Summary Basis of Decision for Flumist ®
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:
Flumist®
Influenza Vaccine (live, attenuated)
AstraZeneca Canada
Submission control no: 129379
Date issued: 2011-01-10
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:
Influenza Virus Type A (H3N2)
Influenza Virus Type B
International non-proprietary Name:
Strength:
Each 0.2 mL dose contains:
106.5-7.5 fluorescent focus units (FFU) of live attenuated influenza virus of each of three strains contained in the vaccine.
*Note that the strength may change with the selection of the contained influenza strains for the specific season but will always be within the specification of 106.5-7.5 FFU.
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02352621
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
FLUMIST® is a registered trademark of MedImmune licensed to AstraZeneca.
2 Notice of decision
On June 22, 2010, Health Canada issued a Notice of Compliance to AstraZeneca Canada for the vaccine FluMist®.
FluMist® is an active immunizing agent that contains live attenuated influenza virus reassortants of each of three strains:
- Influenza Virus Type A (H1N1);
- Influenza Virus Type A (H3N2); and
- Influenza Virus Type B.
FluMist® is indicated for the active immunization of individuals 2 to 59 years of age against influenza caused by virus subtypes A and type B contained in the vaccine.
Influenza illness and its health complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants of the virus. Therefore, influenza vaccines are standardized to the World Health Organization (WHO) recommendation (northern hemisphere) to contain the strains (that is, typically two subtypes A and one type B) representing the influenza viruses likely to be circulating in North America in the upcoming winter.
The market authorization was based on quality, non-clinical, and clinical information submitted. FluMist® has been administered to over 30,000 subjects in controlled clinical studies over multiple years, in various regions, using different vaccine strains. Many clinical studies in the development of FluMist® evaluated the efficacy endpoint of incidence of culture-confirmed influenza-like illness relative to placebo or an injectable influenza vaccine. The efficacy of FluMist® was assessed in nine controlled studies (three of which were active controlled studies) in paediatric subjects and two controlled studies (including one challenge study) in adults.
The efficacy of FluMist® in paediatric subjects was assessed in over 20,000 children over seven influenza seasons. In the placebo-controlled studies, FluMist® consistently demonstrated high rates of efficacy against culture-confirmed influenza illness due to matched strains and against influenza illness due to all strains regardless of antigenic match compared to placebo. In the active comparator studies conducted in children 6 months to 17 years of age, FluMist® consistently demonstrated statistically significant superior efficacy relative to an injectable, trivalent inactivated influenza vaccine against culture-confirmed influenza illness caused by wild-type virus strains antigenically matched to those in the vaccine, as well as against all strains regardless of antigenic match.
Data supporting the efficacy of FluMist® in adults 18 to 59 years of age was generated in two placebo-controlled clinical studies, which included a wild-type influenza challenge study. For the wild-type influenza challenge study, subjects were vaccinated with FluMist®, an active control (injectable influenza vaccine), or a placebo. Twenty-nine days later, subjects were challenged with wild-type influenza (A/H1N1, A/H3N2, or B). Efficacy was measured by wild-type virus shedding or serologic response. FluMist® demonstrated 85% efficacy in preventing influenza illness as compared to the 71% for the injectable influenza vaccine. In a second placebo-controlled study, FluMist® reduced the incidence of any febrile illness by 9.7% as compared to the placebo group.
FluMist® (influenza vaccine [live, attenuated]) is a live, trivalent vaccine for administration by intranasal spray by a healthcare professional. Each 0.2 mL dose contains 106.5-7.5 fluorescent focus units (FFU) of live attenuated influenza virus reassortants of each of the three strains for the specific season. The recommended dose for children, adolescents, and adults aged 9 to 59 years of age is one 0.2 mL dose (0.1 mL per nostril). For children 2 to 8 years of age not previously vaccinated with a seasonal influenza vaccine, two 0.2 mL doses of FluMist® given 4 weeks apart are recommended. Annual revaccination with an influenza vaccine is recommended because immunity declines over time and because circulating strains of influenza virus can change from year to year. Dosage and administration guidelines are available in the Product Monograph.
