Authorisation Procedures

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Procedures have been put in place in the European Union to speed up the availability of vaccines that can be used to protect the population against pandemic influenza.

These procedures, managed by the European Medicines Agency, allow an influenza vaccine to be authorised more quickly than the 18 to 24 months usually required for the authorisation of a medicine in the EU.

The two main procedures for authorisation of pandemic influenza vaccines are:

  • the 'mock-up procedure', which allows a vaccine to be developed and authorised in advance of a pandemic, based on information generated with a virus strain that could potentially cause a pandemic. Once the actual virus strain causing the pandemic is identified, the manufacturer can include this strain in the mock-up vaccine and apply for it to be authorised as a 'final' pandemic vaccine;
  • the 'emergency procedure', which allows for fast-track approval of a new vaccine developed after a pandemic has already been declared. Authorisation of these pandemic vaccines is quicker than for a normal vaccine, as the information submitted by the manufacturer is assessed in an accelerated timeframe (around 70 days instead of 210 days).

A third procedure allows vaccines authorised for use against non-pandemic, 'seasonal flu' to be modified so that they afford protection against pandemic flu.

Special procedures are also in place to monitor the effectiveness and safety of authorised pandemic vaccines once they are being used in the European population.

For further information on these procedures, see:

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The mock-up authorisation procedure

A mock-up vaccine is a type of flu vaccine that is developed well before a pandemic has started. Because the strain of flu virus that will cause a future pandemic is not known, pharmaceutical companies cannot start to prepare a vaccine containing the correct flu virus until a pandemic has started. To get around this problem, the mock-up procedure (also known as the ‘core dossier’ procedure) allows vaccine manufacturers to gain an authorisation for a prototype pandemic vaccine in advance of a pandemic. This approach is unique to pandemic vaccines.

Before a flu pandemic has started

Mock-up vaccines contain a strain of flu virus that is not currently circulating in humans and to which very few people have been exposed. Pharmaceutical companies can gain authorisation for mock-up vaccines after they have carried out full studies looking into how the vaccine is made (its ‘quality’), as well as its safety and its immunogenicity (its ability to trigger the production of antibodies against the virus).

A mock-up vaccine is not intended for use until, firstly, a flu pandemic has started and, secondly, the flu virus responsible has been identified and included in the vaccine. The mock-up vaccine is specially designed to mimic the final vaccine in two ways:

  • in the way the vaccine is ‘constructed’: the methods used to prepare the virus, as well as the composition of the vaccine;
  • in the way the vaccine is used, in people who have no existing protection against the virus.

Because of this the information obtained from the studies with the mock-up vaccines can be used to predict the safety and protective effect of the final vaccines.

To gain authorisation for a mock-up vaccine, the company needs to submit the information from its studies to the European Medicines Agency. In particular, the mock-up vaccine must show that it brings about an appropriate level of protection: according to criteria laid down by the Agency, at least 70% of the people in which the vaccine is studied must develop protective levels of antibodies for the vaccine to be approvable. If the vaccine’s benefits are judged to outweigh its risks, the vaccine will be authorised, but this authorisation will be under ‘Exceptional Circumstances’. This is because full information on the final vaccine’s safety and effectiveness during a pandemic will only be available once a pandemic has started and the flu virus responsible has been included in the vaccine.

During a pandemic

Once a pandemic has been officially declared, the company can replace the flu strain in the mock-up vaccine with the strain causing the pandemic. It can then carry out further studies looking at the quality of the final pandemic vaccine, and start studies investigating the vaccine’s safety and effectiveness in human volunteers.

To speed up the review process, the company supplies the data on the change of virus strain to the Agency. These data are supplied as soon as they are available in a ‘rolling review’ pattern, rather than waiting until it has collected a full dossier of evidence from studies. Once the data are considered to be sufficient to show that the benefits of the final pandemic vaccine outweigh its risks, the company is asked to formally submit a ‘variation’ application to change the flu strain in the authorised vaccine. The Agency’s scientific committee, the CHMP, will then make a recommendation to the European Commission within five days for final approval. This will include recommendations on how the vaccine should be used in different groups of patients.

As soon as the decision has been issued by the European Commission, the vaccine can be made available for use. This will occur as quickly as possible, within 10 to 20 days of the CHMP’s positive opinion.

Data from clinical studies

Because of the emergency nature of flu pandemics, the amount of information collected on the final pandemic vaccine is limited at the time of authorisation. Although a company needs to demonstrate that that its vaccine can be manufactured appropriately with the new flu virus strain, only preliminary data from clinical studies of the final vaccine may be available at the time of authorisation of the final vaccine. Further testing of the vaccine’s safety and effectiveness will continue to take place after administration of the vaccine has begun. The CHMP will continue to evaluate all of the data generated from the ongoing trials once the vaccine is being used.

Based on decades of experience with seasonal flu vaccines, insertion of a new virus strain in a vaccine should not substantially affect the safety or level of protection offered by the final pandemic vaccine once it contains the pandemic flu virus strain. The combination of a full package of information on the mock-up vaccine, supplemented by the data on the manufacture of the pandemic virus strain, is therefore sufficient to demonstrate the vaccine’s benefits and risks when it is used in the pandemic situation. In addition, if there are limited data on the final vaccine, the CHMP will also take information from the published literature and from previous pandemics into account in reaching its opinion on whether the vaccine can be authorised, as well as data from disease control centres.

