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Any endpoint considered appropriate to support approval, whether a surrogate or a clinical endpoint, must be supported by substantial evidence of effectiveness.
The US Food and Drug Administration (FDA) and other National Regulatory Authorities (NRAs) have been developing new criteria for evaluating vaccines against pandemic influenza strains for licensure. Even with aggressive and successful efforts to strengthen and optimize US inter-pandemic production, manufacturing capacity in the United States is currently inadequate for a widespread pandemic. To prepare for the emergence of an influenza pandemic, new approaches and technologies must be evaluated ahead of time. Technologies for developing new influenza vaccines such as cell culture-based and reverse genetics have significantly advanced during the past decade. These technological advances present significant challenges and opportunities to the NRAs because regulatory agencies must develop new scientific criteria to evaluate these vaccines for safety and efficacy and final standards for any vaccine are relevant to the technology used to produce it. New influenza vaccine candidates must be evaluated using a blend of knowledge from the past and the best of current science in assessing their risks and benefits. FDA is actively developing needed pathways and using current regulatory processes, such as accelerated approval, to speed the availability of vaccines against pandemic influenza.
The US FDA's Center for Biologics Evaluation and Research (CBER) regulates vaccines for use in the US and is responsible for their safety and effectiveness. Ensuring an adequate, safe, and effective supply of influenza vaccine each year is one of FDA's highest priorities. Vaccine development and commercialization are complex processes. However, a single set of basic regulatory evaluation criteria applies to vaccines, regardless of the technology used to produce them. Licensure of a new vaccine is based on the demonstration of safety and effectiveness, and the ability to manufacture in a consistent manner. The agency facilitates the development and evaluation of new vaccines by anticipating and addressing the regulatory issues involved. General regulatory issues—such as detection of adventitious agents, and improved test methods that are reliable and sensitive—are applicable to many products and product classes including vaccines. Vaccine-specific issues and challenges, however, include determining correlates of protection necessary for evaluating efficacy, improving assays for potency, or finding animal models that can be used for the evaluation of efficacy when human clinical trials are infeasible or unethical.
FDA has developed mechanisms for advancing new therapies and vaccines through the review process. These mechanisms include fast-track development, accelerated approval, and priority review of marketing applications.
The FDA's fast-track programs are designed to facilitate the development and review of new drugs and biologics that are intended to treat serious or life-threatening conditions, and that demonstrate the potential to address unmet medical needs. The fast track adds to existing programs the possibility of a "rolling submission" for a marketing application. A "rolling submission" allows the applicant to submit portions of a marketing application for review (upon agreement with the FDA) before submitting the complete biologics license application (BLA). An important feature of fast track is that it emphasizes the critical nature of frequent and early communication between the FDA and sponsors to improve the efficiency of product development.
Accelerated approval, 21 CFR 601.40, may be granted for certain biological products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments. Accelerated approval may reduce the development time for a new vaccine. Such an approval is based on adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate endpoint that is based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit. Currently, the use of surrogate endpoints for evaluating vaccine effectiveness is subject to the requirement that the sponsor study the biological product further, to verify and describe its clinical benefit. Recently, the option to pursue an accelerated approval pathway for trivalent inactivated influenza vaccines became available if a shortage of influenza vaccine exists for the US market at the time the new vaccine is approved. In this case, the FDA interprets the regulation as allowing accelerated approval of an influenza vaccine during a shortage because influenza is a serious and sometimes life-threatening illness. The agency has licensed two seasonal influenza vaccines using this regulatory mechanism. Any endpoint considered appropriate to support approval, whether a surrogate or a clinical endpoint, must be supported by substantial evidence of effectiveness. The accelerated approval regulations give the FDA flexibility with respect to the types of endpoints that support marketing approval, but do not affect the quantity or quality of evidence needed to demonstrate substantial evidence of effectiveness or safety.
Products regulated by CBER are eligible for priority review if they provide a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious or life-threatening disease. The FDA has six months to complete the review of a new BLA receiving a priority review designation. The standard review time for a new BLA, not designated as priority, is 10 months.
The general considerations for clinical studies to license a vaccine include demonstration of safety, immunogenicity, efficacy (immunogenicity may be sufficient in some cases), and evaluation of simultaneous administration with other licensed vaccines. Efficacy should be demonstrated ideally in randomized, double-blind well-controlled trials. The endpoints will be product-specific, and may be clinical disease or immune response endpoints, if efficacy against clinical disease has been previously established.
Safety evaluation is the other component in the clinical evaluation of vaccines. Safety is one of the most important considerations when evaluating new vaccines and modifications to currently licensed vaccines. The initial responsibility for determining vaccine safety starts with clinical investigators and vaccine manufacturers. The NRA is responsible for ensuring that clinical trials are carried out under good clinical practices—a requirement essential for evaluating safety data. In general, when evaluating safety, one must compare the risk of the vaccine-preventable disease with the risk of the adverse event(s) possibly associated with the vaccine, and these may change over time.
Currently, all influenza vaccines licensed in the US are derived from viruses grown in chicken eggs, and contain 15 μg of hemagglutinin antigen from each of the three strains selected for that year's vaccine—two influenza A strains (H1N1 and H3N2) and one influenza B strain. For each year's seasonal influenza vaccines, any of the previous three influenza strains in the trivalent vaccine may be replaced with a new strain. Strain changes are based on evaluation of circulating wild-type strains. Public health experts from national influenza surveillance centers, the FDA, and the World Health Organization (WHO) annually evaluate world-wide epidemiological data to determine the virus strains that manufacturers will use to make the vaccines administered in the fall. The process of selecting the strains and manufacturing the final vaccine is a lengthy process that extends from 6 to 8 months. For these strain changes that occur every year, manufacturers must submit a prior approval manufacturing supplement to an existing BLA. FDA does not require clinical data, however, for approval of these annual supplements for licensed manufacturers of inactivated influenza vaccine.
