus, live, attenuated, oral vaccine) is presented as powder for suspension. The vaccination course consists of two doses. The first dose can be administered from the age of 6 weeks. There should be an interval of at least 4 weeks between doses. The administration of the two doses should be completed by the age of 24 weeks. Dosing guidelines are available in the Product Monograph.
Rotarix™ is contraindicated in infants who are hypersensitive to this drug or to any ingredient in the formulation or component of the container, infants who experienced hypersensitivity after previous administration of rotavirus vaccines, and infants with uncorrected congenital malformation (such as Meckel's diverticulum) of the gastrointestinal tract that would predispose for intussusception. Rotarix™ should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Rotarix™ are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Rotarix™ is favourable for active immunization of infants from the age of 6 weeks for the prevention of gastroenteritis caused by rotavirus types G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8].
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Rotarix™ contains live, attenuated, human rotavirus (strain RIX4414), which is used as an active immunizing agent. Rotarix™ is a monovalent vaccine (which belongs to the G1 serotype and [P8] genotype) which induces cross-protection to other types of rotaviruses (G2P[4], G3P[8], G4P[8], and G9P[8]). Rotavirus infection is the leading cause of severe acute gastroenteritis in infants and young children throughout the world. The immunologic mechanism by which Rotarix™ protects against rotavirus gastroenteritis is not completely understood. A relationship between antibody response to rotavirus vaccination and protection against rotavirus gastroenteritis has not been established. Rotarix™ is indicated for active immunization of infants from the age of 6 weeks for the prevention of gastroenteritis caused by rotavirus types G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8].
Manufacturing Process and Process Controls
The human rotavirus is produced in a Vero cell line. The manufacture of human rotavirus is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with ICH guidelines. Results of these tests confirmed cell line identity and absence of adventitious agents/viral contaminants. Genetic characterization also demonstrated genetic stability of the master cell bank ranging from storage to production at the limit of in vitro cell age.
The manufacture of human rotavirus comprises a series of steps which include cell culture, virus inoculation/propagation, virus harvest, clarification, DNA removal, ultrafiltration, and sterile filtration. The consistency of the manufacturing process is ensured through defined production procedures, critical quality tests, in-process limits, and human rotavirus certificate of analysis specifications. Microbial control is maintained throughout the manufacturing process by testing for bioburden as well as for bacterial endotoxins. In-process controls performed during the manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterization studies were performed to provide assurance that human rotavirus consistently exhibits the desired characteristic structure and biological activity.
Comparability of human rotavirus lots was performed and comparable physicochemical characteristics and immunoreactivity were demonstrated.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of human rotavirus are considered acceptable.
Copies of the analytical methods and, where appropriate, validation reports, are considered satisfactory for all analytical procedures used for release and stability testing of human rotavirus.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the real-time stability data submitted, the proposed shelf-life and storage conditions for the drug substance are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
The drug product is supplied as a sterile, lyophilised powder in a single-dose 3 mL Type I glass vial, with a rubber stopper and a flip-off cap, to be reconstituted with a liquid diluent before oral administration. Each vial of product contains not less than 106.0 CCID50 of live, attenuated RIX4414 strain human rotavirus, and the following excipients: sucrose, dextran, sorbitol, amino acids, and Dulbecco's Modified Eagle Medium (DMEM).
Vaccine diluent is filled in a 1.75 mL clean, sterile, glass syringe. Syringes are supplied siliconised, ready to be filled. The plunger stoppers used are of grey butyl rubber. The liquid diluent contains calcium carbonate, xanthan, and water for injection.
Vaccine vials and diluent syringes are packed together or separately depending on the final package (mono- or multi-pack).
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of human rotavirus with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Rotarix™, rationale for choice of formulation, manufacturing process including packaging, information on batches used in in vitro studies for characterization, and discussion on the effect of formulation change on the safety and/or efficacy of Rotarix™. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Data pertaining to the physico-chemical characteristics and biological activity demonstrated biocomparability between the development and commercial batches.