FluMist® is contraindicated for patients with a history of hypersensitivity, especially anaphylactic reactions to eggs, egg proteins, gentamicin, gelatine, or arginine, or to any other ingredient in the formulation. FluMist® is also contraindicated in individuals with a history of hypersensitivity to previous influenza vaccination. FluMist® 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 FluMist® are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of FluMist® is favourable for the active immunization of individuals 2 to 59 years of age against influenza caused by virus subtypes A and type B contained in the vaccine.
3 Scientific and Regulatory Basis for Decision
FluMist® is the first influenza vaccine in Canada that is administered via the intranasal route.
3.1 Quality Basis for Decision
FluMist® is a live, attenuated, cold-adapted, trivalent, influenza virus vaccine administered via a novel intranasal spray delivery system.
FluMist® contains three medicinal ingredients (drug substances) including live attenuated influenza virus reassortants for each of the three strains selected for the yearly influenza season: two Type A influenza strains (A/H1N1 and A/H3N2) and one Type B strain.
Following administration, the attenuated vaccine viruses replicate in the nasopharynx to induce protective immunity. Currently, most influenza vaccines are split-virus vaccines administered by injection that function by stimulating the production of immunoglobulin G (IgG) antibodies. FluMist® is the first influenza vaccine that is administered through the intranasal route. It also has the advantage of direct stimulation of local immunity [mucosal response including production of IgA and cell-mediated immune response (CMI)] as well as induction of a substantial systemic immune response (production of IgG and CMI).
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
The wild-type viruses used to prepare the vaccine strains are recommended annually by the WHO, the Vaccines and Related Biological Products Advisory Committee to the Food and Drug Administration (FDA) Center for Biologics Evaluation and Research (CBER), and the European Medicines Agency (EMA) Ad Hoc Influenza Working Group.
The influenza virus strains in FluMist® are cold-adapted (ca) [that is (i.e.) they replicate efficiently at 25 °C, a temperature that is restrictive for replication of many wild-type influenza viruses); temperature sensitive (ts) (i.e. they are restricted in replication at 37 °C (Type B strains) or 39 °C (Type A strains); and attenuated (att) (i.e. they do not produce classic influenza-like illness in a ferret model of human influenza infection]. The cumulative effect of the antigenic properties and the ca, ts, and att phenotypes is that the attenuated vaccine viruses replicate in the nasopharynx to induce protective immunity with no or restricted replication in the lungs. These biological properties enable the vaccine to elicit a protective immune response without causing clinical disease.
Manufacturing Process and Process Controls
The ca, ts, and att reassortant vaccine virus strains used for the manufacture of FluMist® are produced by genetic reassortment between a wild-type influenza virus and a master donor virus (MDV) strain. Such reassortant viruses contain gene segments encoding haemagglutinin (HA) and neuraminidase (NA) antigens that have been contributed by the wild-type virus, and gene segments encoding other proteins that have been contributed by the cold-adapted master donor viruses which possess the ca, ts, and att phenotypes. Therefore, cold-adapted reassortant vaccine strains derive their antigenic phenotypes from the wild-type strain and their ca, ts, and att phenotypes from the cold-adapted MDV.
FluMist® contains three active components: two attenuated influenza A strains (H1N1 and H3N2 based on the influenza A MDV) and one attenuated influenza B strain (based on the influenza B MDV).
There were no issues in terms of the manufacturing of the drug substance as this is a well established product. The materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.
In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
The results of the characterization studies demonstrated that the commercial refrigerated formulation is comparable to the previously frozen formulations of the vaccine manufactured and utilized in multiple clinical trials.
The refrigerated and frozen formulations were shown to be equivalent in biological properties including phenotypes (att, ca, and ts), replication, and immunogenicity. The genotype, HA inhibition (HAI) titre, and HA expression are equivalent to the master virus seed (MVS).
The sponsor has provided a summary of all drug-related impurities. Appropriate tests are adequately controlling the levels of product- and process-related impurities.
Control of Drug Substance
The specifications and analytical methods used for quality control of the FluMist® drug substance are considered acceptable. Batch analysis results were reviewed and all results complied with the specifications and demonstrated consistent quality of the batches produced.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicated that the impurities of the drug substance were adequately under control. The level of impurities reported for the drug substance was found to be within the established limits.
