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Release of information relating to the approval process for the meningococcal B vaccine (MeNZB) application

Explanatory notes on some issues contained in the minutes of the Vaccine Sub-Committee (VSC) meeting held on 5 April 2004.

Background

The Vaccine Subcommittee (VSC) met on 5 April 2004 to discuss the clinical aspects of the application for approval of the Chiron MeNZB vaccine. The committee considered the preliminary results of a range of clinical trials conducted in adults and children. The definitions of the types of trials and the effects measured in these studies are:

Phase 1 clinical studies

Studies examining the first time a medicine is used in humans. These studies are closely monitored and may be conducted in patients, but are usually conducted in healthy volunteers. These studies are designed to determine the metabolic and pharmacologic actions of the medicine in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on efficacy.

Phase 2 clinical studies

Studies conducted to obtain preliminary data on the efficacy of the medicine for a particular indication or indications in patients with the disease or condition. This phase of testing also helps determine the common short-term side effects and risks associated with the medicine. Phase 2 studies are typically well-controlled, closely monitored, and conducted in a relatively small number of patients, usually involving several hundred people.

Phase 3 clinical studies

Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting efficacy of the medicine has been obtained in Phase 2, and are intended to gather the additional information about efficacy and safety that is needed to fully evaluate the overall benefit-risk relationship of the medicine. Phase 3 studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labelling. Phase 3 studies usually include several hundred to several thousand people.

Definitions:

Efficacy: a measure of the success of a medicine in changing a marker for, or outcome of, a medical condition in a selected patient group participating in a clinical trial. Efficacy can be based on an assessment of outcomes e.g number of heart attacks prevented, or on markers such as amount blood pressure lowered by treatment, or in the case of MeNZB, an immune response to the epidemic strain of meningococcal B. In the clinical studies, a four-fold rise in the level of substances in the blood that killed the bacteria was determined to be an acceptable measure of efficacy for the purposes of epidemic management.

Effectiveness: a measure of the success of a medicine in changing a marker for, or outcome of, a medical condition when the medicine is used in the community.

Immunogenicity: a measure of the ability of a vaccine to stimulate an immune response in vaccinated individuals. In the case of the MeNZB vaccine this was assessed by measuring the level of activity of substances in the blood that killed bacteria of the New Zealand epidemic strain of meningitis. This was measured using a test called the Serum Bactericidal Assay (SBA).

Immunological correlate of protection: the level of immune response that is required to provide protection against an infection.

Reactogenicity: a measure of the ability of the vaccine to produce an irritant or inflammatory response at the site of the injection. Usually measured by measuring the amount of swelling, redness and pain at the site of the injection of the vaccine.

Minutes of the Vaccine Sub-committee meeting - 5 April 2004

Welcome and Apologies:

The meeting opened at 9.15am.
Present: Associate Professor Richard Robson (Chair), Dr Tim Blacmore, Dr Rod Ellis-Pegler, Associate Professor David Holdaway, Dr Stewart Reid, Professor Jeff. Weston, Alison MacDonald (Secretary), Dr Stewart Jessamine.
Visitors: Stewart Jessamine, Rod Allman (Team Leader, Evaluation, Medsafe), Adrian Britt (Advisor Science, Medsafe), Leong Goh (Advisor Science, Medsafe) and Marie Prescott (Advisor Science, Medsafe/MAAC Secretary)

Objective: To consider if the New Medicine Application for Meningococcal B (MeNZB) Vaccine should receive the Minister's Consent for distribution in New Zealand.

Conflict of Interest Statements

Dr Reid stated he had a conflict of interest as he has been a member of the Meningococcal B Vaccine Project Committee for the past five years. Dr Reid abstained from the decision concerning the licensure of the vaccine.
Dr Blackmore stated he had a conflict of interest in that he was able to discuss the vaccine with staff at ESR (Institute of Environmental Science and Research Ltd).

The conflicts of interest were discussed but not considered to influence the discussions or decisions.

NEW MEDICINE APPLICATIONS UNDER SECTION 23.
MeNZB (Meningococcal B) injection suspension 25mcg/0.5mL. TT50-7090.

The Committee considered an application from Chiron for MeNZB (meningococcal B) vaccine.

The Chairman reminded the Committee that the object was to decide if there was sufficient evidence to recommend approval under Section 23 of the Medicines Act 1981.