Manufacturing Process and Process Controls
The drug product is formulated, sterile-filtered, aseptically filled into vials, lyophilized, and labelled using conventional pharmaceutical equipment and facilities.
The validated process is capable of consistently generating product that meets release specifications.
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Rotarix™ is tested to verify that the identity, moisture content, pH, impurities, and potency, are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
The validation process is considered to be complete. Validation reports were submitted for in-process and release testing of the drug product, and no anomalies were present. The results for all of the batches were within the proposed specification limits.
Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.
Stability
Based on the real-time and accelerated stability data submitted, the proposed 36-month shelf-life at 2-8°C for Rotarix™ is considered acceptable. The reconstituted vaccine was shown to be stable for 24 hours at 18-25°C or below; however, it should be used within 8 hours and stored at 2-8°C, after which it should be discarded. The reconstituted vaccine should not be frozen.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of facilities involved in the manufacture and testing of Rotarix™ has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.
The design, operations and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Lactose is a ruminant-derived material (bovine milk) used in the current routine production process of the master seed and working seed, and also as a stabilizer during production. The lactose is considered in compliance with the TSE Note for Guidance.
The gelatin used to prepare the amino acids for the media preparation is obtained from porcine and bovine bones. The gelatin production process was reviewed by the European Commission which concluded that the risk associated with it is minor.
The European Directorate for the Quality of Medicines and Healthcare's Certificate of Suitability for the donor calf serum used in manufacture of the master cell bank was submitted.
Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Steps from the purification process designed to remove and inactivate viruses are adequately validated.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Rotarix™ has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Primary pharmacodynamic (PD) studies were based on two non-GLP (Good Laboratory Practices) studies and a GLP repeat-dose toxicity study. In the non-GLP studies, 21-day old Fischer F344 rats appeared more susceptible to the RIX4414 human rotavirus strain than 5-day old rats. It was shown that vaccine take, defined as the combination of seroconversion and/or viral shedding, was a good indicator of animal exposure to the vaccine. In the repeat-dose toxicity study, seroconversion was observed in 20% of RIX4414 (alone, without excipients)-exposed rats and 10% of Rotarix™-exposed rats. Rotavirus administration induced viral shedding in 20% of RIX4414 recipients and 80% of Rotarix™ recipients. Secondary pharmacodynamic studies were not performed as they are not applicable to vaccines.
Safety pharmacology was also assessed, based on the repeat-dose toxicity study. There were no lesions induced by Rotarix™ in the lungs or heart after oral administration to young Fischer F344 rats. There was no evidence of loose stools, effects on body weight, food consumption, rectal temperature, or histopathological signs of intestinal infection. Intestinal disturbances that could have been expected from live human rotavirus were not induced by the candidate vaccine. Drug interaction studies were not performed as they are not applicable to vaccines.
3.2.2 Pharmacokinetics
Non-clinical pharmacokinetic (PK) studies are not directly applicable to vaccines.
3.2.3 Toxicology
Acute Toxicity
Acute toxicity was assessed within the repeat-dose toxicity study.
Repeat-dose Toxicity
In the repeat-dose toxicity study a four-dose administration was used in order to cover the two clinical administrations foreseen in infants and a possible booster administration. Rats received a dose higher than the recommended human dose and the dose used in the Phase III trial. This dose provides an appreciable safety margin (133-fold based on bodyweight and 10-20-fold for infectivity). The no-effect level was not determined. Combined virology and serology analysis demonstrated a measurable vaccine take in 80% of rats that received Rotarix™ (formulated with the antacid CaCO3) and in 40% of rats that received the vaccine strain alone (without antacid) suggesting the additive value of using calcium carbonate (CaCO3) as an antacid. Although antacid granularity is known to affect the percentage of free virus particles, an estimation of free viral titers per body weight was found to be 3-4 times higher in this toxicity study than in the clinical Phase II/III studies and 6.8 times higher than in the recommended commercial vaccine strength.
