Summary Basis of Decision for BioThrax

Clinical Pharmacology

BioThrax is a vaccine indicated for the active immunization for the prevention of disease caused by Bacillus anthracis (anthrax). BioThrax intended use is for pre-exposure prophylaxis of disease in persons at high risk of exposure. BioThrax is made from cell-free filtrates of cultures grown under microaerophilic conditions of a non-encapsulated strain of Bacillus anthracis. BioThrax works by stimulating the immune system to produce protective antibodies against the Protective Antigen. When the Protective Antigen is blocked, Lethal Factor and Edema Factor are not able to interact with the Protective Antigen and the toxins are thereby neutralized.

In the evaluation of new prevention options for anthrax, conducting placebo-controlled trials in humans would be unethical. Therefore, the effectiveness of BioThrax for the active immunization for the prevention of disease caused by Bacillus anthracis is based primarily on a review of animal studies demonstrating a survival benefit.

The endpoint of the primary pharmacodynamic studies performed with BioThrax was defined as the protection against a challenge with virulent strains of Bacillus anthracis. Additionally, most studies also quantified the immunological response to BioThrax vaccination, measured by anti-Protective Antigen antibody titres. The expected immunogenicity was evaluated in terms of levels of antibody production, class and subclass of antibodies produced, and duration of immune response.

In one non-human primate study, rhesus macaques were vaccinated with BioThrax (0.5 mL) on a 3-dose (0, 1, and 6 months) intramuscular schedule, using either the full human dose (undiluted) or saline-diluted BioThrax (1:5, 1:10, 1:20, or 1:40). Control animals received saline injections or were untreated process controls.

After vaccination rhesus macaques were exposed to a target dose of 200 or 400 LD50 (50% lethal dose) equivalents of aerosolized Bacillus anthracis Ames spores at 12, 30, or 52 months after the first vaccination. After a 3-dose intramuscular priming series, rhesus macaques were almost completely protected against an aerosol challenge at Month 52 (80% [8/10] and 100% [9/9] survival rates for undiluted BioThrax group and 1:5 BioThrax group, respectively). The results showed that the 3-dose intramuscular priming series provided efficacy for up to 4 years in rhesus macaques.

For further details on the clinical pharmacology of the BioThrax vaccine, please refer to the BioThrax Product Monograph which has been approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Health Canada recognizes that there are circumstances in which sponsors cannot reasonably provide substantial evidence demonstrating the efficacy and safety of a therapeutic product in humans as there are logistical or ethical challenges in conducting the appropriate human clinical trials. The Extraordinary Use New Drugs (EUNDs) submission pathway was developed to allow a mechanism for authorization of these products based on non-clinical and limited clinical information (see Guidance Document - Submission and Information Requirements for Extraordinary Use New Drugs [EUNDs]). Accordingly, the efficacy of BioThrax (Anthrax Vaccine Adsorbed) was primarily established based on efficacy studies demonstrating a survival benefit in laboratory animals (see section Non-Clinical Basis for Decision).

The first United States anthrax vaccine was developed in 1954. The National Institutes of Health (NIH) Bureau of Biologics approved Anthrax Vaccine Adsorbed (AVA) in 1970 based on a human clinical trial (the Brachman Field Study) conducted in wool-mill employees. Further efficacy data was obtained through a Centers for Disease Control and Prevention observational (surveillance) study conducted between 1962 and 1974 in persons with occupational risk for anthrax, and demonstrated the clinical effectiveness of BioThrax or the precursor vaccine against anthrax, with at least 3 doses of 6-dose vaccination schedule (Week 0, 2, 4 and Month 6, 12, 18) given by subcutaneous administration.

After approval and many years of use of BioThrax and the precursor vaccine, in the United States of America, studies have been conducted to explore the different dose schedule and route of administration (subcutaneous versus intramuscular).

Study BB-IND 10031

The study conducted by the CDC served as the primary assessment of immunogenicity of BioThrax for use in humans.