New Zealand is in the thirteenth year of an epidemic of Group B Meningococcal disease. There is currently, no commercially available group B meningococcal vaccine against the New Zealand epidemic strain. International experience of similar outbreaks suggests that the epidemic may continue in this country for a further 6 to 10 years. There have been 500-600 cases per year. The current rate in the northern parts of New Zealand is more than 20/100,000. More than 80% of the disease occurs in people under 20 years of age. The highest rate of disease is in Maori and Pacific Island infants under the age of one year. Although the death rate in New Zealand is commendably low at 3.2%, some 15-20% of the survivors are left with a long-term disability, including sensory-neural deafness, skin, digit or limb loss and neurological damage.

An Immunisation Programme with a 'tailor-made' vaccine, containing OMV antigen for the most frequent New Zealand group B sub-type is seen as the most expeditious approach to bring this epidemic to a halt.

This is an unusual application as it is based on incomplete Phase II data for the candidate vaccine. Much of the clinical data supplied relates to a similar Norwegian produced vaccine, based on a different, but closely related sub-group B antigen. The application envisages a rolling submission requesting approval for the use of the vaccine in children and young adults as the results of the Phase II studies in these age groups become available.

The Committee noted that the evaluation of the data relating to the composition, manufacture, quality control, stability and bioavailability of this product was being conducted by the Medicines and Healthcare products Regulatory Agency (MHRA) in Britain and had not been completed.

The NZ vaccine has been developed from the parent Norwegian NIPH MenBvac, substituting the Norwegian B sero sub-type 44/76 with the most frequent current NZ b sero sub-type NZ 98/254, first isolated in 1998. The Norwegian vaccine manufacturing process has been chosen because unlike the Cuban vaccine it does not include any C-polysaccharide. The presence of the C-polysaccharide in the vaccine may obscure cases suffering meningococcal C disease, the second most common form of meningococcal infection in New Zealand.

The initial Phase I and Phase II studies of MeNZB in New Zealand were carried out with vaccine produced by NIPH, Norway, but owing to the need to produce large volumes of vaccine urgently, for the immunisation campaign in New Zealand, and lacking large scale capacity, NIPH entered into a cooperative agreement with Chiron, to allow for the manufacture of further lots in Italy, using a similar process. The vaccine is being produced under Good Manufacturing Process Guidelines.

Earlier studies with meningococcal group C vaccine and more recently field studies with group B OMV vaccines in Norway, Cuba, Chile and Brazil have shown that serum bactericidal antibody (SBA) assays are the most reliable measure of functional antibodies following vaccinations. Unfortunately there is no international agreement as to what titre of antibody is protective. The titre of SBA may depend on the particular batch of complement used in the test. Norwegian studies support the concept that development of SBAs following immunisation appears to indicate a level of clinical protection.

Initial trials by ESR staff have shown that the laboratory was able to consistently demonstrate a two fold or four fold rise in titre, from baseline, when compared with results from three overseas laboratories, but the actual titres varied from laboratory to laboratory. ESR have been able to achieve a 95% consistency in their results of repeat tests, performed weeks or even months apart. A ≥4 x rise in titre, from baseline, is regarded as a satisfactory response in the international studies of OMV vaccines.

This application differs from the usual approach for approval of a new vaccine because the clinical studies cited are phase 1 and II studies. Because of the urgency of the epidemic problem and the risk to New Zealand children it has been considered by the organising committee that it would be unethical to carry out phase III controlled studies before releasing the vaccine for more general use in children and young adults, the vulnerable groups. Instead it had been agreed to undertake controlled release of the vaccine for use in specific age groups, as further data from the phase II trials become available and field experience accumulated in the age groups immunised. In each age group immunised there will be a follow-up surveillance to ascertain the degree of effectiveness of the vaccine and a series of stringent monitoring programmes to ascertain any unforeseen adverse events.

The vaccine is given intramuscularly in three doses with six weeks between doses. Blood samples were taken prior to the first injection, with further samples taken prior to the second and third dose with a fourth sample taken 4 weeks after the last injection.

All of the first five New Zealand studies were carried out in Auckland, following ethical review by an independent Ethics Committee. Studies required written informed consent from participants or parents/legal guardians in the case of children. Each subject was kept under observation for 30 minutes post-injection. They, or the parents, were instructed to complete a diary card on which local and systemic reactions were recorded on the day of the injection and for the following six days. Study staff telephoned participants between 24 and 48 hours after each vaccine administration.

