Clinical Trials in Children of Vaccines to Prevent Disease Caused by Influenza Viruses with Pandemic Potential
Vaccines and Related Biological Products Advisory Committee
February 19, 2009
Influenza disease can be particularly severe in young children with greater overall mortality and higher rates of hospitalizations reported among children aged 0-4 years of age.1 In recent years, human infections with avian influenza viruses have led to increasing concern that one or more of these viruses may evolve into a strain that is able to spread among humans. Several strains of avian subtype H5N1 have been recovered from humans who live or work in close contact with domesticated poultry, and avian subtypes H7, H9, and H10 have been reported to infect humans rarely.2 The World Health Organization (WHO) tracks cases of avian influenza infecting humans; since 2003 nearly 400 human cases of avian influenza due to H5N1 have been reported, of which 63% have been fatal,3 Pandemic influenza is a threat to the global population and children are among those at greatest risk of infection and of severe disease once infected. Because children congregate in groups, share secretions, and have little pre-existing immunity to influenza shed virus at high titer, they are also efficient transmitters of influenza to others.4
FDA is working with influenza vaccine manufacturers and sponsors, other
Sponsors of new vaccines to prevent influenza caused
by pandemic strains have submitted proposals to FDA for studying these vaccines
in clinical trials both in adults as well as the pediatric population. Some trials of pandemic influenza vaccines in
children have already been completed.
For example, NIH sponsored a clinical trial (NCT00133536)
of the licensed H5N1 vaccine (for the
national stockpile) manufactured by sanofi pasteur; this trial was conducted in
children age 2 years to 9 years of age and was designed to enroll 100
children. Results of this study will be
submitted to the FDA as a post-marketing commitment noted in the approval
letter for this product. While this
study was conducted under an Investigational New Drug (IND)
submission with IRB approvals and with FDA oversight, other trials have been
conducted outside the
The issues related to conducting pediatric clinical studies using pandemic influenza vaccine candidates are complex. On the one hand, pandemic preparedness may necessitate that such studies be done in the prepandemic period to provide a sound scientific basis for dose and scheduling recommendations to allow the best opportunity for protection in this population when a pandemic emerges. On the other hand, regulations govern clinical studies in children in order to minimize risk. FDA is seeking the perspectives of the VRBPAC members regarding the prospect of direct benefit to children afforded by studies of pandemic influenza vaccine candidates in this population. Further, we would like to provide an open forum for discussion of the issues related to clinical trials in children. FDA will also present an overview of the Subpart D regulations which describe safeguards for children in clinical investigations, and restrict the settings in which research in children is conducted in order to assure rights and minimize risk to children.
Pediatric Research Equity Act (PREA)
In recent years initiatives at FDA have stimulated and encouraged clinical investigations in children in order to obtain information to support safe and effective use of drugs and biologics in children. The Pediatric Research Equity Act of 2003 (PREA) followed more than a decade of legislative and regulatory attempts to address the lack of pediatric use information in drug product labeling. PREA requires all applications (or supplements to an application) submitted under section 505 of the Act (21 U.S.C. 355) or section 351 of the Public Health Service Act (PHSA) (42 U.S.C. 262) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration to contain a pediatric assessment for all relevant pediatric subpopulations, unless the applicant has obtained a waiver or deferral (section 505B(a) of the Act). In general, PREA applies only to those drugs and biological products developed for diseases and/or conditions that occur in both the adult and pediatric populations. The provisions of this law were reauthorized in Title IV of the FDA Amendments Act of 2007 (FDAAA). The Act also established the Pediatric Advisory Committee (PAC). The Pediatric Advisory Committee advises and makes recommendations to the Commissioner on matters relating pediatric research including IRB referrals under 21 CFR 50.54, and any other matter involving pediatrics for which the Food and Drug Administration has regulatory responsibility. The Committee also advises and makes recommendations to the Secretary pursuant to 45 CFR 46.407 on research involving children as subjects that is conducted or supported by the Department of Health and Human Services. It should be noted that representatives of PAC will be present at the February 19, 2009, VRBAC to hear and participate in the discussion.
The pediatric assessment required under PREA should contain data from pediatric studies for each age group for which the assessment is required. Data should be adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and should support dosing and administration for each pediatric subpopulation for which the drug or the biological product has been assessed to be safe and effective. FDA reviews the pediatric assessments and determines if additional clinical studies in children are needed. Based on specific provisions in the law, FDA may conclude that:
1. The assessment is adequate to support safety and effectiveness in all age groups;
2. Findings in the assessment can be extrapolated from adults or between age groups, if the course of the disease and the effects of the drug are sufficiently similar;
3. Additional studies are deferred, and provided at an agreed upon date;
4. Additional studies are waived, and will never be requested.
Thus, while studies may be required under PREA to support use in a pediatric population or subpopulation, they may also be judged unnecessary or impracticable.
