Summary Basis of Decision for RotaTeq ™

Biopharmaceutics and clinical pharmacology studies are normally not necessary for vaccines, and were not conducted in support of this submission.  The clinical program was divided into five Phase I/II studies and three pivotal Phase III studies.  The goals of the pivotal trials were to determine the efficacy, immunogenicity, and safety of the RotaTeq™ vaccine.  Subjects included 71 942 healthy infants with the majority (68%) being of Caucasian descent.

3.3.1 Pharmacodynamics

Traditional pharmacodynamic (PD) studies in animals were not conducted for RotaTeq™.  The sponsor acknowledges that the EMEA Note for Guidance on Pre-clinical Pharmacological and Toxicological Testing of Vaccines and the WHO Guidelines on Non-clinical Evaluation of Vaccines recommend that immunogenicity studies in animals be conducted.  However, clinical trials for the sponsor's rotavirus vaccine began in 1993, five to ten years prior to the establishment of the EMEA and WHO guidances, respectively.  By 1998, the sponsor had collected a significant amount of clinical data on the PD (immunogenicity and efficacy) of the vaccine in over 1 500 infants.  As a result, pharmacology animal data was irrelevant at this point.  This was further supported by the lack of an appropriate animal model in which to evaluate the immunogenicity of this live viral vaccine and its potential to protect from challenge.

3.3.2 Pharmacokinetics

No clinical pharmacokinetic (PK) studies were conducted as they are not normally necessary for vaccines.

Additionally, as stated in the Note for Guidance on Clinical Evaluation of New Vaccines (Committee for Proprietary Medicinal Products, EMEA), PK studies are generally not required for injectable vaccines because they do not provide information useful for establishing adequate dosing recommendations.  Although this guidance is directed toward injectable vaccines, similar principles apply to oral vaccines.

3.3.3 Clinical Efficacy

Rotavirus gastroenteritis is characterized by the sudden onset of watery diarrhea, fever, and vomiting, which last for an average of six days.  Severity varies from asymptomatic infection to dehydrating gastroenteritis that may be fatal.

The exact mechanism by which natural rotavirus protects against subsequent rotavirus illnesses is not well defined.  A definitive immunologic surrogate marker of protection has not yet been identified.  Immunogenicity studies of natural rotavirus infection have demonstrated that primary rotavirus infection induces serum neutralizing antibody (SNA) responses that are mainly homotypic (i.e. serotype specific), whereas subsequent infections induce broader, heterotypic responses.  Efficacy studies of natural rotavirus disease and rotavirus vaccines have also shown that protection provided by primary infection against any diarrhea appears to be largely specific.

Non-Pivotal Studies

A total of five Phase I/II studies were conducted to select the formulation, potency (dose), and reassortant compositions of RotaTeq™.  Although these early studies were generally controlled trials, they were not considered pivotal.  Four of the five non-pivotal studies contributed data essential to the support of the continued development of the quadrivalent human-bovine rotavirus reassortant vaccine.

An initial Phase I study determined that a single oral dose of a live quadrivalent human-bovine rotavirus reassortant vaccine resulted in a higher observed percentage of subjects with a ≥4-fold rise in SNA titres as compared to the placebo.  This study (which was conducted in adults) was, however, primarily a safety study.

A Phase IIa study followed to determine the immunogenicity and efficacy using a similar quadrivalent vaccine in healthy infants who were 2 to 6 months of age.  The vaccine was found to be efficacious in the prevention of rotavirus infection after the third dose and throughout the first rotavirus season.  It was found that the vaccine can modify the severity of rotavirus disease, providing greater efficacy against severe rotavirus disease.  The vaccine was immunogenic and there appeared to be no significant relationship between rotavirus case status and the antibody responses measured in the study.  The efficacy of the vaccine indicated by this controlled study suggested that it prevented 74.6% of all confirmed cases of rotavirus disease and prevented 100% of severe rotavirus disease. 

