Summary Basis of Decision for Arepanrix ™ H1N1 (AS03-Adjuvanted H1N1 Pandemic Influenza Vaccine)
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:
ArepanrixTM H1N1 (AS03-Adjuvanted H1N1 Pandemic Influenza Vaccine)
AS03-Adjuvanted H1N1 Pandemic Influenza Vaccine
ID Biomedical doing business in Canada as GlaxoSmithKline Biologicals North America
Submission control no: 132070
Date issued: 2010-05-11
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:
- 3.75 µg - [haemagglutinin (HA) split virion monovalent, A/California/7/2009 NYMC X-179A (H1N1) antigen]
- 10.69 mg -squalene
- 11.86 mg - DL-α-tocopherol
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02336650
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On October 13, 2009, an Interim Order was issued by the Minister of Health at the request of the Public Health Agency of Canada to allow the authorization for sale of a vaccine for the novel Influenza A H1N1 virus in response to the influenza A H1N1 pandemic. An Interim Order is issued by the Minister of Health under Section 30.1 of the Food and Drugs Act in rare situations where the Minister believes that immediate action is required to deal with a significant risk, direct or indirect, to human health, public safety, or the environment.
The Minister authorized the sale of the Arepanrix™ H1N1 vaccine (AS03-Adjuvanted H1N1 Pandemic Influenza Vaccine) on October 21, 2009 based on limited clinical testing in humans under the provision of the Interim Order.
Based on the Health Canada review of the available data on quality, safety and immunogenicity, and given the current pandemic threat and its risk to human health, Health Canada considers that the benefit/risk profile of the Arepanrix™ H1N1 vaccine is favourable for active immunization against the H1N1 2009 influenza strain in an officially declared pandemic situation.
As part of the authorization for sale for Arepanrix™ H1N1, Health Canada has requested the sponsor to agree to post-market commitments. Adherence to these commitments, as well as updates to information on quality, non-clinical, and clinical data will be continuously monitored by Health Canada and the Public Health Agency of Canada.
A prototype or "mock" vaccine was developed in the pre-pandemic period using an H5N1 strain. During this period, Health Canada inspected the vaccine manufacturing facilities, evaluated data on the vaccine production process, and reviewed results from both animal and human studies conducted with the mock vaccine. In addition, the safety and effectiveness of the AS03 adjuvant to be used with the vaccine was assessed by Health Canada. All results were considered acceptable. Once the H1N1 virus emerged as the pandemic virus, the manufacturer initiated vaccine production using the strain recommended by the World Health Organization (WHO).
The following data were used to support the authorization for sale of the Arepanrix™ H1N1 vaccine:
- Quality (chemistry and manufacturing) data for the vaccine manufacturing process to support the strain change from H5N1 to H1N1;
- Clinical safety and immunogenicity data from studies in humans to indicate that the H1N1 vaccine has an acceptable safety profile and that the recommended dose is appropriate to produce an adequate immune response; and
- Safety and other data from the review of the prototype H5N1 vaccine.
Data from international clinical studies using similar or related pandemic vaccines that became available during the authorization process were also considered. Further clinical studies and post-market surveillance will be continually assessed post-authorization.
Arepanrix™ H1N1 vaccine is indicated for active immunization against the H1N1 2009 influenza strain in an officially declared pandemic situation. Please refer to the Product Information Leaflet for details on recommended dosage for specific age groups.
Arepanrix™ H1N1 (AS03-adjuvanted H1N1 pandemic influenza vaccine) is a two-component vaccine consisting of an H1N1 immunizing antigen (as a suspension) and an AS03 adjuvant (as an oil-in-water emulsion). The H1N1 antigen (an inactivated, split-virion, influenza A H1N1 virus antigen) is based on the strain derived from A/California/07/2009 (H1N1)v, the strain officially recommended by the WHO for the manufacture of vaccines during the current influenza pandemic. The AS03-adjuvant component is intended to increase the immunogenicity of the pandemic influenza virus haemagglutinin (HA) antigen, thus allowing a dose-sparing mechanism that permits the administration of a smaller dose of antigen while providing comparable immunogenicity to a non-adjuvanted vaccine.
The Arepanrix™ H1N1 antigen component is manufactured in accordance with previously established procedures for the commercially available seasonal influenza vaccine Fluviral®, produced at ID Biomedical Corporation of Quebec, doing business as GlaxoSmithKline Biologicals North America's facilities in Ste. Foy, Québec. Fluviral® has been an approved seasonal flu vaccine in Canada since 1992.
Each 0.5 mL dose of the Arepanrix™ H1N1 vaccine contains 3.75 µg HA derived from A/California/07/2009 (H1N1)v. The AS03-adjuvant component is composed of an oil phase containing the natural, biodegradable oil, squalene (10.69 mg per dose) and DL-α-tocopherol (Vitamin E oil; 11.86 mg per dose), mixed with an aqueous phase composed of an isotonic phosphate buffered saline solution. Polysorbate 80 (Tween 80; 4.86 mg per dose) is used as an emulsifier to stabilize the oil/water interfaces. Each dose also contains 5 µg of the preservative thimerosal. Prior to administration, the contents of the adjuvant vial are withdrawn and mixed in a one-to-one ratio with the contents of the antigen vial.
The authorization for sale for the Arepanrix™ H1N1 vaccine was based on quality and available non-clinical and clinical information submitted for the Arepanrix™ H1N1 vaccine, the Pandemrix™ vaccine (a similar H1N1 pandemic influenza vaccine manufactured by GlaxoSmithKline in Dresden, Germany), and supporting quality and safety data from the prototype H5N1 vaccine.
A number of clinical studies are currently underway in Europe and North America to evaluate the safety and immunogenicity of a two-dose schedule of the Arepanrix™ H1N1 vaccine as well as the Pandemrix™ vaccine. Results from these studies will be assessed by Health Canada as soon as they become available. The preliminary results of two studies with Pandemrix™ have been submitted to Health Canada for review. The first study, D-Pan-H1N1-021, is a Phase II, multicentre, observer-blind, randomized study, while the second study, D-Pan-H1N1-007, is a Phase III, single-centre, observer-blind, randomized study.
Preliminary results from both studies indicate that at Day 21, following one dose of vaccine, both the adjuvanted and non-adjuvanted vaccines met the internationally accepted immunogenicity criteria. A strong immune response was observed, for both formulations, after one single vaccine dose. Given the short amount of time that has elapsed since the initiation of these studies, the persistence of this response cannot be determined at this time, nor is it possible to determine if a second dose or a booster dose will be required at a later date.
In Study D-Pan-H1N1-007, general systemic reactions were more common in the adjuvanted-vaccine group but were considered generally mild. The most common reactions were fatigue, headache, and pain at the injection site (in both the adjuvant and the non-adjuvant groups), and muscle ache (in the adjuvanted-vaccine group). A small percentage (~2%) of Grade 3 (severe) reactions was reported for headache and muscle ache in the adjuvanted-vaccine group and fatigue and shivering in the non-adjuvanted vaccine group. Fever was not reported in either vaccine group.
Clinical data for the use of the Arepanrix™ H1N1 vaccine or the AS03-adjuvant component in pregnant women are not available at the time of publication of this Notice of Decision. In addition, no data are available in breast-feeding women or in children under the age of 3 years.
The vaccine should be injected intramuscularly preferably in the deltoid muscle or anterolateral thigh. Instructions for mixing and administration of the vaccine are available in the Product Information Leaflet.
Arepanrix™ H1N1 is contraindicated for patients with a history of life-threatening anaphylactic reaction to any of the constituents or trace residues of this vaccine as listed in the Product Information Leaflet.
Arepanrix™ H1N1 should be administered under the conditions stated in the Product Information Leaflet taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Arepanrix™ H1N1 are described in the Product Information Leaflet.
Full consideration has been given to international activities and declarations and notices issued by the WHO.
3 Scientific and Regulatory Basis for Decision
On October 13, 2009, an Interim Order was issued entitled, "Interim Order Respecting the Sale of the Vaccine for Novel Influenza A H1N1 Virus". On October 21, 2009, the Minister issued an authorization for sale for the Arepanrix™ H1N1 (AS03-adjuvanted H1N1 Pandemic Influenza Vaccine) pursuant to section 11 of that Interim Order.
As a vaccine was needed almost immediately following its development and manufacture, there was insufficient time to conduct the traditional clinical trials required to authorize a vaccine under the existing regulatory framework. An Interim Order was required to expedite the authorization process so that a vaccine would be available in a timely manner such that it could have maximal benefit on the Canadian population. The Interim Order also specified post-marketing commitments which had to be met by the manufacturer.