Importantly, the FluMist® drug substance is produced in Specific Pathogen-Free (SPF) embryonated eggs which are sourced from SPF chicken flocks that have been established, monitored, and maintained in accordance with European Pharmacopoeia (Ph.Eur.) section 5.2.2.
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 were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Each 0.2 mL dose of refrigerated FluMist® vaccine is formulated with 106.5-7.5 FFU of live attenuated influenza virus reassortants of each of the three strains for the yearly season: two attenuated Type A influenza strains (A/H1N1 and A/H3N2) and one attenuated Type B influenza strain. The final drug product contains the following excipients: sucrose, monobasic potassium phosphate, dibasic potassium phosphate, monosodium glutamate, arginine hydrochloride, and gelatin hydrolysate (porcine Type A).
The final FluMist® product is a blend of three strains of cold-adapted, temperature sensitive, and live, attenuated influenza virus, diluted during blending. The final, blended product is a colourless to pale yellow liquid and is clear to slightly opalescent. It is aseptically filled into 0.5-mL Accuspray™SCF™ (sterile, clean, fill) nasal sprayer barrels to a target volume of 0.23 mL (± 0.03 mL). Once filled, the sprayer barrels are then sealed with pre-sterilized Accuspray™SCF™ plunger stoppers to complete the primary container-closure. The finished product is presented as a 0.2 mL unit dose (approximately 0.1 mL per nostril).
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 drug substance 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. Parameters relevant to the performance of the drug product were not affected by the changes described.
Pharmaceutical development data, including selection of an appropriate container closure system, are considered acceptable. Data provided included composition of FluMist®, rationale for choice of formulation, manufacturing process including packaging, information on batches used for in vitro studies for characterization and for the safety and/or efficacy of FluMist®.
The clinical studies were conducted with both the frozen and refrigerated formulations of FluMist®.
Data pertaining to the physico-chemical characteristics and biological activity demonstrated biocomparability between the development and commercial batches.
Manufacturing Process and Process Controls
The manufacture of FluMist® consists of drug substance thaw, blend, fill, and packaging processes using conventional pharmaceutical equipment and facilities.
The manufacture of FluMist® begins when MVSs are created for the three influenza virus strains that are present in the vaccine. The MVSs are used to inoculate SPF embryonated eggs to produce individual monovalent bulks for each of the three virus strains. The monovalent bulks subsequently blended in the appropriate proportions along with a virus stabilizer, filled into sprayers, and packaged.
There were no issues with this submission in terms of the manufacturing of the drug substance and drug product since this is a well established product.
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. The validated process is capable of consistently generating product that meets release specifications.
Control of Drug Product
FluMist® is tested to verify that its identity, appearance, potency, pH, particulates, sterility, protein content, osmolality, colour, clarity, and levels of bacterial endotoxins 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.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product. The process validation is considered complete.
Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and were found to meet the specifications of the drug product and demonstrate consistency in manufacturing.
The proposed limits are considered adequately qualified. Control of the impurities and degradation products is therefore considered acceptable.
Stability
Based on the real-time and accelerated stability data submitted, the proposed shelf-life of 38 weeks which includes storage for up to 20 weeks at -20 ± 5 °C followed by storage up to 18 weeks at 2 to 8°C is considered acceptable. Due to the fact that different strains have different stability, the manufacturer should provide valid real-time stability data to support the expiry date of their product once manufactured with the new strains recommended by the WHO.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of the facilities involved in the manufacture of the drug product and drug substance was not performed for the following reasons:
- no issues were found in the review or in the laboratory testing portion; and,
- this product has been on the market in the United States for 7 years and the manufacturing facilities have been inspected by the United States FDA with a good safety profile.
Given these reason, it was determined that the risk of not performing the OSE as part of the review process was low.
The design, operations, equipment, and controls of the facilities involved in the production of FluMist® are considered suitable for the activities and products manufactured. All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
Issues of possible contamination of this vaccine by adventitious agents were carefully examined. Risk factors for adventitious agent contamination were identified at different stages of the FluMist® manufacturing process as described in the EMA "Points to Consider on the Development of Live Attenuated Influenza Vaccines". As limited downstream processing can be performed on a live vaccine such as FluMist®, the quality of the starting material is imperative to viral safety. The starting materials used in the manufacturing process are tested to ensure that they comply with regulations applicable to the manufacture of vaccines for human use.
