Regulatory Issues: Pandemic Preparedness Pacing Up - Challenges and opportunities for facilitating the development and licensure of pandemic influenza vaccines - BioPharm International

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Regulatory Issues: Pandemic Preparedness Pacing Up
Challenges and opportunities for facilitating the development and licensure of pandemic influenza vaccines


BioPharm International


Pandemic Influenza Vaccines

FDA's experience with evaluating and testing seasonal influenza vaccines has provided the regulatory framework in which regulatory policies and strategies for pandemic influenza vaccines have been developed. Because seasonal influenza vaccine manufacturers will likely produce pandemic influenza vaccines, increases in their manufacturing capacity and improvements to their existing processes increase the ability to produce pandemic influenza vaccines. The WHO reported that increased consumption of seasonal influenza vaccine in countries that already use the vaccine could raise demand by 60% above the current annual level of distribution.1 Such increases may help companies increase their capacity for pandemic influenza vaccine production.

The regulatory pathway for pandemic vaccines is similar to that of annual influenza vaccine. In March 2006, FDA issued two draft guidance documents for public comment—one for seasonal influenza vaccines and another for pandemic influenza vaccines. The draft documents outline specific approaches for manufacturers to develop new vaccines to increase the supply of safe and effective influenza vaccines for both seasonal and pandemic use.2–3 Final recommendations were issued by FDA on May 31, 2007, and reflect public input, including that of vaccine manufacturers.

FDA's review process for new pandemic influenza vaccines builds on existing knowledge of influenza in comparison to the seasonal vaccine and requires a composite of data to be filed. Chemistry, manufacturing, and control (CMC) data, as well as clinical evaluation (both pre- and post-licensure), are required for licensing a new pandemic influenza vaccine. The agency recommends that manufacturers submit a BLA for any new seasonal and pandemic influenza vaccines. A BLA will enable manufacturers to have separate trade names and labeling to distinguish between the two types of vaccines. A separate BLA will also facilitate better postmarketing adverse event reporting and collection by differentiating the information collected for each type of vaccine.

Clinical Study Requirements

If manufacturers who already have a US-licensed seasonal influenza vaccine that has been demonstrated to prevent influenza use the same manufacturing process for both seasonal and pandemic vaccines, FDA will not require clinical trials that demonstrate prevention of influenza illness. However, studies in humans to assess safety and determine an immune response to the selected pandemic influenza virus strains will be required to support the appropriate dose and regimen. In addition, FDA will seek agreement from sponsors to conduct postmarketing studies to obtain additional information about the vaccine's risk, benefits, and optimal use.

For manufacturers who are not licensed in the US, approval will be based on adequate and well-controlled clinical trials using the accelerated approval pathway, which allows for evaluation based on biological indicators, such as the immune response to the vaccine, that are likely to predict effectiveness. Further clinical studies are required after approval to verify the clinical benefit of the vaccine.

Antibody response, determined by measuring hemagglutination inhibition (HI) titers, is used as a serological marker of the immunological response to influenza vaccine, or efficacy, and may be appropriate for the evaluation of a pandemic influenza vaccine. FDA is recommending that appropriate endpoints include: 1) the percentage of subjects achieving an HI antibody titer ≥1:40, and 2) rates of seroconversion, defined as the percentage of subjects with either a prevaccination HI titer <1:10 and a postvaccination HI titer >1:40, or a prevaccination HI titer ≥1:10, and a minimum four-fold rise in postvaccination HI antibody titer. In a prepandemic setting, it is likely that most subjects will not have been exposed to the pandemic influenza viral antigen(s). Therefore, vaccinated subjects may reach both suggested endpoints. Thus, for studies enrolling individuals who are immunologically naive to the pandemic antigen, one HI antibody assay endpoint, such as the percentage of participants achieving an HI antibody titer ≥1:40, may be considered.

Considerable variability can be introduced into the laboratory assay used to measure HI antibodies because many of these factors include differences in viral strains and red blood cell types, and the presence of nonspecific inhibitors in the assay medium. Thus, suitable controls and assay validation are important for interpreting HI antibody results. Other endpoints and the corresponding immunologic assays, such as the microneutralization assay, may also be used to support the approval of a pandemic influenza vaccine BLA.4

Pandemic influenza vaccines, like seasonal influenza vaccines, must be manufactured using current good manufacturing practices (cGMPs). Some special requirements regarding quality and manufacturing data include:

  • description and characterization of drug substance and drug product
  • information regarding methods of manufacturing, including animal sources, virus sources, cellular sources, microbial cells, and animal cells (to assess for adventitious agents)
  • assay development and validation
  • process controls, especially for safety processes, such as sterilization and virus clearance
  • manufacturing consistency, including reference standards and release testing
  • drug substance specifications
  • reprocessing
  • container and closure system
  • stability studies
  • composition and characterization of final drug product, including excipients, adjuvants, and preservatives
  • specifications and analytical methods for drug product ingredients.


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