An Interim Order may be issued by the Minister of Health under Section 30.1 of the Food and Drugs Act in situations where the Minister believes that immediate action is required to deal with a significant risk, direct or indirect, to human health, public safety, or the environment. The Interim Order takes effect when signed by the Minister of Health and must be confirmed by the Governor in Council within 14 days and tabled both in the House of Commons and the Senate within 15 days of the date that it takes effect. An Interim Order has effect from the time that it is signed but ceases to have effect on the earliest of the day it is repealed, the day on which regulations having the same effect as the Interim Order come into force, or one year after the day on which the Interim Order is signed, whichever is earliest.
Regulatory Premise for the Development of a Pandemic Influenza Vaccine
The development and manufacture of a pandemic vaccine cannot occur until a pandemic strain of influenza is identified. Development of a pandemic vaccine for Canadians and the process for expedited regulatory authorization for its use were based on the extensive groundwork accomplished through pandemic planning activities over several years by both the vaccine manufacturer and the Canadian regulatory authority (Health Canada). These activities were undertaken to ensure that when a pandemic occurred, a safe and effective vaccine against the pandemic strain could be made available as early as possible. Because of the short time frame for the production of vaccine following the appearance of the pandemic H1N1 (pH1N1) virus and the expedited authorization for sale, the clinical trials which normally would have informed these recommendations are, at the time of publication of this document, still in progress. Only preliminary clinical data were available at the time of authorization of the pandemic vaccine.
Health Canada made the following public commitments respecting the regulatory authorization process for a pandemic influenza vaccine(s):
- to provide the "appropriate degree" of regulatory oversight regarding safety, efficacy, and quality of the vaccine;
- to focus regulatory activity on review of a "prototype" (candidate) vaccine during the inter-pandemic period;
- to refine regulatory plans as appropriate and to partner with international authorities on regulatory preparedness; and
- to develop options to allow for emergency use.
In preparation for a possible influenza pandemic, Health Canada focused its regulatory activity on the review of a candidate pandemic vaccine. Since the avian influenza strain H5N1 was initially considered as a likely strain to produce the next pandemic, a vaccine (Arepanrix™ H5N1) was designed and manufactured by GlaxoSmithKline Biologicals North America, at their facilities in Quebec, Canada. This proposed vaccine was manufactured according to standard procedures for the commercially available inactivated split-virion vaccine Fluviral®, but differed in that it contained an adjuvant, an immune boosting component. The strain selected for this vaccine was the A/H5N1/Indonesia/5/2005 rgH5N1 influenza strain based on guidance provided by the WHO. A New Drug Submission (NDS) for the mock H5N1 vaccine had previously been filed to Health Canada and evaluated in preparation for the declaration of a pandemic and the need to review an actual pandemic vaccine.
Review of the Arepanrix™ H5N1 vaccine and a similar adjuvant-containing vaccine (Pandemrix™ H5N1, manufactured by GlaxoSmithKline in Dresden, Germany) which contains the A/H5N1/Vietnam/1194/2004 influenza strain provided a preliminary understanding of the quality, immunogenicity, and safety of potential pandemic vaccines. In the event of the declaration of a pandemic, certain aspects of the review of these vaccines could be used as supportive evidence to help accelerate the assessment of a pandemic vaccine, which would be similarly manufactured, but would incorporate a strain change to an identified pandemic strain. In June 2009, following the declaration of pandemic influenza Phase 6, the novel influenza virus A/California/7/2009 was identified by the WHO as the emergent pH1N1 strain. In response to this announcement, the manufacturer initiated development and production of the pandemic vaccine Arepanrix™ H1N1 and a rolling NDS was filed to Health Canada.
Throughout the evaluation of Arepanrix™ H1N1, studies conducted with the following GlaxoSmithKline influenza vaccines were referenced, where appropriate:
- Vaccines with AS03-adjuvant:
- Arepanrix™ H1N1: strain A/California/7/2009v X-179A, produced in Quebec City, Quebec, Canada;
- Pandemrix™ H1N1: strain A/California/7/2009v X-179A, similar to Arepanrix™ H1N1, but produced in Dresden, Germany;
- Arepanrix™ H5N1: strain A/H5N1/Indonesia/5/2005, produced in Laval and Quebec City, Quebec, Canada;
- Pandemrix™ H5N1: strain A/Vietnam/1194/2004, produced in Dresden, Germany.
- Vaccines without adjuvant:
- Influenza A (H1N1) 2009 Pandemic Monovalent Vaccine (Without Adjuvant): a monovalent, split-virion influenza vaccine, containing the same antigen as that in Arepanrix™ H1N1, but in a different quantity [15 μg haemagglutinin (HA)/0.5 mL].
- Seasonal trivalent vaccines without adjuvant:
- Fluviral®: manufactured in Québec, Canada;
- Fluarix®: manufactured in Dresden, Germany.
Arepanrix™ H1N1 vaccine is similar to Arepanrix™ H5N1 with the major distinction being the different influenza virus strains used in their manufacture. Therefore, safety data available from studies with Arepanrix™ H5N1 and Pandemrix™ H5N1 were considered relevant to the evaluation of Arepanrix™ H1N1 as these vaccines contain the same adjuvant. However, data generated with H5N1 vaccines could not completely predict the safety profile of Arepanrix™ H1N1 as there remained the possibility of adverse events (AEs) associated with the pH1N1 strain.
At the time of authorization, no immunogenicity data were available for Arepanrix™ H1N1; however, all available up-to-date data for Pandemrix™ H1N1 were evaluated and are discussed in section 3.3 Clinical Basis for Decision. Very preliminary clinical trial data on Arepanrix™ H1N1 were also available and considered at time of authorization.
3.1 Quality Basis for Decision
Arepanrix™ H1N1 (AS03-Adjuvanted H1N1 Pandemic Influenza Vaccine) is a novel monovalent vaccine preparation comprised of two components:
- an H1N1 antigen: inactivated, split-virion, A/H1N1 influenza virus antigen containing thimerosal preservative, and;
- an AS03 adjuvant: a preservative-free, oil-in-water emulsion.
The antigen components of Arepanrix™ H1N1 and Pandemrix™ H1N1 are produced at two different manufacturing sites. The adjuvant component is common to both products and is manufactured at the same site. Minor differences between the two vaccines exist in the antigen preparations and their specifications.
The adjuvant component is intended to increase immunogenicity of the pandemic influenza virus HA antigen, thus allowing a dose-sparing mechanism that permits the administration of a smaller dose of antigen while providing comparable immunogenicity to a non-adjuvanted vaccine.
The general method of manufacture for the Arepanrix™ H1N1 vaccine is cross-referenced to the currently approved processes for the production of the Fluviral® seasonal influenza vaccine.
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
The drug substance for Arepanrix™ H1N1 contains an H1N1 antigen (an inactivated, split-virion, influenza A H1N1 virus antigen) based on the strain derived from A/California/7/2009v X-179A, the strain, officially recommended by the WHO for the manufacture of vaccines during the influenza pandemic.
The reference strain was produced by the United States Centers for Disease Control (CDC). The reassortant production strain was generated at the New York Medical Center (NYMC), a WHO-approved site for the manufacture of vaccine production strains. The reassortant production strain contains the HA and neuraminidase (NA) genes of the pH1N1 virus. Other genes present in the reassortant are derived from a human influenza virus A/PR/8/34, which is widely used as a backbone to prepare the annual inter-pandemic seasonal vaccines.
The H1N1 antigen is an opalescent off-white to greyish suspension that may sediment slightly.
Manufacturing Process and Process Controls
The Arepanrix™ H1N1 drug substance is manufactured identically to the drug substance used to produce the Fluviral® seasonal antigens; therefore, the Arepanrix™ H1N1 drug substance can be regarded as a strain change with regard to most aspects of product characterization, manufacturing consistency, and validation.
The H1N1 antigen is prepared from virus grown in the allantoic cavity of embryonated hen eggs. The allantoic fluid is harvested and clarified by centrifugation. Whole virion particles are purified from the allantoic fluid and inactivated by ultraviolet irradiation followed by formaldehyde/thimerosal treatment. Subsequently, the antigen is purified by centrifugation and disrupted (split) with the detergent sodium deoxycholate (DOC) to generate the split-virion drug substance. The DOC and formaldehyde are removed and the antigen is homogenized, sterile filtered, and stored as a monovalent H1N1 drug substance. The drug substance is a suspension containing purified antigen of A/California/7/2009 (H1N1)v inactivated split virions.
The materials used in the manufacture of the drug substance were considered to be suitable and/or met standards appropriate for their intended use. The manufacturing process was considered to be adequately controlled within justified limits.
In-process controls performed during manufacture were reviewed and considered acceptable. The specifications for the raw materials used in manufacturing the drug substance were also considered satisfactory.
Characterization
As a great deal of information was already available on the quality, safety, and efficacy of split-influenza virus products produced at the GlaxoSmithKline facility in Quebec, Canada, extensive characterization of the monovalent split-virion particles for the H1N1 antigen was not necessary. Nevertheless, a limited set of experiments was conducted to confirm the expected composition and structure of the H1N1 antigen. These studies confirmed that the expected antigen was present and that ≥99% of the virus in the drug substance preparations is disrupted (split) by treatment with DOC.