The FluMist® drug substance is produced in SPF Eggs sourced from SPF Chicken Flocks that have been established, monitored, and maintained in accordance with Ph.Eur. 5.2.2.
Plasmids containing the six gene segments from the MDV and the two gene segments from the wild type are used to generate the FluMist® MVS, and are characterized (including sequencing) to ensure that they only contain the appropriate influenza virus gene sequences. These eight plasmids are transfected into Vero cells growing in serum-free medium and the resulting reassortant virus is amplified in SPF CEK cells that are subsequently added to the Vero cell culture. The serum-free Vero Master Cell Bank and Working Cell Bank used in the plasmid rescue process have been extensively tested for adventitious agents in conformance with International Conference on Harmonisation (ICH) guidelines.
Rigorous procedures are in place to ensure that the bovine serum used during manufacture of FluMist® MVSs is exclusively sourced from countries that have been assessed by the Scientific Steering Committee advising the European Commission on Bovine Spongiform Encephalopathy (BSE) as countries that are highly unlikely to present BSE Risk. Pharmaceutical grade porcine gelatin hydrolysate, Type A, is a component of the final FluMist® formulation, and is obtained from healthy animals. A comprehensive risk assessment has been performed to determine that any porcine viruses that may have been present in the pigs would have been inactivated by the low pH and high temperatures used during the manufacturing process. In addition, pigs are not designated as a Transmissible Spongiform Encephalopathy (TSE)-relevant animal species in the European Union.
Throughout the FluMist® manufacturing process, various manufacturing controls are used to prevent the contamination of the intermediates and the drug product by adventitious agents. In addition, the MVS and bulk drug substance are tested using procedures described in the Ph.Eur. to confirm that they are free of adventitious agents. This testing regimen ensures that any intermediate that is contaminated by adventitious agents is not used in subsequent downstream manufacturing operations. Finally, sprayers from each lot of FluMist® are tested for general safety, sterility, and endotoxin.
Given that FluMist® is a live virus vaccine, the manufacturing process does not include traditional procedures to clear viruses. The risk factors for contamination at each stage of the manufacturing process have been identified and precautionary measures have been implemented to eliminate any potential source of contamination in the final filled vaccine.
Each lot of FluMist® drug substance is extensively tested using validated in vivo and in vitro tests to ensure that the attenuated phenotype is maintained and that no adventitious agents have been introduced in the manufacturing process. The level of viral safety testing is high as compared to other live viral vaccines such as the measles, mumps, rubella (MMR) and varicella vaccines, but as with other biologics, there is no guarantee that new technologies will detect previously undetected adventitious viruses.
FluMist® has been sold in the United States market for the past seven years without any viral safety signals. Furthermore, the fact that the virus is grown in embryonated eggs adds a safety factor as any contaminating human pathogen present in the Vero cell derived MVS is unlikely to be amplified in avian embryonic cells.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for FluMist® 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
Both the frozen and current refrigerated formulations of FluMist® were studied, The active agents of the two formulations were live attenuated vaccine strains. The frozen formulation is no longer manufactured; however, studies performed with the frozen formulation have been repeated using the current refrigerated formulation.
3.2.1 Pharmacodynamics
One animal study compared viral replication, immunogenicity, and protection from viral challenge of the frozen and refrigerated formulations of FluMist® in ferrets. Five groups of ferrets (two per group) received two doses (0.5 mL per dose) of vaccine with an interval of 21 days between doses. At Day 36 (15 days after the second dose of vaccine), some animals were challenged with wild-type influenza strains. At Day 39 (3 days after the challenge), the animals were sacrificed and nasal turbinates and lungs were harvested to assess virus replication in these tissues. Both the refrigerated and frozen formulations had similar viral replication and immunogenicity. As well, both fomulations prevented replication of wild-type virus in the lung tissues and significantly decreased the level of replication of the challenge virus in the upper airways.