The BB-IND 10031 study was a randomized, double-blinded, placebo-controlled, multicentre study which evaluated the immunogenicity of BioThrax in regard to the anti-PA IgG using different routes of administration (subcutaneous vs. intramuscular) and different dose schedules. A total of 1,564 subjects were enrolled in BB-IND 10031 study. The objective of the BB-IND 10031 study was to evaluate the effect of changing the route of vaccine administration and reducing the number of doses on the safety and immunogenicity of BioThrax.

As originally approved in the United States of America, BioThrax and the predecessor vaccine were administered as a series of 6 subcutaneous (SC) priming doses over 18 months (0, 2, 4 weeks, and 6, 12, 18 months), followed by annual booster doses. This originally approved route/schedule was compared with the same schedule utilizing the intramuscular (IM) route and also with alternative schedules as specified below:

• 8 SC group - BioThrax administered by the SC route, using the traditional dosing regimen (same as Brachman efficacy trial) at 0, 2, 4 weeks, and 6, 12, 18, 30, and 42 months [Number of subjects (n) = 259];
• 8 IM group - BioThrax administered by the IM route, using the traditional dosing regimen (n = 262) at 0, 2, 4 weeks, and 6, 12, 18, 30, and 42 months (biennial);
• 7 IM group - BioThrax administered by the IM route, using traditional dosing regimen but without the 2-week doses (n = 256) at 0, 4 weeks, and 6, 12, 18, 30, and 42 months;
• 5 IM group - BioThrax administered by the IM route (n = 258) using a dosing regimen at 0, 4 weeks and 6, 18, and 42 months;
• 4 IM group - BioThrax administered by the IM route (n = 268) using a dosing regimen at 0, 4 weeks and 6 and 42 months;
• Placebo (saline) administered by either the SC or IM route, using the traditional schedule (n = 260).
• For the 754 IM group (7 IM, 5 IM and 4 IM arms combined), BioThrax administered by the IM route (n = 782) using a dosing regimen at 0, 4 weeks and at 6 months.

Using an Enzyme-Linked Immunosorbent Assay (ELISA), Immunoglobulin G (lgG) antibodies directed against anthrax Protective Antigen were measured at the Week 8 and Months 7, 13, 19, 31, and 43 time points. The three primary immunogenicity endpoints were: (1) Geometric Mean Concentration (GMC) (mcg/mL), (2) Geometric Mean Titer (GMT), and (3) percentage with 4-fold rise in anti-Protective Antigen antibody titer from baseline.

The criteria for non-inferiority of comparisons based on ratios of GMCs and GMTs and differences in the rates of 4-fold rise in antibody titer were defined as follows:

• Mean antibody concentration ratio: non-inferiority was achieved when the upper bound of the 95% confidence limit was <1.5
• Mean antibody titer ratio: non-inferiority was achieved when the upper bound of the 95% confidence limit was <1.5
• 4-fold rise in antibody titer: non-inferiority was achieved when the upper bound of the 95% confidence limit was <0.10

The results showed that the anti-PA IgG responses induced by intramuscular route of administration were non-inferior when compared to subcutaneous route of administration. From Month 7 onwards, the immune responses, in terms of anti-PA IgG GMC and GMT, elicited by different administration route (8 IM) and reduced vaccination schedules (7 IM, 5 IM, and 4 IM) were non-inferior compared to the originally approved route and schedule (8 SC) four weeks following vaccine administration. However, the immune responses for the 4 IM group evaluated at month 13, 19, and 31 were declined significantly, compared to the other groups.

It is noted that for protection at Week 8, the dose schedule of Week 0, 2, and 4 was much better than the dose schedule Week 0 and 4, in terms of anti-PA IgG level. Therefore, for the non-emergency situation, the Week-2 dose can be omitted and a schedule of Week 0 and 4 is considered sufficient. However, if a speed robust protection is required, the Week-2 dose should be given. To justify that the subjects will be protected against anthrax disease during the time period between the 3-dose (Month 0, 1, and 6) primary series and the 3-year booster (Month 42), sponsor provided a non-human primates (NHPs) study (see section Non-Clinical Basis for Decision).