Study V60P1 was a phase I/II randomised, controlled, observer-blind, single centre study to evaluate the safety, tolerability and immunogenicity of three doses of a meningococcal serogroup B OMV vaccine when administered to healthy adults using either 25 or 50mcg antigen content. Groups 1 and 2 were given the 25mcg or 50mcg dose of the candidate vaccine and Group 3 received 25mcg of the Norwegian vaccine. Results showed that the MeNZB vaccine was immunogenic in adults to a comparable level of the Norwegian vaccine, and that there was no advantage in increasing the antigen level from 25mcg to 50mcg. Adverse events were common, but generally well tolerated and included malaise, muscle pain and nausea. No severe adverse events were reported.

Study V60P2 is a phase II single centre, randomised, observer-blind study to evaluate reactogenicity and immunogenicity of a three dose regimen of three different meningococcal serogroup B OMV vaccines when administered to two cohorts of 8-12 year old healthy school children. Cohort A has been completed and Cohort B commenced in January 2004 and is using the Chiron vaccine. The results of Cohort A showed that children in this age group could mount a satisfactory immune response to the MeNZB vaccine, although the percentage ≥four-fold rise in titre was not as great as in adults, but more than 90% achieved ≥two times response and a titre of ≥1:4. It would appear that Maori and Pacific Island children are more likely to have baseline SBA antibody to NZ98/254 level of ≥1:4 than were Caucasian children. No significant difference in the immune response was noted between ethnic groups. Adverse events were common, but stated to be mild or moderate.

Study V60P3 was a phase II single centre, observer blind, randomised controlled study to evaluate the safety, reactogenicity and immunogenicity of two meningococcal serogroup B OMV vaccines when administered to healthy 16 to 24 months old toddlers. These studies showed that toddlers in the age group 16 to 24 months are able to mount a satisfactory response to the epidemic meningococcal B strain, following immunisation. There was also an immune response to two other strains present in the New Zealand community and it is possible that the MeNZB vaccine will offer some protection against these also. Adverse events were common but not severe and the vast majority of subjects persisted to the end of the studies.

Study V60P5 was a phase II, single centre, observer blind, randomised, controlled study to evaluate the safety, reactogenicity and immunogenicity of MeNZB when administered to 6 to 8 month old healthy infants. This study was commenced in May 2003 and the last subject completed on 14^th November 2003. The infants in this study showed a response to the candidate vaccine in 67% when assessed by % showing ≥4-fold rise in SBA response and continued the pattern of lesser responses with decreasing age, however it is noted that 82% and 86% of the infants had SBA titres of ≥1:4 after the 2^nd and 3^rd immunising doses. The same pattern of adverse events was seen as with the older children, but they tended to be more persistent up to Day 7.

Study V60P4 is a phase I/II open label single centre study to evaluate the safety, reactogenicity and immunogenicity of three doses of the NZ MenB OMV (the Chiron manufactured vaccine) when administered in healthy adults. Ten subjects have been included in the study. To date, serology data are only available up until three weeks after the 2^nd vaccine dose. On the limited evidence presented it appears that the Chiron manufactured MeNZB vaccine is equally immunogenic compared with the NIPH MeNZB when tested against the NZ 98/254 epidemic strain of Meningococcus B and shows a significant immune response to other similar strains of N meninigitidis B.

Only studies V60P4 and the Cohort B arm of V60P2 used the Chiron manufactured vaccine, which is the vaccine, proposed for the New Zealand programme. Neither of these studies has been completed.

Studies were also presented that had been conducted in Norway, South America, Iceland and the Netherlands.

Study VA 98-03(I55PI) was a single blinded, randomised and prospective study in healthy adults investigating immunogenicity and reactogenicity of MenBvac and Menjugate, given in combination or separately. The subjects were aged between 18 and 35 years. MenB/C group received one dose of the combined vaccine followed by two doses of the vaccine at 6-week intervals. The MenB group received three doses of the vaccine at 6-week intervals and the MenC group received one dose of Menjugate then two doses of placebo at 6-week intervals. The study showed that the combined MenB/C vaccine was more immunogenic against meningococci serogroup B antigen than was MenB vaccine alone. The combined vaccine did not induce any inhibitory effect on the meningococci C response. Both the MenB/C and MenB vaccines were associated with an increase of local and systemic adverse events. A combined vaccine with both sero-group B and C antigen may be useful in New Zealand, especially amongst adolescent age groups where meningococcal sero-group C disease is more common.