Safety Pharmacology
One safety pharmacology study was conducted in mice with a number of MVS strains as well as a trivalent formulation of FluMist®. The results of this study indicated that FluMist® vaccine viruses, either in monovalent or trivalent formulation, did not exhibit any neurotropism or neurovirulence.
3.2.2 Toxicology
Single- and Repeat-Dose Toxicity
A repeat-dose toxicity study was conducted in ferrets. Each ferret received up to three intranasal inoculations of either refrigerated FluMist®, the vehicle alone, or saline at Days 0, 28, and 98. The results showed that intranasal administration of refrigerated FluMist® was well tolerated in ferrets. The only treatment-related toxicity identified was a transient suppurative inflammation of the nasal turbinates and cervical lymph node hyperplasia after the first dose, which was likely due to the antigenic response to the vaccine.
Mutagenicity and Carcinogenicity
Mutagenicity and carcinogenicity studies are not normally required for viral vaccines. FluMist® will be given at most once or twice annually. Neither wild-type nor attenuated influenza viruses are considered to be mutagenic or carcinogenic.
Reproductive and Developmental Toxicity
Two reproductive and developmental toxicology studies were conducted in ferrets and rats with refrigerated or frozen FluMist®. Both studies showed that the vaccine had no evidence of maternal or foetal toxicity. In the study conducted with ferrets, two abortions occurred in the vaccine group (out of eighty) as compared to none in the control vehicle group. The relevance of these findings to humans remains unclear.
Local Tolerance
Two studies evaluated acute ocular toxicity in rabbits; one study was conducted with the refrigerated formulation of FluMist® and the other with the frozen formulation. The results showed that both formulations were well tolerated following intraocular administration.
3.2.3 Conclusion
The vaccine formulations used in the pharmacodynamic and toxicology studies were immunogenic and well tolerated. The non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology; single- and repeat-dose toxicity; reproductive and developmental toxicity; and local tolerance.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The pharmacodynamics of FluMist® were assessed through the analysis of immunogenicity described in section 3.3.3 Clinical Efficacy.
3.3.2 Pharmacokinetics
One pharmacokinetic study was performed with the two vehicle formulations (no virus, refrigerated and frozen). As no virus was administered, the results can only be considered as supportive. The aim of this study was to assess the distribution and clearance of the two nasally administered vehicle formulations.
Subjects received two doses of radiolabelled vehicle. Scintigraphic images (images that detect radiation emitted by radioactive substances in the body) were taken at planned intervals. The results showed that the majority of the delivered dose (76.3 ± 18.5%) of the refrigerated formulation vehicle (the product formulation) was initially deposited in the nasal cavity at the dose of 0.2 mL (0.1 mL per nostril). The clearance half-life of refrigerated formulation in the nasal cavity was less than half an hour (0.44 hours). Less than 5% of vehicles were observed in regions overlying the lung and brain.
3.3.3 Clinical Efficacy
FluMist® has been administered to over 30,000 subjects in controlled clinical studies over multiple years, in various regions, using different vaccine strains. Many clinical studies in the development of FluMist® evaluated the efficacy endpoint of culture-confirmed influenza-like illness relative to placebo or an injectable trivalent influenza vaccine (TIV).
Efficacy in the Paediatric Population
The efficacy of FluMist® in paediatric subjects was assessed in over 20,000 children over seven influenza seasons. Nine controlled studies (six placebo-controlled and three active-controlled) support the indication for FluMist® in this patient population. Four of the placebo-controlled studies included analysis following second season re-vaccination. A summary of the efficacy results for each of these studies are provided in the two tables below.