Control of Drug Substance
Guidelines specific for influenza vaccine manufacture are used in setting the specifications, such as WHO [Technical Report Series, Recommendations for Production and Control of Influenza Vaccine (Inactivated)], and the European Pharmacopoeia (Ph. Eur.) [Monograph 0158, Influenza Vaccine (split virion, inactivated)].
The proposed tests, specifications and methods for the release of the Arepanrix™ H1N1 drug substance were very similar to those applied for the Fluviral® seasonal vaccine monovalent bulks.
The specifications and analytical methods used for quality control of the Arepanrix™ H1N1 drug substance were considered acceptable. As the production processes for the Arepanrix™ H1N1 (and Arepanrix™ H5N1) drug substance were considered to be identical to those of the Fluviral® seasonal monovalent bulks, the validation of critical process parameters previously provided and assessed were considered as adequate supportive evidence for the demonstration of in-process quality control. Batch analysis results were reviewed and all results complied with the specifications and demonstrated consistent quality of the batches produced.
Both historical manufacturing data and prospective process analysis were used to support the normal operating and acceptable ranges for critical process parameters. Validations upstream (egg reception to inactivation), and downstream (concentration to sterile filtration) provided for the 2005 commercial scale annual vaccine lots, and revalidation of the upstream facilities (when introduced in 2006) were considered adequate.
The sponsor provided a summary of all potential impurities in the drug substance. 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.
All required safety testing for non-pathogenicity of the reassortant strain were performed.
Evaluation of the commercial production process consistency indicated that the manufacture of the H1N1 drug substance is robust and produces monovalent bulks that meet all in-process acceptance criteria and all release specifications.
The drug substance packaging was considered acceptable.
Stability
Based on the stability data submitted for the Arepanrix™ H5N1 drug substance as well as historical data for Fluviral®, a 12-month shelf-life was granted for Arepanrix™ H1N1 drug substance. A commitment of the vaccine authorization required additional stability testing data to confirm the approved 12-month shelf life.
3.1.2 Drug Product - H1N1 Antigen Component
Description and Composition
The Arepanrix™ H1N1 antigen drug product is a monovalent, inactivated, split-virion (H1N1) antigen, sterile, translucent to whitish opalescent suspension that may sediment slightly. It is formulated with phosphate buffered saline (PBS) to contain 15 µg HA/mL and 20 µg/mL thimerosal, and is presented in a 10-mL, non-siliconized Type I glass vial (10 doses). Vials are sealed with a siliconized gray chlorobutyl stopper and secured with an aluminum seal. All components of the drug product packaging are latex-free.
The filled H1N1 drug product is to be mixed in a one-to-one ratio with the AS03-adjuvant component immediately prior to injection. A larger vial size was chosen for the H1N1 drug product in order to accommodate the adjuvanted vaccine final volume after the transfer of the adjuvant into H1N1 drug product vial.
Given that a 0.5-mL dose of the reconstituted Arepanrix™ H1N1 vaccine will be administered, half of it (0.25 mL), comes from the filled H1N1 antigen drug product. The composition of the filled H1N1 antigen drug product is listed per 0.5-mL dose.
All non-medicinal ingredients (excipients) used to formulate the H1N1 antigen drug product are the same as for the licensed Fluviral® seasonal influenza vaccine, and are of compendial grade [United States Pharmacopeia (USP) or Ph.Eur.].
Pharmaceutical Development
Formulation development for the H1N1 antigen drug product was largely based on previous experience with GlaxoSmithKline Biologicals' other AS03-adjuvanted (pre-) pandemic influenza vaccines Pandemrix™ H5N1 and Prepandrix™ H5N1 (manufactured with variant H5N1 antigens), and previously licensed in the European Union.
Pharmaceutical development data, including selection of an appropriate container closure system, were considered acceptable. Data provided included composition of the H1N1 antigen drug product, rationale for choice of the formulation, manufacturing process including packaging, and information on batches used for in vitro studies for characterization and for the safety and/or efficacy of the H1N1 antigen drug product.
Manufacturing Process and Process Controls
The H1N1 antigen drug product is formulated using conventional pharmaceutical equipment and facilities. The required quantity of H1N1 antigen drug substance and the required quantity of excipients for the formulation are calculated based on the target volume desired. The drug product final bulk is then filled into multi-dose vials.
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and found to be acceptable. The manufacturing process was considered adequately controlled within justified limits. The validated process was capable of consistently generating product that meets release specifications.
Control of Drug Product - Antigen Component
The H1N1 antigen drug product was tested to verify that the HA identity, HA and thimerosal content, appearance, pH, osmolality, sterility, and levels of bacterial endotoxins are within acceptance criteria. The test specifications and analytical methods were considered acceptable; the shelf-life and the release limits, for individual and total degradation products, were within acceptable limits.
The manufacturing process for the H1N1 antigen drug product is a simple blending operation that involves mixing of the H1N1 drug substance to the required HA concentration and adjustment to the target volume with a PBS-thimerosal solution. There are no other processing steps or materials added, thus any impurities in the drug product are identical to those present in the drug substance. The concentration of these impurities would be expected to be lower due to the dilution of the monovalent drug substance during the formulation process.
The test specifications were considered acceptable to control the drug product with one exception. The transportation and storage of the H1N1 antigen drug product appeared to be associated with the formation of visible protein aggregates. Health Canada requested that the sponsor provide a quantitative specification for the drug product final container based on a validated physicochemical method for the presence of sediments, as described in the specification for visual appearance.
Due to the fact that no stability data were available for Arepanrix™ H1N1 at the time of licensure, this specification will need to be implemented in the manufacturer's stability monitoring plan.
Data from final batch analyses were reviewed and considered acceptable according to the specifications of the drug product. The process validation was considered complete. Three consecutively manufactured final product lots were tested in Health Canada laboratories, evaluated, and found to meet the specifications of the drug product and demonstrated consistency in manufacturing.
Stability
Based on stability data for the Arepanrix™ H5N1 antigen drug product and historical data for Fluviral®, an 18-month shelf-life at 2 to 8°C for the Arepanrix™ H1N1 antigen drug product was deemed acceptable. However, as part of the post marketing commitments, Health Canada required the provision of stability results to confirm the 18-month shelf-life.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies.
3.1.3 Drug Product - AS03-Adjuvant Component
Description and Composition
The AS03-adjuvant component is a whitish, homogenous liquid (milky), oil-in-water, preservative-free emulsion that is mixed with the H1N1 antigen drug product prior to injection to formulate Arepanrix™ H1N1. The AS03 adjuvant is composed of an oil phase containing the natural, biodegradable oil squalene, and DL-α-tocopherol (Vitamin E), mixed with an aqueous phase composed of an isotonic PBS solution. Polysorbate 80 (Tween 80) is used as an emulsifier to stabilize the oil/water interfaces.
The adjuvant is presented in a 10-dose Type I-glass vial to be mixed with the H1N1 antigen drug product for extemporaneous formulation of the Arepanrix™ H1N1 vaccine. Filled vials are closed with grey butyl latex-free rubber stoppers and capped with flip-off caps.
The adjuvant is not intended for use alone. The entire content of the final container is transferred to a multi-dose antigen container and mixed in a one-to-one ratio prior to use.
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 the AS03 adjuvant with the excipients was demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process made throughout the pharmaceutical development were considered acceptable upon review. Parameters relevant to the performance of the AS03 adjuvant were not affected by the changes described.
Manufacturing Process and Process Controls
The manufacture of the AS03 adjuvant comprises a series of steps which include the preparation of the oil and aqueous phases and the subsequent formulation of the oil-in-water emulsion (adjuvant bulk). Oil droplet size reduction and emulsion stabilization are achieved through high-shear and high-pressure homogenizations. The adjuvant bulk is then sterile filtered and filled without further formulation steps. The product is contained in glass vials and is referred to as AS03.
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 found to be acceptable. The manufacturing process was considered adequately controlled within justified limits.
The specifications for all of the ingredients, with the exception of squalene, were acceptable as they met Ph. Eur. standards. Currently, there is no pharmacopoeial standard for squalene. The specifications outlined for squalene were judged acceptable based on the fact that the level of contaminants was determined to pose no safety risk.
Characterization
Detailed characterization studies were performed to provide assurance that the AS03 adjuvant consistently exhibited the desired characteristic composition.
Control of Drug Product - AS03-Adjuvant Component
The AS03 adjuvant was tested to verify that its identity, appearance, pH, particle size, fill volume, sterility, and bacterial endotoxins were all within acceptance criteria. The test specifications and analytical methods were considered acceptable; the shelf-life and the release limits, for individual and total degradation products, were within acceptable limits.
Data from final batch analyses were reviewed and considered acceptable according to the specifications of the drug product.