A second Phase IIa study was conducted in healthy infants, 2 to 4 months of age.  One of the primary objectives of this study was to identify a new buffer/stabilizer liquid formulation that would induce an SNA response post-dose 3 against the G1 strain, similar to the response induced by the formulation that was current at that point in time.  The results of the study indicated that each of the buffer/stabilizer liquid formulations studied were similar to the un-buffered formulation with respect to the percent of subjects with a ≥3-fold rise in SNA to the G1 strain.  The point estimates for efficacy for the buffer/stabilizer liquid formulation suggest that these formulations are efficacious and further studies to investigate their efficacy are warranted.  Insufficient data were generated from this study to declare any of the formulations to be efficacious against G1- and G2-serotype specific rotavirus disease of any severity or against moderate-to severe rotavirus disease.

Finally, a separate Phase IIa study assessed the efficacy and immunogenicity of the pentavalent (G1, G2, G3, G4, and P1) formulation of the vaccine in healthy infants.  During the first rotavirus season post-vaccination, all three potencies of the pentavalent vaccine were efficacious against all degrees of severity of rotavirus gastroenteritis that occurred at least 14 days following the last dose and that were caused by any of the human G-serotypes in the vaccine.  All of the vaccine regimens were shown to be efficacious regardless of the severity of rotavirus gastroenteritis through the second and third rotavirus seasons post-vaccination.  The efficacy results from this study provided the basis for assigning the expiry potency and for including the monovalent (P1) human-bovine rotavirus reassortant in the vaccine intended for authorization. 

This study could not assess statistically significant differences among pentavalent vaccines as the sample size was not large enough.  Further studies with larger sample sizes that also evaluate the efficacy of the vaccine against any human rotavirus serotypes have been recommended.

Pivotal Studies

Two of the three Phase III pivotal studies provided data demonstrating the efficacy of RotaTeq™.  All three studies were multicentre, randomized, placebo-controlled, double-blinded, and were conducted under in-house blinded conditions.  In all cases, subjects were given either the vaccine or the placebo as a three-dose regimen, with the first dose administered between 6-12 weeks of age.  Subsequent doses were given during separate visits at 4-10 week intervals.  The third and final dose was administered to infants up to 32 weeks of age. In both pivotal efficacy studies, subjects were healthy infants, 6-12 weeks of age with no:

• known history of congenital abdominal disorders, intussusception, or abdominal surgery;
  
  
• known hypersensitivity to any component of the rotavirus vaccine, e.g. neomycin or trypsin;
  
  
• Known or suspected impairment of immunologic function;
  
  
• prior administration of any rotavirus vaccine;
  
  
• fever (defined as rectal temperature of ≥100.5°F or ≥38.1°C) at the time of immunization;
  
  
• history of prior rotavirus disease, chronic diarrhea, or failure to thrive;
  
  
• clinical evidence of active gastrointestinal illness (note that infants with gastroesophageal reflux disease [GERD] were permitted to participate in the study as long as the GERD was well controlled with or without medication);
  
  
• receipt of oral polio vaccine, given within 42 days prior to study entry or during the trial;
  
  
• receipt of IM, oral, or IV corticosteroid treatment within 2 weeks prior to vaccination;
  
  
• receipt of blood products, including immunoglobulin (Ig), within 3 months prior to study entry;
  
  
• immunocompromised individuals who resided in the same household as the subject.

Protocol 006: Safety and Efficacy in Healthy Infants of Pentavalent (G1, G2, G3, G4, and P1) Human-Bovine Rotavirus Reassortant Vaccine

The first pivotal study took place at 356 primary study sites in several countries.  The United States contributed 50% of the enrollment, Finland contributed 33%, and the remaining percent were distributed among countries in the rest of Europe, Asia, and Latin America.  In total, 34 644 subjects received the vaccine product while 34 630 received a placebo.  The mean age at enrollment for both groups was 9.8 weeks and both sexes were equally represented.

The primary efficacy evaluations in these studies examined efficacy against all severities (mild, moderate, and severe) of rotavirus gastroenteritis.  There were a variety of secondary objectives for this study including the effect on hospitalizations and emergency department visits for rotavirus gastroenteritis.