Rotarix™ appeared to be immunogenic and non-toxic. The vaccine did not induce clinical signs, any clinical disease symptom, hyperthermia, or inflammatory signs in the gastrointestinal tract or adjacent lymph nodes. Administration of Rotarix™ was not associated with toxicological changes or histopatholigical lesions (including gut draining mesenteric lymph nodes and Peyer's patches). No differences were seen between Rotarix™ and the control and there was no evidence of intussusception. Other biological substances can be absorbed and metabolized without any toxicity. Statistical analysis could not be conducted in this study as the sample size was too small.
Genotoxicity
Genotoxicity studies were not performed, and were not required.
Carcinogenicity
Carcinogenicity studies were not performed, and were not required.
Reproductive and Developmental Toxicity
The reproductive toxicity of Rotarix™ was not evaluated as Rotarix™ is a pediatric vaccine and is not indicated for use in women of childbearing age.
Local Tolerance
Specific studies on local tolerance were not performed as microscopic investigations of the oesophagus, stomach, small and large intestine were performed in the repeat-dose toxicity study.
Other Toxicity Studies
Specific immunogenicity studies were not performed since microscopic investigations of the major lymphoid organs (thymus, spleen, lymph nodes, Peyer's patches) did not show treatment-related effects in the repeat-dose toxicity study. Also, lymphoid organ weights did not differ from the organ weights of control animals at any time point of sacrifice.
Neurovirulence testing in monkeys was conducted. No unexpected clinical or histopathological evidence of involvement of the central nervous system attributable to the inoculated working seeds was observed.
3.2.4 Conclusion
The studies conducted in the non-clinical program provided information on the safety and immunogenicity of Rotarix™ and support the use of the vaccine in clinical studies. Rotarix™ was well tolerated with no occurrence of serious adverse effects.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Clinical pharmacodynamic evaluations were conducted by the sponsor, which examined information on the characteristics of the immune response from clinical studies which enrolled healthy subjects including: evaluation of the level of specific antibodies produced; duration of antibody titres; and evaluation of the level of neutralizing antibodies.
3.3.2 Pharmacokinetics
No clinical pharmacokinetic studies were conducted for Rotarix™, as they are generally not required for vaccines
3.3.3 Clinical Efficacy
One pivotal Phase III study and 13 non-pivotal studies were used to evaluate the efficacy of Rotarix™. No biopharmaceutic studies were conducted.
Pivotal Study
The pivotal trial provided primary efficacy analysis on 17 867 subjects until one year of age. The G1P[8] type was the most prevalent type with 39 (44%) episodes among the 89 severe RV GE episodes identified during the efficacy follow up period. The primary efficacy endpoint, vaccine efficacy against severe RV GE caused by the circulating wild-type RV strains during the period starting from two weeks after Dose 2 until one year of age, was 84.7%. The HRV vaccine was effective in protecting against severe RV GE episodes caused by the G1 type with a vaccine efficacy of 91.8%. The HRV vaccine also provided protection against severe RV GE due to G9 and G3 types, indicating cross protection.
Hospitalizations due to RV GE were significantly reduced by 85.0%. The HRV vaccine showed a trend towards protective efficacy against severe RV GE starting from the first dose with efficacy of 50.7%. Vaccine efficacy against severe RV GE with a score >11 on the 20 point scale was 84.8%. However, some countries had small sample sizes and low incidence rate of severe RV GE, which severely impaired the statistical significance.
For efficacy during the second year, 14 237 subjects were analyzed. The number of severe RV GE episodes reported during the second year was substantial (incidence rate of 1.5%). During the 2-year follow up, vaccine efficacy against severe RV GE was 80.5%.
During the second year, a stronger RV season, the serotype predominance shifted to the emerging G9 type versus the G1 wild-type during the first year. The HRV vaccine was efficacious against severe RV GE caused by both G1 and G9 types that were dominant and also against those caused by G3P[8] and G4P[8] types. Efficacy against severe RV GE caused by the G4 type was observed during the second year while a small number during the first year failed to reach statistical significance. Fewer cases were reported in the HRV group compared to the placebo group during the first and second years for the G3 type, with the difference between groups not reaching statistical significance in the second year. A trend towards protection against the G2P[4] type that does not share any of the immunodominant recognized outer capsid antigens of the HRV was seen.