Stability
Based on real-time, long-term, and accelerated stability data submitted, the proposed 36-month shelf-life at 2-8°C for the AS03 adjuvant was considered acceptable.
The compatibility of the adjuvant with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.4 Final Vaccine Product (Antigen Component and Adjuvant Component)
Description and Composition
At the time of vaccine administration, the contents of the adjuvant vial are withdrawn and mixed in a one-to-one ratio with the contents of the antigen vial. After mixing, ten individual Arepanrix™ H1N1 vaccine doses of 0.5 mL can be withdrawn.
Each 0.5mL-dose of Arepanrix™ H1N1 contains 3.75 µg HA derived from A/California/7/2009(H1N1)v, 10.69 mg of squalene, 11.86 mg of DL-α-tocopherol, 4.86 mg of polysorbate 80, and 5 µg thimerosal as a preservative.
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 the H1N1 antigen drug product and the AS03 adjuvant with the excipients was demonstrated by the stability data presented on the proposed commercial formulation.
Control of Final Vaccine Product
All release tests were carried out on the H1N1 drug product and on the AS03 adjuvant individually. No release testing was performed on the combined product.
Stability
Each of the vaccine components should be stored between 2 to 8°C. Health Canada granted an 18 month shelf life to the H1N1 antigen component and a 36 month shelf life to the AS03 adjuvant. After mixing the antigen and adjuvant components, Arepanrix™ H1N1 should be used within 24 hours.
3.1.5 Facilities and Equipment
The design, operations, equipment, and controls of each of the facilities involved in the manufacture of the H1N1 antigen drug substance, the H1N1 antigen drug product, and the final vaccine product (Arepanrix™ H1N1) are the same as those for the manufacture of Fluviral®, and have been previously reviewed and found acceptable for the activities and products manufactured. The facilities used to manufacture the AS03 adjuvant were also deemed acceptable. All sites are compliant with Good Manufacturing Practices.
3.1.6 Adventitious Agents Safety Evaluation
Three raw materials of animal origin are used to manufacture the H1N1 split, inactivated virion antigen drug product:
- the A/California/7/2009 NYMC X-179A virus strain used for antigen production and obtained from the NYMC;
- the embryonated hens' eggs used for the propagation of virus seed stocks [specific pathogen-free (SPF) eggs] and for routine production of the antigen monovalent bulks (non-SPF, flock-controlled eggs); and
- the sodium deoxycholate used to split influenza virus and derived from bile (bovine and ovine) sourced from transmissible spongiform encephalopathy (TSE)-free countries.
The manufacturing of sodium deoxycholate material received a Certificate of Suitability for TSE-risk evaluation from the European Directorate for the Quality of Medicines.
There is only one raw material (squalene) of animal origin used to prepare the AS03 adjuvant. Squalene is prepared from shark liver oil by molecular distillation. Shark liver does not fall under the scope of the TSE guidelines [European Medicines Evaluation Agency (EMEA) guidance 410/01].
There are no excipients of human origin in Arepanrix™ H1N1.
Reducing the risk of a contaminating adventitious agent of any microbial class is addressed in multiple ways within the manufacturing process for Arepanrix™ H1N1. The adventitious agent safety program is articulated around three axes:
- Validation of the antigen production process for its capacity to inactivate adventitious agents and eliminate bioburden.
- Control of biologically-derived starting and raw materials.
- Control of adventitious agents at appropriate stages during the production process, including testing of production intermediates and the final product.
The current programs in force for both vaccine components provide sufficient and often redundant control steps applicable to all classes of relevant adventitious agents, thus ensuring the safety of Arepanrix™ H1N1 with respect to adventitious viral and non-viral agent contamination.
3.1.7 Conclusion
The Chemistry and Manufacturing information submitted for Arepanrix™ H1N1 demonstrated that the H1N1 antigen drug substance, the H1N1 antigen drug product, the AS03-adjuvant drug product, and final vaccine product (Arepanrix™ H1N1) were consistently manufactured to meet the approved specifications. The specifications for all components were acceptable for the intended use of Arepanrix™ H1N1.
All recommendations and decisions regarding release of this product were made in appropriate consideration of the relative risk-benefit balance for the declared pandemic.
3.2 Non-Clinical Basis for Decision
Two immunogenicity studies were conducted with Arepanrix™ H1N1 in naïve mice. In addition, the non-clinical evaluation of the Arepanrix™ H5N1 vaccine in mice and ferrets was considered as it focused on different aspects related to the pharmacology and safety profile of the vaccine.
3.2.1 Pharmacodynamics
Immunogenicity Studies
The ability of the vaccine to induce an immune response was investigated in mice and ferrets.
Results from two immunogenicity studies conducted with naïve female mice (C57B1/6) demonstrated an increased immune response in mice that received either Arepanrix™ H1N1 or Pandemrix™ H1N1 following a two-dose administration.
The immunogenicity and efficacy of Arepanrix™ H5N1 was also examined in ferrets. Survival data showed that where a sufficient dose of antigen was used, the ferrets were protected from a lethal challenge of H5N1 virus. However, it should be noted that the lethal challenge test showed that no protection was afforded by the unadjuvanted H5N1.
Non-clinical studies were also carried out to identify the mechanism by which the AS03 adjuvant, in combination with the split H5N1 influenza antigen, promotes strong and persistent humoral and cellular immune responses. Several aspects of the mode of action were studied in mice including the biodistribution and cellular localization of the AS03 adjuvant and the split H5N1 influenza antigen. As well, the AS03 adjuvant was investigated with respect to its impact on various aspects of innate immunity such as co-stimulation, pro-inflammatory response, and the secretion of chemokines, known to play a key role in regulating the quantitative and qualitative aspects of the adaptive immune response. The available data indicated that AS03 adjuvant does not act as a delivery system for the split H5N1 influenza antigen, but rather works as an immuno-stimulant at the injection site and in local lymph nodes by promoting the maturation of antigen presenting cells, increasing co-stimulatory properties, and promoting the production of cytokines including interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ). AS03 does not appear to provide an adjuvant effect for antigens injected at sites remote from the adjuvant, thus there is no evidence of a generalized stimulation of the immune system.
Secondary Pharmacodynamics
No secondary pharmacodynamics studies were conducted with Arepanrix™ H1N1 or Arepanrix™ H5N1.
Pharmacodynamic Drug Interactions
No studies were conducted to evaluate possible pharmacodynamic drug interactions with Arepanrix™ H1N1 or Arepanrix™ H5N1.
3.2.2 Toxicology
Single-Dose Toxicity
Single-dose toxicity studies are discussed in the Local Tolerance section below.
Repeat-Dose Toxicity
One repeat-dose toxicity study was conducted in New Zealand White rabbits that evaluated the toxicity of a similar seasonal influenza vaccine adjuvanted with AS03. Each rabbit was administered an AS03-adjuvanted A/H3N2 influenza antigen or the AS03 adjuvant alone. All doses were administered at >100-fold the dose intended for human testing on a body-weight basis. The toxicity of a two-dose booster series administered 6 weeks after the primary immunizing series was also evaluated.
There were no clinically-apparent effects on the health of the test animals. At acute sacrifice time-points, clinical laboratory testing revealed slight acute changes in serum globulins and/or fibrinogen, as well as platelet counts and/or white blood cell counts, in animals receiving either treatment. These changes were transient and were interpreted to be consistent with acute inflammation. Changes to clinical pathology parameters and histopathologic findings such as mild to moderate sub-acute inflammatory infiltrates, fasciitis, perivascular and perineural inflammation, and/or fibrosis at the injection site were consistent with an inflammatory response to the adjuvant and/or vaccine administration.
The presence of the AS03 adjuvant was the major determinant of severity after the primary immunizing series, but the presence of antigen in addition to adjuvant was associated with some increased frequency and severity of local inflammatory findings after the booster series. Importantly, there were indications that the lesions would resolve over time.
Genotoxicity
Genotoxicity studies were not conducted with Arepanrix™ H1N1 or Arepanrix™ H5N1.
Genotoxicity of influenza antigen prepared by the same methods used in the manufacture of Arepanrix™ H1N1 and H5N1 were performed in the past. The genotoxicity of the AS03 adjuvant was also assessed in two in vitro tests (reverse mutation test in bacteria and gene mutation in mouse lymphoma cells) and in one in vivo test (micronucleus test in the rat after intravenous administration). No indication of genotoxicity was evident.
Carcinogenicity
Carcinogenicity studies were not conducted with Arepanrix™ H1N1 or Arepanrix™ H5N1.
Reproductive and Developmental Toxicity
Reproductive and developmental toxicity studies were not performed for Arepanrix™ H1N1.
Two reproductive studies were conducted with AS03-adjuvanted H5N1 vaccines (Arepanrix™ H5N1 and Pandemrix™ H5N1). These studies evaluated the effect of an AS03-adjuvanted H5N1 antigen on embryo-foetal as well as peri- and post-natal development in naïve or pre-immunized rats following intramuscular (IM) administration. None of the dosing regimens were administered during or near the implantation phase of the embryos. As a result, the use of an AS03-adjuvanted vaccine in early pregnancy could not be adequately assessed.