Subpart D--Additional Safeguards for Children in Clinical Investigations
2001 FDA implemented regulations [21 CFR 50 Subpart D] providing additional
safeguards to protect children in clinical research of FDA-regulated products
to be consistent with Health and Human Services (HHS) regulations [45 CFR part 46, subpart D] adopted
in 1983. While the HHS regulations
addressed federally funded research, the FDA regulations covered all clinical
research conducted under
Under 21 CFR Subpart D, clinical investigations in children can be approved by an IRB and proceed only if the clinical investigation:
50.51 Does not involve more than minimal risk, or
50.52 Presents the prospect of direct benefit for the individual subject, or
50.53 Is likely to yield generalizable knowledge about the subjects' disorder or condition.
In the context of these regulations, minimal risk is most commonly defined as the level of risk encountered in daily life of a child. Receipt of an investigational vaccine and study procedures, including venipuncture to obtain blood for serological assessments, involve greater risk than is encountered daily. Thus, 21 CFR 50.51 would not usually be applicable to vaccine research in healthy children.
Likewise, 21 CFR 50.53 would not ordinarily apply to vaccine research because healthy children in preventive vaccine trials do not have a “disorder or condition” about which an investigation could obtain generalizable knowledge.
Most clinical research of vaccines in healthy children is approved by IRBs under 21 CFR 50.52, with the understanding that the study treatment offers the prospect of direct benefit to the child subject. Usually, the expectation of benefit is based on clinical studies in adults demonstrating effectiveness or activity of the product in treating or preventing disease affecting children. For vaccines, meaningful antibody responses observed in adults are sometimes used to support the prospect of direct benefit for children.
If an IRB finds that a clinical investigation offers the prospect of direct benefit to children, they must also find that the risk is justified by the anticipated benefit, and that the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches. In addition, adequate provisions must be made for soliciting the assent of the children and permission of their parents or guardians.
If an IRB does not find that a clinical investigation involving children as subjects meets the requirements of 50.51, 50.52, or 50.53, the clinical investigation may proceed only if it:
50.54 Presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.
An IRB cannot approve research under this provision but must refer it to the FDA Commissioner for panel review.
If referred by an IRB to the FDA Commissioner, approval of clinical investigations under 21 CFR 50.54 (opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children) becomes the responsibility of the Pediatric Advisory Committee (PAC). The Commissioner, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, determines whether any of 50.1, 50.2, 50.3 or 50.4 apply and if the investigation can proceed.
For example, in 2002 a referral for panel review was made under Subpart D (21 CFR 50.54 and 45 CFR 46.407) for a clinical trial of a smallpox vaccine in children. The NIH-sponsored trial, entitled “A Multicenter, Randomized Dose Response Study of the Safety, Clinical and Immune Responses of Dryvax® Administered to Children 2 to 5 Years of Age”, was referred by 1 (Harbor-UCLA) of 3 IRBs that reviewed the trial. Summary minutes of the referring IRB’s discussion revealed a view that vaccine would not offer the prospect of direct benefit to the individual child, except in the highly remote (with the information available to the committee) possibility that the individual child was exposed to smallpox, further noting that smallpox was eradicated in the 1970’s, save for stocks at CDC and in Russia. The reviewing panel, convened by the Office of Human Research Protections of HHS, consisting of 10 experts, provided written opinions regarding the smallpox vaccine trial, which are publicly available. Most panel members agreed that the trial was approvable under 21 CFR 50.54 and HHS regulations 45 CFR 46.407, i.e., that it presented an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. A few panel members held the view that the investigation was also approvable due to a prospect of direct benefit. Ultimately, this study was not conducted because other means of addressing availability of smallpox vaccine was pursued by HHS.
Considerations regarding pediatric clinical trials using pandemic influenza candidate vaccines
Currently, data needed to support approval for pandemic influenza vaccines include clinical safety and immunogenicity data derived from trials in adult subjects. Data to support the selected dose and regimen are currently based on the evaluation of 1) hemagglutination inhibition (HI) antibody titers ≥ 1:40, and 2) rates of seroconversion.5 It is anticipated that data to establish the safety and immunogenicity of the product in adults would be collected prior to studying the product in the pediatric population. As discussed further below, one approach to developing pandemic influenza vaccine candidates for the pediatric population would be to extrapolate the immune response obtained in adults to the pediatric population. However, very limited experience exists with regard to the immune response induced by pandemic influenza vaccine candidates in the pediatric population.