Vaccine efficacy against RV GE-related hospitalizations was 81.5% during the second year, over the 2-year follow up it was 83.0%. Vaccine efficacy against severe RV GE with a score >11 on the 20 point scale was 81.5% during the second year and 82.1% during the entire follow up period. Similar efficacy results were obtained with the total vaccinated cohort from Dose 1 up to visit 6: vaccine efficacy against severe RV GE caused by the circulating wild-type RV was 80.3%.
Regarding immunogenicity, results in this study showed that the anti-rotavirus IgA antibody seroconversion rate was 76.8% at one or two months after Dose 2 in a small subset of subjects. Since immunogenicity was evaluated in a subset of subjects, it was not possible to correlate seroconversion with protection against severe RV GE. The persistence of immunogenicity was not studied through the 2-year follow up. A total of 254 pre-term subjects were also observed in this study (52 in the long-term first year follow up); however, due to the small size and limited number of available results no conclusion can be drawn with respect to immunogenicity and efficacy. Due to lack of sufficient data in pre-term infants, the sponsor will conduct a Phase IIIb study in Europe to assess immunogenicity, reactogenicity, and safety in pre-term infants.
Consistency lots showed similar vaccine efficacy, with overlapping confidence intervals. The efficacy data supporting lot to lot consistency are considered to be a stronger category of evidence than antibody response data, as an antibody correlate of protection remains undefined.
In conclusion, the Phase III pivotal study demonstrated that Rotarix is efficacious and immunogenic, although data is currently insufficient on the persistence of immunogenicity and on pre-term infants.
Non-Pivotal Studies
In study Rota-004 (Finland), a statistically significant decrease in the percentage of subjects reporting any or severe rotavirus gastroenteritis (RV GE) was detected in the human rotavirus (HRV) vaccinated group. Protective efficacy against severe RV GE was 90.0%; efficacy against any RV GE was 73.0%. No infants were hospitalized in this study. In study Rota-006 (Latin America), a statistically significant decrease in the percentage of subjects reporting any or severe RV GE, as well as those hospitalized, was detected in the HRV group. Efficacy to prevent severe RV GE ranged from 65.8-85.6% depending on the viral concentration. Efficacy against any RV GE ranged from 55.7-70.0%; protective efficacy against hospitalization for RV GE ranged from 65.4-93.0%. In these two studies, the HRV vaccine showed better protection against severe disease than against RV GE of any severity. No reduction in mortality was observed in Latin America (where infant mortality rates are high) due to HRV vaccine. In study Rota-006, the protective efficacy against severe disease caused by the G9P[8] serotype ranged from 54.4-77.4% depending on viral concentrations. As the attack rate of non-G1, non-G9 serotypes was low, an accurate estimation of cross-protective efficacy results could not be generated for the individual serotypes G2, G3, and G4.
Vaccine efficacy in the second year of life was also analyzed. In study Rota-004, protection against any and severe RV disease was 72.8% and 83.4%, respectively. In study Rota-006, efficacy against severe RV disease was 78.1% for the pooled vaccine groups; conclusions regarding statistically significant clinical protection during this period were limited. Within the limits of the small sample size, two doses of HRV vaccine (pooled HRV vaccine groups) significantly decreased the incidence of any and severe RV GE during the combined efficacy follow up period: 47.5% and 74.7%, respectively. Study Rota-007 was not conclusive for efficacy due to the small number of documented RV GE cases. Vaccine estimates were similar between children who were breast-fed and those who were not breast-fed.