The Brachman Study

A controlled field study conducted in the 1950's using an earlier version of the BioThrax vaccine was administered to wool-mill workers who were at an occupational risk for exposure to anthrax spores. At the time of the Brachman study, the yearly average number of human anthrax cases (both cutaneous and inhalational) in these textile mills was approximately 1.2 cases per 100 employees.

The Brachman study included 1,249 workers [379 received anthrax vaccine, 414 received placebo, 116 received incomplete inoculations (with either vaccine or placebo) and 340 were in the observational group (no treatment)] in four mills in the North-Eastern United States that processed imported animal hides. The workers were followed over a 2-year period. During the trial, 26 cases of anthrax were reported.

Assessment of the vaccine's effectiveness included all cases of anthrax that occurred in persons who received at least three doses of vaccine or placebo, and received subsequent doses on schedule. The calculated efficacy of the vaccine to prevent all types of anthrax disease combined was 92.5% (95% confidence interval = 65% to 100%). Given this observation the study was stopped for ethical reasons, and all employees were immunized. This resulted in a dramatic reduction of anthrax in the wool-mill workers, despite continued occupational exposure to anthrax spores.

Efficacy Summary

BioThrax (Anthrax Vaccine Adsorbed) has been shown to be effective for prevention of anthrax disease as demonstrated in non-clinical and clinical studies. The overall therapeutic benefits of BioThrax therapy as inferred from a comprehensive review of animal and human study data, outweighs the known and expected risks of the product. Therefore, Health Canada has authorized the sale of BioThrax as an Extraordinary Use New Drugs (EUNDs) accordance with the Guidance Document - Submission and Information Requirements for Extraordinary Use New Drugs [EUNDs] pathway.

For more information, refer to the BioThrax Product Monograph, approved by Health Canada and available through the Drug Product Database

Clinical Safety

The most frequently reported adverse events with use of BioThrax were headache, arthralgia, erythema, injection-site erythema, pyrexia, myalgia, and injection-site pain.

Approximately 60% of the 1,564 clinical trial subjects who received BioThrax by any route, intramuscular or subcutaneous, were reported to have injection-site adverse reactions, and approximately 20% of recipients reported systemic adverse events, the vast majority of which were rated as 'mild'. The proportion of participants with severe injection site or systemic adverse reactions reported by adverse reaction category after each dose was very low (generally <1%). For more details on the reported adverse events and their frequency, consult the BioThrax Product Monograph.

Serious adverse events determined to be possibly associated with the administration of BioThrax by any route or schedule in 1,564 study subjects included generalised allergic reaction, pseudotumor cerebri with bilateral disc edema, aquaductal stenosis with generalised seizure, arthralgia of the metacarpophalangeal joints, ductal carcinoma of the breast, and supraspinatus tendon tear.

No adverse safety interactions were reported in a study involving concurrent treatment with antibiotics.

Post-Market Adverse Reactions

The following adverse events have been reported spontaneously. Since these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The reports included below are listed due to one or more of the following factors: seriousness of the event, number of reports, or strength of causal relationship to the drug.

• Blood and lymphatic system disorders: lymphadenopathy
• Gastrointestinal Disorders: nausea
• Immune system disorders: allergic reactions (including anaphylaxis, angioedema, rash, urticaria, pruritus, erythema multiforme, anaphylactoid reaction, and Stevens Johnson syndrome)
• Nervous system disorders: paresthesia, syncope, dizziness, tremor, and ulnar nerve neuropathy
• Musculoskeletal, connective tissue, and bone disorders: arthralgia, arthropathy, myalgia, rhabdomyolysis, and alopecia
• General disorders and administration site conditions: malaise, pain, cellulitis, and flu-like symptoms
• Psychiatric disorders: insomnia
• Skin and Subcutaneous disorders: pruritis, rash, and urticaria
• Vascular disorders: flushing

Infrequent reports were also received of multisystem disorders defined as chronic symptoms involving at least two of the following three categories: fatigue, mood-cognition, and musculoskeletal system.

For more information, refer to the BioThrax Product Monograph, approved by Health Canada and available through the Drug Product Database