Results of the study indicated that the vaccine is efficacious against naturally-occurring rotavirus gastroenteritis of any severity, caused by the composite of serotypes contained within the vaccine (G1, G2, G3, and G4).  The vaccine is efficacious through the first and second rotavirus seasons occurring at least 14 days following the third vaccination.  The vaccine reduces the incidence of health care contacts, including hospitalization and emergency department visits, for rotavirus gastroenteritis relative to placebo. Based on limited data, the vaccine also appears efficacious through the first rotavirus season occurring at least 14 days following the third vaccination against naturally-occurring rotavirus gastroenteritis of any severity caused by the G9 serotype.  In addition, the vaccine is immunogenic based on the G1 SNA response of a ≥3-fold rise from baseline to the last dose, and is generally immunogenic overall.

Although the majority of patient results were reported, some results remain outstanding.  Overall, primary efficacy was estimated to be approximately 74% which was similar to that demonstrated in the Phase II efficacy studies.  The results showed that RotaTeq™ incurs protection consistent with that provided by natural infection and with results of previous Phase II studies. 

Protocol 007: Study of Efficacy, Safety, and Immunogenicity of RotaTeq™ at Expiring Potency

A second pivotal study was conducted to evaluate the efficacy, safety, and immunogenicity of RotaTeq™ at expiry potency.  The Food and Drug Administration's Center for Biologics Evaluation and Research requested that this study be conducted due to differences in how the vaccine was produced and released between the previous Phase II and Phase III studies.  The Phase III study utilized the pentavalent vaccine with a potency similar to that of the middle-potency pentavalent vaccine regimen used in earlier non-pivotal studies.  The purpose of this was to confirm the efficacy, immunogenicity, and safety of the assigned expiry potency of vaccine produced using the final process, formulation, and potency assay intended for authorization.

The study included a total of 651 subjects in the vaccine group and 661 subjects in the placebo group.  The mean age at enrollment was 10.1 weeks in the vaccine group and 9.1 weeks in the placebo group.  Both sexes were equally represented.

The primary objective of the study was to evaluate the efficacy of a three-dose regimen of oral RotaTeq™ at expiry potency against naturally occurring rotavirus caused by the composite of the serotypes contained within the vaccine (G1, G2, G3, and G4) occurring at least 14 days following the third dose.  One of the key secondary objectives included the assessment of the immunogenicity of RotaTeq™ at expiry potency as measured by the SNA responses to vaccine serotypes (G1, G2, G3, G4, P1, and WC3), and serum rotavirus IgA in a subset of subjects.  Other secondary objectives were also evaluated.
                  
An intention-to-treat analysis of efficacy was also performed, including all cases that even potentially satisfied the case-definition and occurred any time following the first vaccination.  The efficacy point estimate was 45.2%.  The vaccine was efficacious against moderate-and-severe (76.3%) and severe disease (100%). These results are consistent with the protection provided for by natural infection as well as results from previous studies.

The efficacy estimate against all naturally occurring serotypes was close (72.7%) to the primary efficacy estimate.  Larger studies in geographic areas with more diverse serotypes should be conducted to adequately evaluate this result.

Immunogenicity

As part of Protocol 007, antibody responses to the vaccine were evaluated by several assays in a subset of ~150 subjects.  Serum samples (collected pre-dose 1 and 42 days post-dose 3) were tested by enzyme-linked immunosorbent assay (ELISA) for SNA against the serotypes contained within the vaccine (G1, G2, G3, G4, P1, and WC3).  Serum anti-rotavirus IgA was also measured.

The results indicated that the immunogenicity of RotaTeq™ at expiry potency with respect to post-dose 3 geometric mean titres (GMTs) for SNA responses to G1 and serum anti-rotavirus IgA was as expected based on the potency being evaluated and data from the previous Phase II studies.  In general, however, the proportion of subjects who had ≥3-fold rise in SNA to G1, G2, G3, G4, and P1 was generally lower than the proportion who received the middle-potency pentavalent vaccine regimen in the previous non-pivotal study.  Overall, RotaTeq™ at expiry potency was immunogenic.