The first study assessed the reproductive toxicity of Pandemrix™ H5N1 and an AS03 adjuvant administered alone. Six groups of female rats (n = 48 per group) were given one IM dose as follows:
- Group 1: saline, 200 μl
- Group 2: AS03 adjuvant, 200 μl
- Group 3: saline/Pandemrix™ H5N1, 200 μl
- Group 4: Pandemrix™ H5N1, 200 μl
- Group 5: saline/aluminium (AL)-adjuvanted whole H5N1 influenza vaccine (whole H5N1, Al), 100 μl
- Group 6: whole H5N1/Al, 100 μl
On Day 30, the treated females were paired with males. Forty-four rats per group with a positive indication of mating were then treated on Days 6, 8, 11, and 15 after mating. Twenty-two of these rats were sacrificed at Day 20 and another 22 were allowed to deliver and rear their young to Day 25 of age. Measures of reproductive toxicity and maternal health were assessed.
Treatment of maternal rats with any of the dose regimens did not adversely affect their clinical condition, body weight or food consumption throughout the study. In addition, mating performance, fertility, and length of gestation or ability to give birth to a live litter were unaffected. In neonates, reflex development was unimpaired, but among offspring from dams treated with the AS03 adjuvant alone, 13 offspring from 7 litters did not show the air righting reflex before Day 21 of age. The AS03 adjuvant did not affect the attainment of the surface righting reflex or the ability of offspring to show startle response reflexes or the pupil reflex. There was an increased incidence of foetal malformations including markedly thickened/kinked ribs (medially) and bent scapulae in the AS03-adjuvant group; however, the findings observed in the AS03-adjuvant group were not observed in the Pandemrix™ H5N1-vaccine group which also contains AS03, hence, the toxicological significance is uncertain.
A second reproductive study was conducted with Arepanrix™ H5N1. One hundred and ninety-two female rats were assigned to four groups (n = 48 per group) and were given one IM dose according to the following schedule: Day-28 (pre-mating), gestation-days (GD) 7, 9, 12, 16, and postnatal-day (PND) 7. The four groups were dosed as follows:
- Group 1: saline (PBS), 200 μl
- Group 2: AS03 adjuvant, 200 μl (pre-mating) and AS03 adjuvant/PBS mixture (1:1, 100 μl:100 μl) on GD 7, 9, 12, 16 and PND 7
- Group 3: PBS 200 μl (pre-mating) and Arepanrix™ H5N1 200 μl (1.5 μg HA) on GD 7, 9, 12, 16 and PND 7
- Group 4: Arepanrix™ H5N1 200 μl (1.5 μg HA) pre-mating, GD 7, 9, 12, 16 and PND 7
Twenty-eight days after the initial dose, each treated female was paired with one untreated male. After confirmation of mating, the females were allocated to either the Caesarean-section (C-section) cohort or the littering cohort.
In the C-Section cohort, there was an increase of post-implantation percent loss for Group 4 (Arepanrix™ H5N1 administered pre-mating and during gestation) animals (7.76%) as compared to the other groups (1.95% for Group 1; 3.88% for Group 2; and 4.44% for Group 3, respectively). The increased post-implantation percent loss for Group 4 exceeded the historical mean (2.65%) for percent loss and the historical control range (0 to 6.7%).
Among other variations in foetuses from the C-section cohort, dilated ureter was observed in a greater number in the test groups (that is [i.e.], 5 foetuses from Group 3, 3 foetuses from Group 4, and 2 foetuses from Group 2) than in the control group (1 foetus from Group 1).
Notably, none of the findings cited above were common to both studies and hence the toxicological significance is again uncertain.
Local Tolerance
Single-dose toxicity was assessed as part of a local tolerance study performed in rabbits with a model A/H3N2 antigen (A/Wisconsin/67/05) produced with the same manufacturing process as that used to produce the antigen component of Arepanrix™ H1N1 and Arepanrix™ H5N1.
In this study, New Zealand White rabbits were administered one IM injection of an AS03-adjuvanted H3N2 antigen at a dose containing 15 μg of HA (i.e. approximately 20-fold higher than the intended human dose on a body-weight basis), the AS03 adjuvant alone, or saline. Injections were administered into the thigh muscle. Following injection, the rabbits were observed for dermal reactions (erythema and oedema were each graded separately on five-point scales) and clinical signs until Day 4. At this time, rabbits were sacrificed and microscopic examination of the injection sites was performed.
There were no deaths or clinical observations noted in the study. Upon visual examination, dermal reactions were unremarkable, with minimal oedema in two of the AS03 adjuvant-treated males, one control female, and two vaccine-treated females. These findings were considered incidental and unrelated to treatment.
There were no adverse observations noted at necropsy. Minimal or mild sub-acute inflammation of the subcutaneous and/or epimysial tissues was noted in animals receiving the AS03 adjuvantwith or without influenza antigen. There were no microscopic findings associated with the injection of the vaccine.
3.2.3 Summary and Conclusion
The vaccine formulations used in the toxicology studies were immunogenic and well tolerated. The non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, acute and repeated-dose toxicity, local tolerance, female fertility, embryo-foetal toxicity, and post-natal toxicity up to the end of the lactation period.
The toxicity studies conducted with the various strain variants were considered to be representative of Arepanrix™ H1N1.
3.3 Clinical basis for decision
At the time of authorization, several clinical studies were underway in North America, Japan, and Europe to evaluate the safety and immunogenicity of a two-dose schedule of two similar AS03-adjuvanted vaccines: Arepanrix™ H1N1 and Pandemrix™ H1N1. Results from these studies will be assessed by Health Canada as they become available. Preliminary results from two studies conducted with the Pandemrix™ H1N1 were submitted to Health Canada for review.
No clinical protection data were generated for either of these AS03-adjuvanted H1N1 vaccines nor for the similarly manufactured Arepanrix™ H5N1 vaccine and Pandemrix™ H5N1 vaccines. The ability of Arepanrix™ H1N1 and Pandemrix™ H1N1 to elicit protection against infection has to be assessed by their use post-authorization. Their potential for efficacy however, can be estimated based on the ability to induce an appropriate immune response according to guidelines established by the WHO and other international agencies. The European Medicines Agency (EMA) and the Center for Biologics Evaluation and Research (CBER) have published criteria that were used to assess the immunogenicity of the influenza vaccines used in the clinical studies discussed in section 3.3.2 Clinical Efficacy (Immunogenicity).
The main data and information considered in the clinical evaluation of Arepanrix™ H1N1 were the following:
- data for Pandemrix™ and Arepanrix™ H1N1 including preliminary results from clinical studies with H1N1 pandemic vaccines; and
- data for Arepanrix™ H5N1.
In addition, data from international clinical studies using similar or related pandemic vaccines became available during the authorization process and were also considered. Further clinical studies and post-market surveillance continue to be assessed post-authorization.
3.3.1 Pharmacodynamics
The pharmacodynamics of Arepanrix™ H1N1 were assessed through the analysis of immunogenicity described in section 3.3.2 Clinical Efficacy (Immunogenicity).
3.3.2 Clinical Efficacy (Immunogenicity)
The immunogenicity of the influenza vaccines was evaluated based on immune responses elicited by the vaccines as measured by the level of antibodies against the envelope protein HA of the H1N1 virus [as detected by the haemagglutination inhibition (HI) assay]. The level of antibodies against HA is expressed as geometric mean titres (GMT). The following serological parameters are generated by the HI assay and are used as endpoints to assess vaccine immunogenicity:
- Seroconversion rate (SCR) - the proportion of subjects who were either seronegative at pre-vaccination and have a potentially protective post-vaccination titre of ≥1:40, or who were seropositive at pre-vaccination and experienced a 4-fold increase in titre post-vaccination;
- Seroconversion factor (SCF) - ratio of the post-vaccination HI antibody titre divided by the pre-vaccination antibody titre;
- Seroprotection rate (SPR) - the proportion of subjects with an HI antibody titre ≥1:40 following vaccination.
Studies conducted with H1N1 Vaccines
Prior to authorization, the preliminary results of two studies (Study D-Pan-H1N1-021 and Study D-Pan-H1N1-007) conducted with Pandemrix™ H1N1 were reviewed.
Study D-Pan-H1N1-021
Study D-Pan-H1N1-021 is a Phase II, multicentre, observer-blind, randomized study underway in Europe. The purpose of this study is to evaluate the safety and immunogenicity of a two-dose schedule of Pandemrix™ H1N1, which contains the same H1N1 strain as Arepanrix™ H1N1. The study compares the use of Pandemrix™ H1N1 to a non-adjuvanted vaccine, which contains a higher level of H1N1 antigen (also produced by GlaxoSmithKline Biologicals in Dresden, Germany). Subjects were randomized to receive Pandemrix™ H1N1 (n = 62) or a non-adjuvanted H1N1 vaccine (n = 66).