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.
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:
Manufacturers and researchers actively study new manufacturing methods for influenza vaccines, such as cell-culture-based and recombinant technologies, along with adjuvants and other dose-sparing techniques.
Adjuvants have been used in a number of vaccines against other bacterial and viral pathogens, and are being investigated for use in influenza vaccines. The purpose of formulating vaccines with adjuvants is to increase the immune response to the vaccine, thus allowing either a decrease in antigen dose, a greater efficacy, or both. Alum is the only adjuvant used in influenza vaccines in the US, and has been used extensively. MF59, an oil and water emulsion, has been used in influenza vaccines in Europe since 1997.5 Small studies of inactivated nonadjuvanted pandemic influenza vaccines have demonstrated that more antigen per dose and more than one dose will probably be necessary to elicit immune responses comparable to those elicited following a single dose of an annual seasonal inactivated influenza vaccine.6
If a new adjuvant is added to the vaccine formulation, the result is considered a new product and requires the submission of a new BLA. Data supporting the safety of the adjuvanted formulation and the added benefit over the unadjuvanted formulation must be included in the BLA. Early studies should demonstrate the rationale for adding the adjuvant, e.g., evidence of enhanced immune response, antigen-sparing effects, or other advantages, and data supporting selection of the dose of the adjuvant itself. If the vaccine is a hemagglutinin-based product, the HI antibody assay may be appropriate to evaluate the immune response. The FDA recommends that if proof-of-concept and other studies are favorable, Phase 3 studies should be pursued in the interpandemic period.
For initial dose and formulation selection, a comparative clinical study of adjuvanted versus nonadjuvanted vaccines that both contain the same amount of antigen should demonstrate that the immune response elicited by the adjuvanted antigen is better than that elicited by the same antigen alone. For differences in HI antibody titer and seroconversion rates, the lower confidence limit on the appropriate point estimate excluding equality (i.e., the value 1 for the ratio parameter or 0 for the difference parameter) may be sufficient to demonstrate the added value of the adjuvant.
Cell culture and recombinant influenza vaccines are also under development, and may eventually replace the use of chicken eggs to produce influenza vaccines. Although egg-based manufacturing has been successful and cost effective, non-egg based manufacturing has potential advantages in affording more flexibility, and may allow greater yield of product. The FDA considers the use of a new cell substrate as a new product, and therefore, influenza vaccines manufactured in cell cultures require the submission of a new BLA. Cell-culture technology is used in the manufacture of other vaccines, and product characterization is important in using this technology for influenza vaccine manufacture. FDA recently published a draft guidance on the characterization and qualification of cell substrates and other biological starting materials used in the production of viral vaccines for the prevention and treatment of infectious disease.7 This guidance outlines FDA's current recommendations.
FDA is evaluating other technologies under investigation for potential use in the development of seasonal and pandemic influenza vaccines, such as alternative delivery systems and routes of administration, and use of immune stimulators. These technologies are at different stages of development, and they all present unique challenges to regulatory authorities.
Scientific, technological, and regulatory challenges must be addressed to facilitate the development of effective pandemic influenza vaccines. The FDA is actively developing pathways and using current regulatory processes such as fast track, priority review, and accelerated approval to facilitate the availability of vaccines against pandemic influenza. The agency has made significant strides, as evidenced by the April 2007 approval of the first US vaccine for humans against the H5N1 influenza virus. The approval of this vaccine is an important step in enhancing the nation's readiness against a possible pandemic. The vaccine is included in the national stockpile for distribution by public health officials, if required. The agency continues to work closely with its partners in the industry, academia, and other NRAs to diversify and strengthen influenza vaccine manufacturing and supply to aid the US in pandemic preparedness.
Norman W. Baylor, PhD, is the director of Office of Vaccines Research and Review at Center for Biologics Evaluation and Research, FDA, Rockville, MD, 301.827.5105.
1. US Food and Drug Administration. Draft guidance for industry. Clinical data needed to support the licensure of pandemic influenza vaccines. Rockville, MD; May 2007. www.fda.gov/cber/gdlns/panfluvac.htm.
2. US Food and Drug Administration. Draft guidance for industry. Clinical data needed to support the licensure of seasonal inactivated influenza vaccines. Rockville, MD; May 2007. www.fda.gov/cber/gdlns/trifluvac.htm.
3. World Health Organization. Global pandemic influenza action plan to increase vaccine supply. WHO/CDS/EPR/GIP/2006.1. Geneva; 2006.
4. Rowe T, et al. Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays. J Clin Microbiol. 1999;37:937–943.
5. Wadman M. Race is on for flu vaccine. Nature 2005;438:23. amedeo.com/lit.php?id=16267526.
6. Testimony of Anthony S. Fauci, MD, director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, on "Pandemic Influenza: The Road to Preparedness" before the Committee on Foreign Relations, United States Senate, 2005; Nov 9.
7. US Food and Drug Administration. Draft guidance for industry. Characterization and qualification of cell substrates and other biological starting materials used in the production of viral vaccines for the prevention and treatment of infectious diseases. Rockville, MD; Sept. 2006. www.fda.gov/cber/gdlns/vaccsubstrates.htm.