To confirm that the final vaccines are as safe and effective as expected, their effects will be closely monitored after they have been authorised. This is especially important for certain groups of patients for whom limited data are expected to be available at the time of the final pandemic vaccine’s authorisation, such as children and pregnant women.

Authorisation of pandemic flu vaccines using the ‘mock-up’ approach

The emergency authorisation procedure

The Agency has also set up a pathway for the fast-track approval of new vaccines developed during a pandemic. In contrast to the mock-up approach, the authorisation of these vaccines requires submission of a new, full dossier of information. Companies developing new vaccines therefore need to gather more data than are needed to change the virus strain in a mock-up vaccine. This includes a more complete package of information showing how well the vaccine works when given to human volunteers, and its side effects.

In the emergency procedure, companies utilise the ‘rolling review’ process, supplying data on vaccines under development as they become available, rather than waiting until they have collected the full dossier of data. This allows the CHMP to evaluate the data in real time, so that the final vaccine can be approved as quickly as possible.

Once enough data has been gathered to show that the vaccine’s benefits outweigh its risks, the company is obliged to make a formal application to the European Medicines Agency, so that the vaccine can be authorised for use. The CHMP then carries out an accelerated assessment of the full dossier of information, issuing an opinion after around 70 days. This opinion is transmitted to the European Commission, which is expected to take around 25 to 45 days to issue a decision. The vaccine can then be made available for use.

Vaccines authorised using the emergency procedure are given ‘Conditional Approval. This means that, although the vaccine’s benefits outweigh its risks, the data used to support the authorisation are not yet comprehensive. The authorisation is granted on the condition that the company will supply the additional information requested, such as the results of further studies, once the vaccine is on the market.

Once they have been authorised, further steps are taken to monitor the safety and effectiveness of pandemic flu vaccines.

Authorisation of pandemic flu vaccines using the ‘emergency’ procedure

Modification of seasonal flu vaccines

Seasonal flu vaccines are modified every year, to make sure that they can protect against the flu strains expected to cause flu in the next winter flu season. Some of these vaccines can be modified so that they can protect against pandemic flu. This can be done by replacing the flu virus strain they contain with the strain causing the pandemic.

There is no special pathway to allow companies to obtain a marketing authorisation more rapidly when converting an existing seasonal flu vaccine into a vaccine to protect against pandemic flu. Companies using this approach therefore need to submit full clinical data on the vaccine’s safety and its ability to bring about protection before the change in flu strain can be authorised. This procedure usually takes around 70 days.

Because most seasonal flu vaccines are authorised at national level, the responsibility for authorising these types of conversions will mostly lie with the regulatory authorities in individual EU Member States, rather than with the European Medicines Agency.

Seasonal flu vaccines are not normally effective in a pandemic, although they can be used alongside pandemic vaccines to provide protection against the flu virus expected to be circulating during the flu season.

Monitoring of safety and effectiveness after authorisation

Once pandemic vaccines have been authorised and are being used in the population, special steps are put in place to monitor their safety and effectiveness. These studies look at all groups of patients receiving the vaccine but monitor people at risk of complications from pandemic flu particularly closely, such as people with weak immune systems, children and pregnant women. For many pandemic vaccines, there will be limited data available on these risks groups at the time of their authorisation.

Decisions on which groups should receive the vaccines, and when they should receive them, will be made by the government in each EU Member State. These decisions will be based on the information provided by the European Medicines Agency on how each vaccine should be used.

Safety

As for all medicines, safety issues may arise when a vaccine is used on a large scale. Side effects that are too rare to show up even in a large clinical trial might only become apparent when very large numbers of people receive a vaccine.

The Agency requires vaccine manufacturers to carry out further safety studies and to put special pandemic risk management plans in place once their pandemic vaccines are being used in the general population. This allows companies and regulatory authorities to monitor the safety of pandemic flu vaccines very closely and take swift action if any safety issues emerge.

As part of these plans, there will be systematic surveillance of around 9,000 subjects who receive each vaccine at the start of each vaccination programme, as well as active surveillance of ‘at-risk’ groups. The Agency will review information from these studies on a weekly basis.

In addition, certain effects that might be seen with pandemic vaccines have been classified as ‘adverse events of special interest’. These effects have been seen with some vaccines in the past and need to be monitored very closely. Even if not caused by a pandemic vaccine, any cases of these adverse events will need to be reported to companies and to regulatory authorities for assessment as a matter of urgency. They include problems affecting the nervous system, anaphylaxis (severe allergic reactions) and vaccination failure.

Effectiveness

Companies will also be obliged to confirm the effectiveness of pandemic vaccines in preventing pandemic flu after authorisation. As part of their post-authorisation commitments, companies will provide information from their ongoing clinical studies, including studies looking at vaccination in all age groups and in the ‘at-risk’ groups.

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