Conclusion

In conclusion, the clinical efficacy studies submitted have provided adequate data to support the use of RotaTeq™ in the indicated population.  Each pivotal study was conducted with several objectives in mind using large sample sizes and a variety of study centres.  RotaTeq™ was found to be both efficacious and immunogenic, despite some minor discrepancies between the results of the different studies.

3.3.4 Clinical Safety

Non-Pivotal Studies

As described above, five Phase I/II studies were conducted in order to support the safety and efficacy of RotaTeq™. 

The initial Phase I study was conducted mainly to assess the safety of the vaccine.  The results indicated that eight placebo recipients (out of a total of eleven) had at least one adverse event (AE).  Three vaccine-related AEs (out of twenty vaccine recipients) were also noted.  Although there were no deaths or SAEs, it was suggested that this be monitored in future trials.  Results found that the vaccine was generally well tolerated.   

Three separate Phase IIa studies as well as one Phase IIb study indicated that the vaccine is generally well tolerated.  In addition, all buffer/stabilizer formulations as well as the unbuffered formulation are generally well tolerated. 

Finally, it should be noted that in one study the incidence of viral shedding was statistically higher for the high-dose and middle-dose pentavalent vaccines, and for the monovalent P1 vaccine.  It was recommended that another study with a larger sample size be conducted to evaluate the potential association of intussusception with the human-bovine rotavirus reassortant vaccine.

Pivotal Studies

Descriptions of the studies below including study design and inclusion criteria can be found in Section 3.3.3.

Protocol 006: Safety and Efficacy in Healthy Infants of Pentavalent (G1, G2, G3, G4, and P1) Human-Bovine Rotavirus Reassortant Vaccine

One of the primary objectives of this study was to assess the safety of RotaTeq™ with respect to intussusception within 42 days of any dose of vaccine/placebo.  Following the three-dose vaccination, parents/legal guardians were contacted on Days 7, 14, and 42 after each vaccination and asked about all serious AEs (SAEs) including intussusception.  Following the subject's final vaccination and 42 days of safety follow-up, the parent/legal guardian was contacted at 6-week intervals until Day 365 from the first vaccination or the study site's end-of-study date, whichever came first.  In addition, a subset of subjects was followed for acute gastroenteritis episodes (AGEs) through one or two full rotavirus seasons following vaccination. 

An independent Safety Endpoint Adjudication Committee (SEAC) reviewed and judged all potential cases of intussusception as they occurred by examining the relevant medical records and diagnostic tests in a blinded fashion.  The study utilized an unblinded Data and Safety Monitoring Board (DSMB) for interim monitoring of intussusception and SAEs.  The DSMB unblinded the treatment arm of confirmed cases of intussusception and made recommendations for continuing the study based on pre-defined safety boundaries as well as clinical judgement.  These safety boundaries were designed such that the study would be stopped early if the relative risk of intussusception in any of two overlapping day ranges (1-7 and 1- 42 days after any vaccination) was increased in a statistically significant manner among recipients of RotaTeq™ versus placebo recipients.

The results of the study found that within 42 days following vaccination, the vaccine does not increase the risk of intussusception relative to placebo.  In addition, there was no clinical evidence of increased risk of intussusception associated with the vaccine within 7 days, 14 days, or 60 days following vaccination or within 365 days following the first vaccination.  Furthermore, relative to the placebo, RotaTeq™ reduced the incidence of health care contacts, including hospitalization and emergency department visits due to infection with rotavirus gastroenteritis. 

Administration of other authorized vaccines was permitted in all studies.  The safety of RotaTeq™ when used concomitantly with pre-specified authorized vaccines was evaluated in a subset of subjects enrolled in Protocol 006.  This included the following vaccines: Haemophilus influenzae tybe b and hepatitis B vaccine, diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine, inactivated poliovirus vaccine (IPV), pneumococcal conjugate vaccine, and hexavalent vaccines.  RotaTeq™ was well tolerated and the frequency of AEs observed was generally similar to that seen when the concomitant vaccines were administered with placebo.  The concomitant administration of RotaTeq™ with oral polio vaccine (OPV) has not been studied.