The quantity of HA antigen (potency) was initially determined by chromotographic methods. Subsequent analysis by Single Radial Immunodiffusion Assay (SRID), the approved potency assay method, showed that the potency as determined chromatographically had been under-estimated. Consequently, the dose of Pandemrix™ H1N1 administered to subjects contained 5.25 µg H1N1 HA/0.5 mL (instead of 3.75 µg H1N1 HA, the currently recommended dose for Arepanrix™ H1N1). The potency of the non-adjuvanted vaccine was 21 µg H1N1 HA/0.5 mL.
Preliminary results indicate that at Day 21, following one dose of vaccine, both Pandemrix™ H1N1 and the non-adjuvanted vaccine met the internationally accepted immunogenicity criteria.
| Vaccine | Day | Geometric Mean Titre (GMT) | Seroconversion Rate (SCR) | Seroconversion Factor (SCF) | Seroprotection Rate (SPR) |
|---|---|---|---|---|---|
| Pandemrix™ H1N1 vaccine (H1N1 + AS03) n = 62 | Day 0 | 8.6 | Not Applicable | Not Applicable | 10.9% |
| Day 21 | 360 | 98.4% | 41.4 | 98.4% | |
| Non-adjuvanted H1N1 vaccine (H1N1) n = 66 | Day 0 | 10 | Not Applicable | Not Applicable | 15.2% |
| Day 21 | 414 | 95.5% | 41.4 | 97.0% |
At Day 21, both treatment groups exhibited somewhat higher immunogenicity in younger subjects (18 to 40 years) compared to older subjects (41 to 60 years); however, both the EMA and CBER criteria were satisfied in each age groups for both vaccines.
Study D-Pan-HIN1-007
Study D-Pan-H1N1-007 is a Phase III, single centre, observer-blind, randomized study underway in Europe. Similar to Study D-Pan-H1N1-021, the purpose of this study is to evaluate the safety and immunogenicity of a two-dose schedule of the Pandemrix™ H1N1 as compared to a non-adjuvanted vaccine. Subjects were randomized to receive Pandemrix™ H1N1 (n = 61) or the non-adjuvanted H1N1 vaccine (n = 66). For this study, subjects were stratified by age (18 to 40 years, 41 to 50 years, and 51 to 60 years). In both groups, subjects were given one dose of vaccine, followed by a second dose 21 days later. Blood sampling was conducted at baseline and at Day 21 and will continue to be sampled at Day 42, 6-months, and 12-months post-dose 1.
The potency of the vaccine dose met the release specification of 3.75 µg H1N1 HA/0.5 mL for Pandemrix™ H1N1 and 15 µg H1N1 HA/0.5 mL for the non-adjuvanted H1N1 vaccine.
Similar to the results from Study D-Pan-H1N1-021, following one dose of vaccine, both Pandemrix™ H1N1 and the non-adjuvanted vaccine met the internationally accepted immunogenicity criteria; however, the immune response after a single dose of the non-adjuvanted vaccine was slightly lower than that generated by Pandemrix™ H1N1.
| Vaccine | Day | Geometric Mean Titre (GMT) | Seroconversion Rate (SCR) | Seroconversion Factor (SCF) | Seroprotection Rate (SPR) |
|---|---|---|---|---|---|
| Pandemrix™ H1N1 vaccine (H1N1 + AS03) n = 61 | Day 0 | 8.6 | Not Applicable | Not Applicable | 9.4% |
| Day 21 | 384 | 96.7% | 43.3 | 100% | |
| Non-adjuvanted H1N1 vaccine (H1N1) n = 66 | Day 0 | 10.7 | Not Applicable | Not Applicable | 18.2% |
| Day 21 | 331.9 | 84.8% | 31 | 93.9% |
Despite the fact that all EMA and CBER criteria were satisfied, when analysed by age group, the immune response as assessed by SCR, SCF, and SPR was generally lower in the older sub-group (41 to 60 years) for recipients of both vaccines.
Immunogenicity Summary - Studies conducted with H1N1 Vaccines
Preliminary results from both studies indicate that at Day 21, following one dose of vaccine, both the Pandemrix™ H1N1 vaccine and the non-adjuvanted vaccines met the internationally accepted immunogenicity criteria. A strong immune response was observed for both formulations after one single vaccine dose. Given the short amount of time that has elapsed since the initiation of these studies, the persistence of this response could not be determined at this time, nor was it possible to determine if a second dose or a booster dose would be required at a later date.
Supportive studies conducted with H5N1 Vaccines
Paediatric Study D-Pan-H5N1-009/-022/-023
A sequential study (with three Phases: A, B, and C) was conducted in children aged 3 to 9 years. The study was a randomized, open-label study. Each of the three phases included a group who received a unique dose of Pandemrix™ H5N1 and a control group who were administered Fluarix® (a trivalent seasonal influenza vaccine). The doses for the Pandemrix™ H5N1 vaccine groups were as follows:
- Phase A (D-Pan-H5N1-009): half-dose H5N1 HA (1.9 μg ) and ½ adjuvant (AS03B);
- Phase B (D-Pan-H5N1-022): full-dose H5N1 HA (3.8 μg ) and ½ adjuvant (AS03B);
- Phase C (D-Pan-H5N1-023): full-dose H5N1 HA (3.8 μg ) and adjuvant (AS03A).
Each subject was given one dose of Pandemrix™ H5N1 or Fluarix® on Day 0 and a second dose on Day 21. Patients were stratified by age (3 to 5 years and 6 to 9 years) and were followed for 24 months after the first vaccination.
Despite some observed differences, all three H5N1-dose formulations were highly immunogenic when administered in two doses, 21-days apart. Much lower responses were recorded after the first dose, suggesting that two doses will be needed for this age group.
3.3.3 Clinical Safety
Very preliminary short-term safety data were available at the time of the authorization for Arepanrix™ H1N1. No serious adverse event was reported in 263 subjects within 6 days following immunization with Arepanrix™ H1N1. Safety data from other AS03-adjuvant containing vaccines (Pandemrix™ H1N1, Arepanrix™ H5N1, and Pandemrix™ H5N1) were also relevant to the evaluation. Data generated from H5N1 vaccines could not entirely predict the safety profile of Arepanrix™ H1N1 as there remains a possibility for AEs associated with the pandemic influenza strain.
Studies conducted with H1N1 Vaccines
The design of Study D-Pan-H1N1-021 and Study D-Pan-H1N1-007 are described in section 3.3.2 Clinical Efficacy (Immunogenicity).
Study D-Pan-H1N1-021
The preliminary report for Study D-Pan-H1N1-021 summarizes only serious adverse events (SAEs). There were no withdrawals due to SAEs and no pregnancies were reported. One SAE considered related to vaccination was reported. This was an apparent allergic reaction in a 41-year old female who had a history of multiple allergies and mastocytosis. The subject was in the non-adjuvanted vaccine group.
Study D-Pan-H1N1-007
Study D-Pan-H1N1-007 provided preliminary reactogenicity data (solicited local and general AEs reported within 7 days of vaccination) indicating that solicited local and general symptoms were reported more frequently in the groups receiving Pandemrix™ H1N1 compared to those receiving the non-adjuvanted H1N1 vaccine. Although general systemic reactions were more common in the adjuvanted-vaccine group, they were typically considered to be mild. Pain at the injection site was the most frequently reported solicited AE. The most common reactions were fatigue, headache, and pain at the injection site (in both the adjuvanted- and the non-adjuvanted-vaccine groups), and muscle ache (in the adjuvanted-vaccine group).
| Solicited General Symptoms | Pandemrix™ H1N1 Vaccine n = 62 | Non-adjuvanted H1N1 Vaccine n = 62 |
|---|---|---|
| Fatigue | 33.9% | 29.0% |
| Headache | 27.4% | 17.7% |
| Muscle Aches | 33.9% | 11.3% |
A small percentage (~2%) of Grade 3 (severe) reactions were reported for headache and muscle ache in the Pandemrix™ H1N1 group, and fatigue and shivering in the non-adjuvanted vaccine group. These reactions did not last more than 1 day. Fever was not reported in either vaccine group. The median duration of local and general reactions was 1 to 3 days, with a maximum of 7 days (in the adjuvanted-vaccine group).
| Type of Symptoms | Pandemrix™ H1N1 Vaccine n = 64 | Non-adjuvanted H1N1 Vaccine n = 66 | |
|---|---|---|---|
| General Symptoms | Overall | 57.8% | 43.9% |
| "Related" to the vaccine | 51.6% | 36.4% | |
| Grade 3 (severe) | 6.3% | 3.0% | |
| Local Symptoms | Overall | 87.5% | 34.8% |
| "Related" to the vaccine | 87.5% | 34.8% | |
| Grade 3 (severe) | 1.6% | 0.0% |
Only one SAE was reported, a migraine which occurred in a subject from the non-adjuvanted vaccine group. The migraine started on Day 14, lasted for 2 days and the subject recovered. This SAE was assessed as not being related to the vaccine. There were no adverse events of special interest (AESI) reported and no special clinical patterns for the reported events.