It is possible that pediatric subjects respond differently to these vaccine candidates with regard to magnitude and kinetics of the hemagglutination inhibition (HI) or neutralizing antibody titer induced. Thus, it may be important to conduct clinical trials in children to quantify the immune response obtained in response to pandemic influenza vaccine candidates. In addition, these trials may provide information about the pediatric pandemic influenza vaccine dose and regimen that would result in a maximum immune response in a pediatric population. Information that a lower vaccine dose in children results in acceptable antibody titers would support the choice of a possibly safer yet immunogenic dose for children, and better inform decisions about allocation of a limited vaccine supply during a pandemic.
As with human influenza viruses, the H5N1 avian strains are changing over time. Avian strains being developed as vaccines now may not be closely related to the strains that will later cause a pandemic. Also, while the current focus in pandemic preparedness is on influenza A subtype H5N1, influenza A subtypes with H2, H7, H9, or other hemagglutinins may also have pandemic potential. If clinical studies in children are considered essential to pandemic preparedness, additional studies may be needed as avian strains drift and as other subtypes become the focus of pandemic concerns. Multiple vaccine manufacturers are pursuing licensure of different formulations of pandemic influenza vaccines. Consequently, substantial numbers of children may be enrolled in these vaccine trials over the years.
amount of safety data needed for a particular sponsor's pandemic influenza
vaccine to support approval for use in the pediatric population will depend on
available clinical data for that sponsor's
Considerations for conducting pediatric clinical trials with pandemic influenza vaccine candidates should include the following:
for prevention of seasonal influenza are generally very safe. Seasonal influenza vaccine production follows
well-established manufacturing processes and millions of children and adults
are vaccinated yearly with new vaccine strains.
Due to time constraints on production and vaccine distribution in a
yearly cycle, no clinical studies are required in the
The licensed H5N1 vaccine manufactured by sanofi pasteur is produced using the same manufacturing process and facility as for seasonal influenza production. Like the seasonal influenza vaccine, it contains no adjuvant. Based on manufacturing alone, this vaccine might be considered a “strain change”, similar to yearly strain changes. However, clinical studies of this H5N1 vaccine in adult subjects determined that a larger dose is required for the pandemic strain vaccine than for the seasonal vaccine and that 2 inoculations were needed to achieve acceptable antibody titers. Whether the safety profile of these larger doses in young children is acceptable cannot be determined with certainty without at least limited studies in children.
Some of the pandemic influenza vaccine candidates currently in development have made use of novel adjuvants, including MF-59 and other oil-in-water emulsions, to improve and broaden immune responses to the influenza antigens. It is also expected that formulating with an adjuvant will enable use of lower amounts of antigens, which could be critical to the manufacture of sufficient doses in a pandemic setting. These adjuvants are not currently components of any vaccine licensed and marketed in the US, however, some of these are components of vaccines licensed in Europe [e.g., Fluad® (Novartis), a seasonal influenza vaccine for adults 65 years and older is formulated with MF-59] . Although published data derived from clinical trials using these novel adjuvants have not identified serious safety issues6, theoretical safety concerns have been raised, such as the possibility that non-specific, self-directed immune responses might be stimulated using novel adjuvants. Unlike the licensed, unadjuvanted H5N1 in the national stockpile, an extensive record of safe use of a corresponding seasonal influenza vaccine formulated with a novel adjuvant is not available.
Evaluation of clinical benefit
No definitive evidence of human-to-human
transmission of H5N1 currently exists, and thus, the risk of a pandemic is
difficult to quantify. At present, no
human or avian cases of H5N1 disease have been reported in the Western
Hemisphere, though possible future introduction to North American birds by
migratory ducks or geese from
Conducting pediatric studies of H5N1 vaccines in areas of the world where related H5N1 influenza has been reported in humans, or among children of poultry workers in areas where H5N1 avian influenza has been reported, presents one way of addressing the requirement under 21 CFR 50.52 of providing direct benefit to the child participants. It may be difficult to conduct such studies, but the data from these different populations could provide useful information.
According to PREA, clinical studies of a new vaccine in children may not be necessary if the course of the disease and the effects of the vaccine are sufficiently similar in adults and children. In these situations pediatric effectiveness may be extrapolated from adequate and well-controlled studies in adults and across age groups in children. For example, the smallpox vaccine, ACAM2000, was licensed in 2007 for use in persons determined to be at high risk of infection without age restriction; no clinical studies in children were conducted. FDA concluded that data from clinical studies in adults, along with the historical experience with vaccinia smallpox vaccines, were sufficient to support this indication.
Some data suggest that there may be similarities of influenza vaccine effects across age groups: for pandemic influenza, most adults and children are expected to be immunologically naïve to the vaccine subtype and strain. Data derived from studies conducted with the licensed H5N1 pandemic influenza vaccine in adults showed that 2 doses are required to achieve a meaningful immune response. Children experiencing seasonal influenza antigens for the first time are also immunologically naïve to influenza subtype and strain and require 2 doses to achieve acceptable responses. Among human cases of H5N1 disease, WHO reported in 2006 that the highest case fatality rate was in the 10-19 year age group (73%), followed by 20-29 year olds (62%), and children < age 9 years (~42%).8 In another report of 29 human cases from Viet Nam, the course of H5N1 disease in adults and adolescents was similarly severe9.