Four further studies are being planned in New Zealand, two in the United Kingdom and one in Norway.

The Chiron MeNZB is a new vaccine and the current data supplies provided very limited data on its effectiveness. The majority of the justification for its use in New Zealand relies on its similarity to the 'parent' Norwegian vaccine MenBvac, or the NZ meningococcal B OMV vaccine, MeNZB, manufactured by the Norwegian Institute of Public Health. The extensive studies on MenBvac have demonstrated its efficacy in inducing an immune response and raising SBA antibodies, but its efficacy is preventing invasive meningococcal serotype B has not been proven. The effectiveness of these vaccines in very young infants is still to be verified, because of a lower immune SBA response, and a suggestion that young children produce antibodies with lower affinity. The vaccine is associated with a high frequency of short term local and systemic adverse events.

The entire measure of efficacy for MeNZB, initially will be immunogenicity. This is being measured by the serum bactericidal assay (SBA). The original Goldschneider study from the 1960s indicated that a SBA of ≥1:4 correlated with protection from meningococcal disease. Evidence of efficacy was not compelling. It was clear that there was no clear immunological corrolate of protection, which was reinforced by reporting SBA results in three different ways. Moreover the EIA results were presented, but often de-emphasised. It may well be that the SBA stands up as a reliable measure of immunogenicity and therefore protection, but it should be remembered that the SBA is best validated for serogroup C disease.

It is reasonable to extrapolate from the Norwegian safety data and to infer that the vaccine is safe. This is not to say that rare severe adverse side-effects will not occur during roll-out, and there is a clear need to carefully monitor the safety data.

The Committee was concerned that there was no efficacy data for the proposed vaccine, and were not convinced that the efficacy and safety monitoring during the roll out was sufficient to maintain public safety and confidence. Ongoing measures of effectiveness as well as adverse event should be clearly established if the vaccine is to see wide introduction into the New Zealand population as a Government - endorsed programme.

The Committee agreed that prior to be vaccinated informed consent forms must be read and signed by the person about to receive the vaccine, or parent/guardian in the case of a child or infant. This would be standard in schools when the mass immunisations were carried out, but information consent must be obtained from parent/guardian/caregiver of pre-schoolers and infants and those people not of school age. The forms should clearly highlight concerns concerning efficacy of the vaccine. The forms are to be circulated to members of the VSC prior to distribution for comments and if necessary a telephone conference to discuss.

No data have been provided for infants less than 6 months and therefore the indication should limit use in subjects 6 months of age and older.

The Committee agreed that a letter be sent to the Director of the Meningococcal Vaccine Strategy team advising that as a condition of provisional consent of this product the following would be required to be carried out by the Meningococcal Vaccine Strategy Team and reported back to Medsafe:

• Informed consent forms be provided to person about to be vaccinated (or parent/guardian in the case of children under the age of 15 years). These forms clearly identify concerns about efficacy.
• Laboratory diagnosis of Meningococcal infection
• Identification of vaccine failure.

Committee recommendations:

That the application for Meningococcal B (MeNZB) vaccine be approved under Section 23 of the Medicines Act 1981 for the primary immunisation against group B meningococci with the P1.7-b, 4 Por protein (New Zealand strain) in individuals aged 6 months or older. The population at risk should be vaccinated with MeNZB to prevent serious systemic disease (septicaemia and meningitis) caused by New Zealand strain serogroup B meningococci.

This approval is subject to the following:

• That Independent Safety Monitoring Board (ISMB) should have in their terms of reference a requirement to provide an opinion on the advisability of discontinuing the roll out on the ground of futility because of poor effectiveness of the vaccine or other factors.
• That a patient information sheet is to be reviewed by the VSC, as the information should indicate that this vaccine cannot guarantee protection as it is not effective against all serotypes of Meningococcus.
• That the datasheet be reviewed by the VSC and amendments made by the company to include the removal of the wording 'common' and 'very common' on page 4 of the datasheet and provide absolute percentages.
• That the evaluation of Part II data relating to the composition, manufacture, quality control and stability of this product is found to be acceptable.
• The Consent form is to be reviewed by the VSC.

04.06.2004
After email discussion among the VSC members it was decided that Medsafe should not be involved in deciding what is or is not required for informed consent, as this is outside the VSC jurisdiction and it is more appropriate for the ethics committees.
However, it was recommend that the VSC should flag that in their opinion informed consent should be obtained and leave the detail for an ethics committee who would consider the consent form for vaccination in schools.