Eleven non-pivotal trials estimated the immunogenicity of HRV vaccine through IgA seroconversion rates, RV antigen shedding, and vaccine take. In study Rota-003, higher seroconversion rates were observed with increased dose levels, after both the first and second dose. In study Rota-006, no important differences were observed between concentrations with regard to seroconversion, but there was a trend towards higher geometric mean concentrations (GMCs) in subjects who seroconverted when higher viral concentrations were administered. In Rota-007, overall high seroconversion rates were observed. The seroconversion rate and GMC for the low dose level was lower, but no differences were observed between groups that received higher concentrations. Although higher viral concentrations were used in Rota-005, seroconversion rates as well as antigen shedding rates were in the same range as those observed in the lower virus concentrations groups in Rota-003 and -004. Vaccine take tended to be higher in the higher concentration group than in the lower viral concentration group. After the first dose in study Rota-003, the seroconversion rate ranged from 50.0-88.0%. The seroconversion rates after the second dose ranged from 72.2-95.7%. Both seroconversion and vaccine take rates increased from Dose 1 to Dose 2 in all groups. In study-006 the increase in seroconversion rates from Dose 1 to Dose 2 was ≥20%; vaccine take increased by 11%. There was no substantial increase in GMCs between doses, suggesting that the second dose only induced a response in subjects who did not seroconvert after the first dose. Lower seroconversion rates were observed in studies Rota-014 and-013 which studied the impact of concomitant administration of oral poliovirus vaccine (OPV) with the HRV vaccine following the Expanded Program on Immunization (EPI) schedule. In Study-033, peak antigen shedding after the first dose was observed on Day 7 (50.0% of subjects); by Day 30 none shed viral antigen. After the second dose the shedding rate was 17.4% on Day 3 and 4.2% on Day 7; none shed antigen by Day 10. In the Singapore study -007, which included older subjects, antigen shedding was higher. Few subjects shed viral antigen by Day 60 after the first dose (1.1% in Study-006). There was no difference in the rate of vaccine take between concentrations.
Infectivity of transmitted vaccine strain after oral intake in the absence of buffer is expected to be limited due to the gastric barrier. The lot-to-lot consistency of three consecutive production lots of HRV vaccine was demonstrated in Study-033 in terms of the ratios of GMCs, seroconversion rates, and the asymptotic standardized 90% CIs on differences in seroconversion rates 2 months after the second dose.
Several factors that may impact on the immune response were determined:
- Concomitant administration of OPV with HRV may reduce the immune response to RV vaccine.
- The presence of maternal anti-rotavirus antibodies, including the IgG and neutralising antibodies, is likely a factor that accounted for a decreased immune response to the HRV vaccine.
- Breast-feeding may be associated with lower seroconversion rates among children receiving HRV vaccine as suggested by two meta-analyses. Within the limitations of the subanalysis of immunogenicity according to feeding criteria, due to a small number of subjects in each subgroup, it can be concluded that breastfeeding had a limited impact on HRV immunogenicity.
In three studies (Rota-004, -005, and -006) the persistence the specific serum IgA was followed using blood samples taken at one year of age (also at two years of age in Rota-004). At one year of age, 70% of the vaccinated infants remained seropositive; levels of serum anti-rotavirus IgA antibodies remained high and higher than in the placebo groups (18% in the placebo group vs. 76% in the HRV group in Rota-004). At one year of age, the IgA seroconversion was maintained in 90% of the babies who seroconverted after vaccination and was maintained in 85% of the babies at two years of age indicating that the immune response persists up to the second year of life.
Concomitant administration of routine childhood vaccinations (DTPa, DTPw, HBV, IPV, N. meningitidis C, OPV, and S. pneumoniae) with HRV was evaluated in several of the studies, as well as the ongoing Phase III studies Rota-024 and -036. Results demonstrated that HRV vaccine is immunogenic and does not impair the immunogenicity of any of the concomitantly administered routine pediatric vaccines over the course of more than one season (17 months follow-up period).