| Study | Year | Number of Doses | Subject Age Range | Efficacy of FluMist® as compared to Placebo for all three matched strains |
|---|---|---|---|---|
| ||||
| AV006 | 1 | 2 | 15 to 711 months | 93.4% |
| 1 | 88.8% | |||
| 2 | 1 | 100.0% | ||
| D153-P501 | 1 | 2 | 12 to 35 months | 72.9% |
| 2 | 1 | 84.3% | ||
| D153-P502 | 1 | 2 | 6 to 35 months | 85.4% |
| 2 | 1 | 88.7% | ||
| D153-P504 | 1 | 2 | 6 to 35 months | 73.5% |
| 2 | 1 | 73.6% | ||
| 1 | 1 | 57.7% | ||
| 2 | 1 | 65.2% | ||
| D153-P513 | 1 | 2 | 6 to 35 months | 62.2% |
| D153-P522 | 1 | 2 | 11 to 24 months | 78.4% |
In the placebo-controlled studies, FluMist® consistently demonstrated higher rates of efficacy than the placebo against culture-confirmed influenza illness due to matched strains, as well as against influenza illness due to all strains regardless of antigenic match.
During the first seasonal outbreak following FluMist® vaccination, absolute efficacy against matched strains ranged from 62 to 93%. In analyses for all strains regardless of antigenic match, FluMist® absolute efficacy during the first season ranged from 49 to 86%. In two of the placebo-controlled studies, previously unvaccinated children demonstrated higher efficacy following two doses of FluMist®, although statistically significant efficacy was achieved following one dose. As a result, two doses of vaccine are recommended in children 2 to 8 years of age who have not been previously vaccinated with seasonal influenza vaccine.
Four studies examined the efficacy of second-season re-vaccination. Following second-season re-vaccination, the efficacy of FluMist® ranged from 74 to 100% for matched strains and from 47 to 87% for all strains regardless of antigenic match. Efficacy against matched strains after second-season re-vaccination was either the same as, or higher than, efficacy after the primary (first season) vaccination. In two separate studies, two doses of FluMist® in Year 1 were associated with efficacy that persisted into the subsequent season; however, given that circulating strains of influenza virus can vary from year to year, annual re-vaccination is recommended as protection is lower in the second year following vaccination.
| Study | Number of Doses | Subject Age Range | Efficacy of FluMist® as compared to Trivalent Influenza Vaccine (TIV) for all three matched strains |
|---|---|---|---|
| D153-P514 | 2 | 6 to <72 months | 52.7% |
| D153-P515 | 1 | 6 to17 years | 34.7% |
| MI-CP111 | 1 | 6 to 59 months | 44.5% |
Three active-controlled studies were conducted in children 6 months to 17 years of age. Subjects received FluMist® or an injectable TIV. FluMist® consistently demonstrated statistically significantly superior efficacy relative to the comparator against culture-confirmed influenza illness caused by wild-type virus strains antigenically matched to those in the vaccine, as well as against all strains regardless of antigenic match. Compared to the TIV, FluMist® reduced the number of cases of culture-confirmed influenza illness by 35 to 53% for illness due to matched strains, and by 32 to 55% for illness due to all strains regardless of antigenic match.
Efficacy in the Adult Population
The efficacy of FluMist® in adults (18 to 64 years of age) was assessed in four controlled studies (two placebo-controlled, one active-controlled, and one placebo- and active-controlled). One of the placebo-controlled clinical studies included a small wild-type influenza challenge study. The results of these studies support the indication for FluMist® in this patient population and are summarized in the tables below.
| Study | Number of Doses | Subject Age Range | Efficacy of FluMist® as compared to Placebo for all three matched strains |
|---|---|---|---|
| D153-P507 | 1 | ≥60 years | 42.3% |
| AV009 | 1 | 18 to 64 years | FluMist® can statistically significantly reduce: severe febrile influenza-like illness (not any febrile influenza-like illness) and febrile upper respiratory illness |
| AV003 | 1 | 18 to 40 years | After a challenge with wild-type influenza virus the efficacy for FluMist® was 85% versus placebo and 71% for the trivalent injectable influenza vaccine versus placebo. |
| Study | Number of Doses | Subject Age Range | Efficacy of FluMist® as compared to Trivalent Influenza Vaccine (TIV) for all three matched strains |
|---|---|---|---|
| D153-P516 | 1 | ≥60 years | -49.4% The efficacy of FluMist® compared to TIV was not statistically different. |
| AV003 | 1 | 18 to 41 years | Attack rates after a challenge with wild-type influenza virus were similar between FluMist® and TIV recipients (7% versus 13%) |
For the wild-type influenza challenge study, subjects were vaccinated with FluMist®, an active control (injectable influenza vaccine), or a placebo. Twenty-nine days later, subjects were challenged with wild-type influenza (A/H1N1, A/H3N2, or B). Efficacy was measured by wild-type virus shedding or serologic response. FluMist® demonstrated 85% efficacy in preventing influenza illness as compared to the 71% for the injectable influenza vaccine.