P007:  Study of Efficacy, Safety, and Immunogenicity of RotaTeq™ at Expiry Potency

A secondary objective of Protocol 007 was to assess the safety of RotaTeq™ at expiry potency with respect to all AEs within 42 days of any dose of vaccine or placebo.  Parents/legal guardians were asked to record any AEs that occurred within 42 days following any vaccination.  In addition, they were asked to record daily temperature elevations (days 0 to 7 after each dose), behavioural changes (irritability), and the number of episodes of vomiting and/or diarrhea.

The results of the study indicated that there were no statistically significant differences in incidences of AEs between the group that received RotaTeq™ at expiry potency and the placebo except for reports of watery stool, sinusitis, and atopic dermatitis.  The incidences of watery stool and sinusitis were statistically higher in the placebo group, while atopic dermatitis had a significantly higher incidence in the vaccine group.  There was no significant increase in diarrhea, irritability, or vomiting in the group that received RotaTeq™ at expiry potency within 7 days following any vaccination.  There was a significant increase in elevated temperature within the 7 days following the first vaccination visit  in the group that received RotaTeq™ at expiry potency (13.4%) compared to the placebo group (8.8%) and following any vaccination in the group that received RotaTeq™ at expiry potency (30.0%) compared to the placebo group (23.9%).

During the study, five subjects were medically evaluated for suspected intussusception.  The SEAC determined that none of these were confirmed cases of intussusception.  All five of these subjects were randomized to the placebo group.

Results of the study indicated that the vaccine was generally well tolerated.  Enrollment of subjects during seasons not typically associated with respiratory and gastrointestinal illnesses probably contributed to the relatively low reporting of all AEs of clinical interest (i.e. diarrhea, vomiting, and elevated temperatures).  This was the first study to show a statistically significant difference in elevated temperatures among recipients of RotaTeq™ at expiry potency as compared to placebo recipients.  This finding should be evaluated in future studies.

Fecal rotavirus vaccine strain shedding was evaluated among all collected AGE samples that tested positive for stool antigen enzyme immunoassay (EIA).  There was one subject in whom vaccine virus strain shedding was detected.  This subject received RotaTeq™ at expiry potency and the AGE sample was collected three days post-dose 1, which is consistent with when vaccine virus replication peaks in the intestinal tract.  Fecal rotavirus vaccine virus strain shedding has been observed infrequently in previous studies and should be evaluated in future studies.

Protocol 009: Comparison of the Immunogenicity and Safety of Three Consistency Lots of RotaTeq™ in Healthy Infants

This study took place at ten sites in the United States.  The primary objective of the study was to demonstrate consistency in the antibody responses to three manufactured lots of RotaTeq™, based on the SNA post-dose 3 GMTs against rotavirus serotypes G1, G2, G3, G4, and P1 and to evaluate the safety of RotaTeq™.

Parents/guardians were asked to record any AEs in the same manner as that described for Protocol 007. The study concluded that RotaTeq™ was generally well tolerated. There were no statistically significant differences among subjects who received RotaTeq™ relative to those who received placebo with respect to the risk of diarrhea, irritability, vomiting, or elevated temperatures within 7 days following each vaccination (compared to elevated temperatures in Protocol 007 and consistent with prior Phase II studies).

Enrollment of subjects year-round, with a significant proportion enrolled during seasons typically associated with respiratory and gastrointestinal illnesses probably contributed to the relatively high reporting of all AEs of clinical interest (i.e. diarrhea, vomiting, and elevated temperatures).

During the study, two subjects were evaluated by the SEAC as potentially having a case of intussusception.; The cases were negatively adjudicated.  Of the two subjects, one received RotaTeq™ and the other placebo.  Additional studies of the pentavalent human-bovine reassortant rotavirus vaccine, particularly with regard to intussusception, serotype-specific efficacy, and immunogenicity when administered with concomittant vaccines are near completion.