3.3.4 Clinical Safety
Pivotal Study
The primary safety endpoint, examined in 63 225 subjects, was to determine the safety of the HRV vaccine with respect to definite IS within 31 days after each vaccination. There were no apparent differences in clinical characteristics of the IS cases (as symptoms or length of hospitalization) between the treated and placebo groups, and no differences were noted between the groups in terms of the interval from vaccination to onset of IS. All subjects had a complete recovery, except one who recovered with sequelae. Of the 25 definite IS cases, 13 (six in the HRV group) were within the risk window, and 8 of the 13 cases were assessed as related to treatment. The observed risk difference and relative risk values suggest that there is no increased risk of IS in the HRV group vs. placebo. There was no statistically significant increase in the percentage of subjects reporting definite IS from Dose 1 up to the third visit in the HRV group compared to the placebo. SAEs assessed as related to vaccination included 9 subjects out of 25 with definite IS. Data from 20 169 subjects followed until approximately one year of age had a risk difference and relative risk suggesting no increased risk of IS from Dose 1 up to visit 4 in the HRV group vs. placebo.
In the second-year efficacy subset (15 129 subjects analyzed for safety followed from visits 4-6 at 24 months of age), no IS cases and no increased risk of IS from Dose 1 up to visit 6 in the HRV group vs. placebo group were observed.
An additional hospital-based, multicentre study was conducted to assess the incidence of IS in children <2 years of age in Latin America. The report provided estimates of the incidence of IS in children under 1 year of age (range: 1.9 to 105.3 per 100.000 subject years) and 2 years of age (range: 0.9 to 62.4 per 100.000 subject years). Some limitations existed in the estimation of the incidence rates however. In study Rota-023, a total of 1975 subjects reported at least one SAE (including IS) during the period from Dose 1 to visit 3; the overall SAE profile was characterized by significantly fewer SAEs in the HRV group (293.0 per 10 000) compared to the placebo (331.8 per 10 000). There were fewer hospitalizations in the HRV group. Significantly fewer vaccine-treated subjects reported SAEs related to GE compared to placebo recipients.
SAEs related to nervous system disorders were evenly distributed between HRV and placebo groups (29 cases in each group). A potential imbalance in favour the placebo was noted for convulsions, however all cases were assessed as not related to vaccination and do not appear to support a causal link with HRV. The SAE safety profile from visit 4 up to visit 6 (second year, at 24 months of age) was also in favour of HRV with fewer GE-related SAEs reported in the HRV group. All SAEs were assessed as not related to vaccination.
There were no significant differences between groups for discontinuations due to adverse events. In the HRV group, 19.3 per 10 000 and in the placebo group, 15.2 per 10 000 dropped out at visit 3 due to SAEs. In the HRV group 18.0 per 10 000 and in the placebo group, 17.7 per 10 000 dropped out at visit 3 due to non-serious AEs. Between visits 3 and 4, six subjects in the HRV group and ten in the placebo group dropped out due to SAEs; only one subject withdrew due to a non-serious AE. Between visits 4 and 6, six subjects in the HRV group and seven in the placebo group dropped out due to SAEs; three subjects (one from the HRV group) withdrew due to a non-serious AE.
Two periodic safety update reports (PSURs) summarizing safety data collected through post-marketing surveillance and clinical studies (unblinded cases) were submitted. Data confirmed the clinical trial results.
In conclusion, Rotarix appears to have an acceptable safety profile although data are somewhat lacking. Future studies should confirm this safety profile.
Non-Pivotal Studies
The safety data from ten non-pivotal studies in infants were submitted. The evaluation focused on the occurrence of fever, diarrhea, and vomiting reported during the solicited follow up by each subject. For the reactogenicity analyses, a total of 14 032 doses of the HRV vaccine and 4963 doses of placebo were considered in the ten studies. The incidences of any symptoms (solicited or unsolicited) were reported at similar frequencies in the vaccine and placebo groups. The majority of the solicited symptoms were determined as related to vaccination but there were no significant differences between vaccine and placebo groups. There were no alerting signals in terms of reactogenicity and the reactogenicity profile of the HRV vaccine was similar to the placebo for all symptoms in studies conducted without co-administration of other vaccines. Where DTPa-based and DTPw-based vaccines were administered concomitantly, fever was reported on the day of vaccination. There was no increase in symptoms after the administration of the second and third doses (when given in some trials). For all studies there were no differences in the use of medications between HRV groups and the placebo groups.