The efficacy of FluMist® was assessed in adults over 60 years old in two controlled clinical studies. One study showed 42.3% efficacy for FluMist® compared to placebo, which was lower than in pediatric population after 1-dose schedule. The other study showed that FluMist® was not better than the TIV in terms of efficacy. Based on these results, FluMist® has not been indicated for this population (≥60 years of age).
Immunogenicity
The immunogenicity of FluMist® was assessed in a subset of subjects. Immunogenicity was measured based on immune responses elicited by the vaccine as measured by the level of antibodies against the HA envelope protein of the influenza viruses (as detected by the HAI assay). The immunogenicity results support the ability of FluMist® to induce an immune response to the virus subtypes contained in the vaccine. The relationship between this immune response and the protective ability of the vaccine has not been established; therefore, the clinical relevance of the immune response induced by FluMist® is not known.
Concomitant Vaccine Administration
Three studies evaluated the immune response and safety after concomitant administration of FluMist® with MMR, varicella, and the oral polio vaccine (OPV). The results of these studies demonstrated that in general, the immune responses induced by the MMR, varicella, and OPV vaccines were not interfered with by the concomitant administration of FluMist®.
3.3.4 Clinical Safety
The safety of FluMist® was assessed in the clinical studies discussed in section 3.3.3 Clinical Efficacy as well as in additional supportive clinical studies.
Safety in the Paediatric Population
Over 12,900 children and adolescents 6 months to 17 years of age in the controlled studies received at least one dose of refrigerated FluMist® in Year 1 and provided data for the pooled safety analysis. The most common solicited adverse events (AEs) observed during Days 0 to 10 post-dose 1 which occurred in 1% of FluMist® recipients included: runny/stuffy nose, cough, decreased appetite, irritability, abdominal pain, decreased activity (including tiredness, weakness, and malaise), headache, vomiting, sore throat, muscle ache, chills, and fever.
In addition, a potentially medically significant serious adverse event (SAE) was observed within 42 days of dosing in a subject 2 to 17 years of age: one case of Kawasaki's disease.
Wheezing
One active-controlled study investigated wheezing events in children 6 to 59 months of age. The safety endpoint of primary interest was the rate of medically significant wheezing occurring through 42 days after final vaccination. Medically significant wheezing (MSW) was defined as the presence of wheezing on physical examination accompanied by at least one of the following:
- a sign of respiratory distress: tachypnoea, retractions, or dyspnoea;
- hypoxaemia (O2 saturation <95%); or
- a new prescription for daily bronchodilator therapy (not on an "as needed" basis).
The percentage of all subjects who reported MSW was similar between groups (3.9% for FluMist versus (vs.) 3.1% for injectable influenza vaccine recipients); however, upon analysis by subgroup, the rates of wheezing were statistically significantly higher for FluMist® recipients who were <24 months of age at the time of vaccination (5.9% for FluMist® vs. 3.8% for injectable influenza vaccine recipients). The rate of wheezing was not increased in recipients >24 months of age.
The percentage of subjects who reported a solicited event/AE of wheezing from Days 0 to 28 after each dose was similar between groups: for all subjects, 2.8 to 3.4% for FluMist® (depending on dosage group) vs. 2.5 to 3.1% for injectable influenza vaccine recipients; however, in one subgroup analysis (for subjects <24 months of age in the one-dose group only), the solicited event/AE rate of wheezing was statistically significantly higher: 5.2% for FluMist® recipients vs. 1.5% for injectable influenza vaccine recipients. In the same study, a statistically significantly higher rate of hospitalizations (for any cause) through 180 days after final vaccination dose was observed in children 6 to 11 months of age (6.1% for FluMist® vs. 2.6% for the injectable influenza vaccine) as well as for respiratory hospitalizations (3.2% for FluMist® vs. 1.2% for the injectable influenza vaccine). The rate of hospitalizations was not increased in FluMist® recipients ≥12 months of age.