Studies conducted with H5N1 Vaccines
The safety of Arepanrix™ H5N1 was evaluated in two pivotal studies: Q-Pan-001 and Q-Pan-002. Solicited local and general symptoms were collected during a 7-day follow-up period, and unsolicited symptoms were recorded up to Day 84 (Q-Pan-001) and Day 42 (Q-Pan-002). Serious AEs were recorded, described, and analysed up to 6 months after vaccination in both pivotal studies. The safety profile of Arepanrix™ H5N1 was further supported by data obtained in additional studies performed with Pandemrix™ H5N1. Taken together, the safety database obtained with Arepanrix™ H5N1 and Pandemrix™ H5N1 is based on a total of approximately 10,000 vaccinated subjects.
Integrated Safety Summary of AS03 combined with H5N1 Antigen
At the time of authorization, eight clinical studies with complete follow-up through to 6 months post-immunization, which provide a total safety population of 12,197 subjects >18 years of age, were pooled for integrated analysis. In these studies, patients were administered either an AS03-adjuvanted H5N1 vaccine (n = 9873), a non-adjuvanted H5N1 vaccine (n = 636), or a control (saline placebo or Fluarix®; n = 2408). The strain used in the H5N1 vaccines was either A/Vietnam/1194/2004 or A/Indonesia/5/2005.
Subjects were given diary cards to record solicited AEs for 7 days post-vaccination and unsolicited AEs for up to at least 29 days following administration of the second dose. Solicited local AEs included pain, redness, swelling, induration, and ecchymosis. Solicited general AEs included fever, fatigue, headache, myalgia, shivering, arthralgia, and increased sweating. Medically-attended AEs (MAEs) were recorded for up to 50 days (in most studies) or 182 days (in two studies). Serious AEs were recorded up to 180 days post-vaccination. The severity of AEs was graded as mild (1), moderate (2), or severe (3).
The findings of the integrated safety analysis suggested that local injection site AEs were more common in recipients of the AS03-adjuvanted H5N1 vaccine as compared to control groups. Local pain was the most frequently reported among these events, and grade-3 local pain was also increased in adjuvanted-vaccine recipients.
General solicited AEs such as fatigue, malaise, myalgia, and arthralgia, were increased in AS03-adjuvanted H5N1 vaccine recipients relative to control subjects, but severe complaints were uncommon. Low grade temperature elevations occurred approximately twice as frequently among AS03-adjuvanted H5N1 vaccine recipients relative to control subjects in the 7 days following treatment. Temperatures ≥39ºC were very slightly more frequent in AS03-adjuvanted H5N1 vaccine recipients than among control subjects.
There was no increased incidence of axillary, supraclavicular, or all objective lymph node enlargement among recipients of the AS03-adjuvanted H5N1 vaccine compared with control subjects. There was a tendency for axillary or lymph node pain to be noted more frequently by AS03-adjuvanted H5N1 vaccine recipients, but this was not severe, and was transient.
Among unsolicited AEs, six Medical Dictionary for Regulatory Activities Preferred Terms (MedDRA PTs) were increased among AS03-adjuvanted H5N1 vaccine recipients in contrast to controls: injection-site reaction, injection-site warmth, injection-site pruritus, malaise, nausea, and insomnia. All had a close temporal association with injections, were transient, and differed little in duration as experienced in either vaccination group. All of these events were consistent with the post-marketing safety profile of GlaxoSmithKline's licensed influenza vaccines.
There was no apparent increased incidence of MAEs or SAEs among AS03-adjuvanted H5N1 vaccine recipients, nor was there an obvious clustering of MAEs or SAEs in a particular Primary System Organ Class among AS03-adjuvanted H5N1 vaccine recipients.
Sixteen AESIs/potential immune-mediated disorders (pIMDs) occurred in the AS03-adjuvanted H5N1 vaccine group (n = 9873) in contrast with one such event among control subjects (n = 2408), including facial palsy, neuritis, psoriasis, polymyalgia rheumatica, Grave's disease, uveitis, and scleroderma. The number of subjects for each reported diagnosis was very small, and in many cases the causal association with the vaccine could not be determined.
The theoretical risk of inducing or promoting autoimmune disease has been raised with adjuvanted vaccines, due to their ability to interact with immune cells. The AS03-adjuvant component, an oil-in-water emulsion, does not act as a delivery system. The adjuvant potential is local and is not expected to promote an immune response against an antigen outside of the administration zone. It has been shown in vitro that the AS03 adjuvant activates antigen-presenting cells, monocytes, and macrophages. This effect is transitory (about 72 hours); however, a potential effect of stimulated immune cells, following their migration from the local injection site to the lymph nodes is still not completely known.
Paediatric Study D-Pan-H5N1-009/-022/-023
The details of the design of Study D-Pan-H5N1-009/-022/-023 are described in section 3.3.2 Clinical Efficacy (Immunogenicity).
Results of this study indicate that for both age strata (3 to 5 years and 6 to 9 years), a slightly higher incidence of AEs was observed in the AS03-adjuvanted H5N1 vaccine groups as compared to the control (Fluarix®) groups. The observed differences were seen in each of the three phases, with all vaccine formulations.
Pain at the injection site was the predominant local AE and was more frequently observed in the AS03-adjuvanted H5N1 vaccine groups than in the control group. In Phase B, the incidence of other local AEs was low and occurred with no marked difference between the vaccines or age groups. For Phase C, the incidence of local AEs was higher in the AS03-adjuvanted H5N1 vaccine group (full dose) compared to the control group. Solicited general AEs (mostly headache and fever in 6 to 9 year olds and irritability in 3 to 5 year olds) occurred more frequently after administration of the full H5N1 HA/full AS03 adjuvant group (Phase C), compared to the control groups and to formulations with a lower dose of adjuvant. Unsolicited AEs also occurred more frequently after administration of the full H5N1 HA/full AS03 group, but only a few were assessed as being causally related to the vaccine.
Overall, AEs occurred more frequently in children aged 6 to 9 years of age as compared to those 3 to 5 years of age. Serious AEs were rarely reported and none were fatal. Grade 3 AEs occurred with a low frequency (<10%) in both age groups, in Phases A and B. In Phase C (full dose of H5N1 HA and adjuvant), the incidence of Grade 3 solicited symptoms was low, except for a slightly higher occurrence of Grade 3 fever (for both age strata) and Grade 3 loss of appetite (3 to 5 year-olds only). The occurrence of Grade 3 fever is notable: it was reported in 10% of children aged 3 to 5 years and 14.3% of children aged 6 to 9 years, as compared to 0% in children who were part of the control group.
Two AEs that occurred in this study are of special note. One 3-year old child in Phase B displayed liver enzyme abnormalities and was later diagnosed as having autoimmune hepatitis, possibly related to the AS03-adjuvanted H5N1 vaccine. An analysis of this case determined that the condition pre-dated the immunization. Secondly, one child in Phase C developed uveitis which resolved with residual mydriasis. This was possibly related to the AS03-adjuvanted H5N1 vaccine.
Considering the comparable immunogenicity results following the administration of any of the three formulations and the apparent increase in AEs associated with the higher adjuvant content for this age group, a formulation with half the antigen and adjuvant doses was recommended for use in children 3 to 9 years of age for immunization against H5N1 strains. Based on these findings, the same recommendation should be made for the administration of Arepanrix™ H1N1 for children aged 3 to 9 years as it contains the same AS03-adjuvant component.
Pregnancy and Lactation
Clinical data for the use of the Arepanrix™ H1N1 vaccine or the AS03-adjuvant component in pregnant women were not available at the time of authorization. In addition, no data are available in breast-feeding women or in children under the age of 3 years.
Thimerosal
Arepanrix™ H1N1 contains minute quantities of the preservative thimerosal. Large cohort studies of health databases have demonstrated that there is no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disorders. Similar large-scale studies have not specifically addressed prenatal exposure to thimerosal-containing vaccines in pregnancy; however, thimerosal containing influenza vaccines have been used for years in pregnant women with no evidence to suggest a special safety concern.
3.3.4 Additional Issues
As part of the marketing authorization for Arepanrix™ H1N1, Health Canada required that the sponsor agree to several commitments to be addressed post-market. Commitments include the following:
Clinical
- The issuance of a Healthcare Professional Communication (HPC), in collaboration with Health Canada, indicating by which means the vaccine was authorized, including currently known aspects relating to the vaccine's safety and immunogenicity and the types of adverse events requiring prioritized reporting.
- The commitment to perform all activities/studies described in the submitted Arepanrix™ H1N1 Risk Management Plans (RMP) including the submission of monthly aggregate safety data and the completion of ongoing trials.