For two fatal cases in the ongoing study Rota-028/029/030, autopsy results were complemented with investigations in different organs tissues for RV RNA by RT-PCR. Both tested negative and were not unblinded before the analysis of the study. Analyses by RT-PCR of the blood samples collected in study Rota-003 for AST/ALT analysis were performed to investigate if a pattern of RV detection in the blood of vaccine recipients may exist. Five vaccines (7%) were positive, all at seven days post-Dose 1; vaccine virus RNA was found in four cases. The presence of vaccine strain RV RNA in serum was correlated with vaccine strain shedding and IgA seroconversion post-Dose 1. No serious adverse events (SAE) were observed in these subjects.
In the pooled analysis, 24 subjects (0.33%) discontinued due to SAEs. Nineteen (13 in the HRV group) were due to fatalities; however, none of the SAEs were considered related to treatment. Twenty five subjects (20 in the HRV group [0.31%] and five in the placebo [0.27%]) discontinued due to non-serious AEs; eight were considered related to HRV vaccination. In Rota-013, five subjects (four received HRV) discontinued due to an SAE. Three were fatalities, however only one SAE (in the placebo group) was considered to be related to treatment.
In study Rota-036, HRV vaccine was shown to have a good safety profile with no fatal events reported. However, a potential imbalance in favour of the placebo for the SAE of pneumonia (28 cases from Dose 1 through visit 7, with 24 in the HRV group) was observed; no biological explanation could be given for this observation.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk assessment
Rotavirus is a common cause of gastroenteritis in children; overall, approximately 20% of all childhood gastroenteritis is caused by Rotavirus. Rotavirus is associated with considerable healthcare utilization with approximately 35% of children with Rotavirus gastroenteritis seeing a physician, 15% visiting an emergency department, and 7% requiring hospitalization.
Rotarix is proposed for active immunization of infants from the age of 6 weeks for the prevention of gastroenteritis caused by rotavirus types G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8].
Although the non-clinical program was somewhat lacking, the clinical program data are sufficient to declare that Rotarix is efficacious for the intended indication. Rotarix appears to be efficacious and immunogenic, although there was insufficient data on persistence of immunogenicity or data in pre-term infants in a larger sample size which will be addressed in a Phase IIIb study.
The clinical program showed that Rotarix has an acceptable safety profile and is well tolerated. Rotarix did not increase the risk of intussusception relative to placebo within 31 days following vaccination. Significantly fewer SAEs were observed in the HRV vaccine group through to the second year follow-up period. The proportion of SAEs linked to gastroenteritis disease was also lower in the vaccine group during the period of 2-4 months after vaccination.
Overall, the clinical efficacy, especially against severe rotavirus gastroenteritis and rotavirus-associated hospitalizations, outweighs the slight increase in risk of mild diarrhea and mild vomiting associated with vaccination. The risk/benefits ratio is therefore considered favourable for Rotarix.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Rotarix is favourable for active immunization of infants from the age of 6 weeks for the preventions of gastroenteritis caused by rotavirus types G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: RotarixTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2005-02-24 |
| Submission filed | 2006-11-01 |
| Screening | |
| Screening Acceptance Letter issued | 2006-12-13 |
| Review | |
| On-Site Evaluation | 2007-06-04 - 2007-06-07 |
| Quality Evaluation complete | 2007-10-02 |
| Clinical Evaluation complete | 2007-10-05 |
| Labelling Review complete | 2007-09-20 |
| NOC issued by Director General | 2007-10-09 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ROTARIX | 02300591 | GLAXOSMITHKLINE INC | ROTAVIRUS VACCINE (RIX4414 STRAIN), LIVE, ORAL, ATTENUATED (HUMAN) 1000000 CCID50 / 1.5 ML |