Serious Adverse Events
In the pooled safety analysis for subjects 6 months to 17 years of age who were administered FluMist®, the majority of the SAEs were infectious, respiratory or gastrointestinal events, including pneumonia, gastroenteritis, asthma, and otitis media. Rare SAEs assessed as at least possibly related to FluMist® included febrile seizure events, encephalitis, idiopathic thrombocytopaenic purpura, Kawasaki acute laryngitis, and acute pansinusitis.
Safety in the Adult Population
A total of 3,301 adults (18 to 59 years of age) received FluMist® dosing and provided data for the pooled safety analysis in controlled studies. In these studies, solicited events were documented for 6 days post-vaccination. The most common solicited AEs observed during Days 0 to 6 post-dose which occurred in 1% of FluMist® recipients included: runny/stuffy nose, headache, sore throat, malaise, muscle ache, cough, chills, fever, decreased appetite, abdominal pain/stomach ache, and vomiting.
Serious Adverse Events
The majority of the SAEs reported by adult subjects who had received FluMist® were infectious events.
Immune Compromised Individuals
Safety and shedding of vaccine virus following FluMist® administration were evaluated in 57 human immuno-deficiency virus (HIV)-infected and 54 HIV-negative adults 18 to 58 years of age in a randomized, double-blind, placebo-controlled study. In this study, there were no SAEs attributable to FluMist®, and vaccine virus shedding in HIV-infected individuals was comparable to that seen in healthy populations. No adverse effects on HIV viral load or CD4 counts were identified following FluMist® administration. The effectiveness of FluMist® in preventing influenza illness in HIV-infected individuals has not been evaluated.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The ages of the study population for the placebo-controlled and active-controlled efficacy studies ranged from 6 months to 97 years. The clinical study results showed that:
- For children 6 months to 17 years of age:
- FluMist® can provide protection against culture-confirmed influenza illness caused by subtypes antigenically matched to those in the vaccine. Both one-dose and two-dose regimens of FluMist® demonstrated efficacy against culture-confirmed influenza illness; however, two doses of FluMist® can provide better protection compared to one dose for the children who were not previously vaccinated with seasonal influenza vaccine. In addition, the safety profile of two doses of FluMist® was comparable to one dose and both were well tolerated.
- For adults 18 to 64 years of age:
- FluMist® can reduce severe febrile influenza-like illness and febrile upper respiratory illness. Additionally, FluMist® also showed protection against challenge with wild-type influenza virus strains in a small number of subjects (10 subjects per group per strain) 18 to 41 years of age.
- For adult ≥60 years of age:
- FluMist® showed efficacy against culture-confirmed influenza illness caused by subtypes antigenically matched to those in the vaccine. Efficacy was lower as compared to the results in the children (42.3% vs. 62.2%-93.4%). Based on the current data, the indication for elderly subjects ≥60 year of age is not supported.
The results of the clinical studies have demonstrated that FluMist® is highly and consistently efficacious. FluMist® was well tolerated in the study population with the exception of wheezing events in children <24 months of age. For children <24 months of age, significant benefit (efficacy) was observed; however, due to the increased risk of wheezing in children <24 months of age, FluMist® has not been indicated for this age group.
For annual registration of FluMist®, a safety study must be conducted in adults for any new strain included in FluMist®.
In addition to clinical study data, the post-market experience with FluMist® in other countries, which includes more than 10 million doses distributed between 2003 and 2008, confirms the profile of safety and tolerability established in the clinical development program.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of FluMist® is favourable for the active immunization of individuals 2 to 59 years of age against influenza caused by virus subtypes A and type B contained in the vaccine. 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: Flumist®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2009-05-21 |
| Submission filed: | 2009-07-21 |
| Screening | |
| Screening Acceptance Letter issued: | 2009-08-28 |
| Review | |
| Quality Evaluation complete: | 2010-06-18 |
| Clinical Evaluation complete: | 2010-06-21 |
| Labelling Review complete: | 2010-06-08 |
| Notice of Compliance issued by Director General: | 2010-06-22 |