- To submit interim and final reports of all clinical trials and post-market studies as soon as they become available.
- To agree to provide patients and healthcare professionals continuous access to updated information regarding Arepanrix™ H1N1.
- To provide Health Canada as well as the Public Health Agency of Canada (PHAC) with information on any signal leading to a change in the balance of the risk-benefit profile.
- To conduct the agreed upon follow-up evaluation for any adverse events noted in pregnant women.
- To provide data concerning safety and immune response in at least one immunocompromised population and assess the feasibility of examining safety in persons with pre-existing autoimmune disease in GlaxoSmithKline's ongoing clinical program. GlaxoSmithKline is to also pursue collaboration with existing Federal and Provincial systems to support the development of effectiveness estimates for the Arepanrix™ H1N1 vaccine. GlaxoSmithKline is to continue discussions with PHAC/CIHR Influenza Research Network (PCIRN) and/or other investigators to determine any potential opportunities for collaboration.
- To provide Health Canada with the final results of the ferret challenge studies by the end of November, 2009.
Chemistry and Manufacturing
- To submit ongoing data on the stability of the antigen component of the vaccine to confirm its approved 18-month shelf-life.
- To submit monthly trend analyses on key quality control test results of the final antigen vaccine container.
- To report on a bi-weekly basis on any issues arising in the production of the antigen.
- To submit, for review and approval, a bridging study report prior to the implementation of new reference preparations used to quantify the level of antigen in the vaccine.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
On June 11, 2009, the WHO declared pandemic influenza Phase 6 in response to the spread of a novel influenza A virus (pandemic H1N1). The novel virus, A/California/7/2009, was identified by the WHO as the emergent pH1N1 strain. In response to this announcement, the manufacturer (GlaxoSmithKline) initiated vaccine production using the strain recommended by the WHO.
Due to the requirement to produce a vaccine promptly in response to the pandemic and in the absence of previous experience with vaccines for the pandemic strain, the initial development of the H1N1 pandemic vaccine, Arepanrix™ H1N1, was based on the assumption that the vaccine, based on the new pandemic strain, would behave in a similar manner to the H5N1 vaccine. This would mean that individuals would require two vaccine doses and the addition of an adjuvant to the vaccine in order to elucidate a meaningful immune response. The need for a dose-sparing mechanism was another reason for adding the adjuvant. However, preliminary data from different international sources using H1N1 vaccines, as well as results obtained from studies conducted with Pandemrix™ H1N1 demonstrated a very strong immune response in adults following the first dose of both adjuvanted-H1N1 vaccines and non-adjuvanted-H1N1 vaccines.
The adjuvant component of Arepanrix™ H1N1 is intended to increase the immunogenicity of the pH1N1 HA antigen, thus allowing a dose-sparing mechanism that permits the administration of a smaller dose of antigen while providing comparable immunogenicity to a non-adjuvanted vaccine. Theoretically, it is possible that the altered inflammatory response associated with the use of adjuvants could result in a small number of immunologically-mediated AEs. Such events could also be induced by natural infection or by the vaccine antigen itself without adjuvant. Events such as these would only become apparent through careful post-marketing surveillance.
The data available at the time of authorization regarding the safety of the AS03 adjuvant clearly showed an increased incidence of local and systemic reactions when the adjuvant was used, although most of these events were generally mild. Data concerning a possible link to an increased risk of immune-mediated events and AESI were inconclusive. An association between the occurrence of rare events and the use of the AS03 adjuvant can neither be ruled out, nor be definitively established.
Clinical data on the use of AS03-adjuvanted vaccines were not available for some population groups: pregnant and breast-feeding women, children under the age of 3 years, persons at risk from immunosuppression or severe disease, First Nations people, and the Inuit population.
Due to the need to produce a vaccine promptly in response to the pandemic, only limited, preliminary data from pre-clinical and clinical studies with the Arepanrix™ H1N1 vaccine were available at the time of authorization. As required under normal circumstances, a clear benefit/risk profile for Arepanrix™ H1N1 could not be established based on the limited available data. Health Canada recognized, however, that under the exceptional pandemic circumstances, consideration had to be given to the following issues:
- The available immunogenicity data suggested that Arepanrix™ H1N1 would provide protection against H1N1 infection, although confirmation was needed through further studies and post-marketing use. The potential benefits of Arepanrix™ H1N1 compared to non-adjuvanted H1N1 vaccines included dose-sparing and the possibility that it could provide a better immune response (including possible cross-protection and immune persistence). Further evidence is required to support the potential benefits of Arepanrix™ H1N1. The adjuvanted vaccine provided an antigen-sparing mechanism that permitted the availability of sufficient doses to immunize the Canadian population.
- The timely availability of a pandemic vaccine to vaccinate Canadians was essential. A switch to a non-adjuvanted formulation of the vaccine would have meant that no vaccine would be available for the Canadian population by November, 2009. At the time of authorization under an Interim Order, the public was at a significant risk of being exposed to the H1N1 2009 influenza virus which could have resulted in potentially serious or life-threatening disease.
The submitted data suggested that the Arepanrix™ H1N1 vaccine was generally well tolerated. The limitations and potential risks described above were to be addressed by post-marketing commitments. Based on the data reviewed up to the date of authorization, the value of the Arepanrix™ H1N1 vaccine as prophylaxis to protect against the threat of pandemic H1N1 exceeded the theoretical risks of the vaccine.
Arepanrix™ H1N1 was authorized for sale based on limited clinical testing in humans under the provision of the October 13, 2009 Interim Order. The authorization was based on the Health Canada review of the available data on quality, safety, and immunogenicity, and given the pandemic threat and its risk to human health, Health Canada considered that the benefit/risk profile for the Arepanrix™ H1N1 vaccine was favourable for active immunization against the H1N1 2009 influenza strain in an officially declared pandemic situation.
3.4.2 Recommendation
A Notice of Compliance (NOC) is normally issued if substantial evidence of quality, safety and efficacy/effectiveness is provided, and an acceptable benefit/risk profile in full compliance with the Food and Drugs Act and Regulations can be demonstrated.
Health Canada reviewed the available data on quality, safety, and immunogenicity for the Arepanrix™ H1N1 vaccine. However, as the clinical data available at the time of authorization was minimal and most clinical trials were ongoing, an acceptable benefit/risk profile in full compliance with the Food and Drugs Act and Regulations could not be demonstrated and an NOC could not be issued. In response to the ongoing novel influenza A H1N1 pandemic, the Minister of Health deemed that immediate action was required in the interest of public health and an authorization for sale for the Arepanrix™ H1N1 vaccine was granted under an Interim Order. The Interim Order was issued by the Minister of Health at the request of the Public Health Agency of Canada to allow for the authorization for sale of a vaccine for the novel Influenza A H1N1 virus in response to the influenza A H1N1 pandemic. This Interim Order applies to existing circumstances in which significant risks, direct or indirect, to human health, public safety, or the environment are present, and there is insufficient time to conduct traditional clinical studies to obtain the evidence of safety and effectiveness required by the Food and Drug Regulations to issue an NOC for a new vaccine. The Interim Order is effective for 12 months.
Full consideration was given to international activities and declarations and notices issued by the WHO.
Based on the Health Canada review of the available data on quality, safety and immunogenicity, and given the pandemic threat and its risk to human health, Health Canada considered that the benefit/risk profile of the Arepanrix™ H1N1 vaccine was favourable for active immunization against the H1N1 2009 influenza strain in an officially declared pandemic situation.
4 Submission Milestones
Submission Milestones: ArepanrixTM H1N1 (AS03-Adjuvanted H1N1 Pandemic Influenza Vaccine)
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting (Pandemic): | 2007-01-30 |
| Rolling New Drug Submission (NDS) filed | |
| Part 0 (Administrative information, Cross-Reference to Rolling NDS for H5N1 Adjuvanted Vaccine - Control Number: 115398) | 2009-08-18 |
| Screening | |
| Screening Acceptance Letter issued: | 2009-09-02 |
| Part 1 Submission filed (Risk Management Plan and Product Labels): | 2009-09-14 |
| Part 2 Submission filed [Chemistry and Manufacturing (C and M) (H1N1 Drug Substance), Toxicology (H5N1), and Preliminary Clinical (H1N1) information): | 2009-09-30 |
| Part 3 Submission filed [C and M (H1N1 Drug Product) and Preliminary Clinical (H1N1) information)]: | 2009-10-15 - 2009-10-16 |
| Review | |
| On-Site Evaluation: | 2009-09-30 - 2009-10-02 |
| Quality Evaluation complete: | 2009-10-21 |
| Clinical Evaluation complete: | 2009-10-21 |
| Labelling Review complete (during informal discussions in advance of formal ArepanrixTM H1N1 submission): | 2009-07-20 |
| Interim Order issued: | 2009-10-13 |
| Authorization for sale (under Interim Order) issued: | 2009-10-21 |