Thus, one approach to using pandemic influenza vaccines in the pediatric population in the absence of clinical data in this population may be by extrapolating pandemic influenza vaccine immunogenicity data from clinical studies in adults. However, it may also be the case that while data supporting effectiveness can be extrapolated to children, there may still be reason to evaluate the safety profile more fully in the pediatric population.
Children are especially vulnerable to mortality and morbidity of influenza illness, including pandemic influenza. Effective strategies to control transmission of pandemic influenza will include vaccination of children In the event of an influenza pandemic, children will be vaccinated with available vaccines. It is critical that pandemic influenza vaccines are developed that are safe and effective for children. The considerations in formulating regulatory pathways to licensure of these products for the pediatric population are complex as the benefits of vaccinating pediatric subjects outside a pandemic are insufficiently defined, true effectiveness of the vaccine can only be studied during an influenza pandemic, and the safety database available for these products is limited.
At VRBPAC, committee members will be asked to comment on the need to conduct clinical trials of candidate pandemic influenza vaccines in the pediatric population for pandemic preparedness. If clinical studies in children are considered necessary prior to an outbreak of pandemic influenza, the committee’s views on the scope of such studies will be sought. The specific questions to be addressed will be posed at VRBPAC.
Summary of Clinical Trials of Vaccines against Influenza Strains with Pandemic Potential Conducted in Pediatric Population
· NCT00133536: This trial of the licensed H5N1 vaccine (for the national stockpile) manufactured by Sanofi Pasteur is sponsored NIH/DMID. Study 04-077 is "A randomized, double-blinded, phase I/II, study of the safety, reactogenicity, and immunogenicity of intramuscular inactivated influenza A/H5N1 vaccine in healthy children aged 2 years through 9 years". The trial was designed to enroll 100 subjects, randomly assigned to influenza A/H5N1 vaccine and 20 subjects into the placebo group (5:1). This trial completed follow-up in April 2007 for primary endpoints, which included: (1) Proportion of subjects achieving a serum neutralizing antibody titer of 1:40 against the influenza A/H5N1 virus. (2) Geometric mean titer and the frequency of 4-fold or greater increases in hemagglutination inhibition and neutralizing antibody titers. The study was IRB approved. Submission of results of this study to the FDA was a post-marketing commitment noted in the approval letter for that product. Antibody results for this trial are not yet available at Clinicaltrials.gov.
· NCT00402649 is a follow-on study to the trial above (NCT00133536). It enrolled 23 subjects (aged 2-10 years) who were previously enrolled and assigned to placebo at the three clinical sites in the DMID 04-077, along with up to 32 subjects from a single site who were incorrectly dosed in that study. Subjects received at least 2 and up to 3 doses of the vaccine approximately 28 days apart. Limited safety and immunogenicity results from this study are available at Clinicaltrials.gov.
This is phase II study of a pandemic candidate vaccine manufactured by
GlaxoSmithKline conducted among children 3 years to 9 years of age in
This phase II study of a
pandemic influenza vaccine was conducted by CSL in
Safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in infants and children. Nolan T et al., Vaccine. 2008 Nov 25;26(50):6383-91. A prototype inactivated, aluminum adjuvanted, split-virus, clade 1 H5N1 vaccine (A/Vietnam/1194/2004/NIBRG-14) in infants and children aged 6 months to <9 years. Healthy infants and children (N=150) received two doses of 30mcg or 45mcg H5 HA with AlPO(4) adjuvant 21 days apart.
A phase 2 trial conducted by
Sanofi Pasteur in
Novartis Vaccines is currently enrolling children into a trial conducted
A search of the literature identified an additional study of investigational pandemic influenza vaccines evaluated in children:
immunogenicity of a prepandemic influenza A (H5N1) vaccine in children” Vajo Z
et al. Pediatr
Infect Dis J. 2008 Dec;27(12):1052-6.
In a study conducted in
Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations
21 CFR Parts 50 and 56: Additional Safeguards for Children in Clinical Investigations of FDA Regulated Products
Case Fatality Rate for H5N1 Influenza by Age
Source: World Health Organization. Epidemiology of WHO-confirmed human cases of avian influenza A(H5N1) infection. Wkly Epidemiol Rec. 2006;81:249–60
2. Avian Influenza (Bird Flu): Implications for Human Disease
3. WHO Epidemic and Pandemic Alert and Response: Confirmed Human Cases of Avian Influenza A(H5N1) http://www.who.int/csr/disease/avian_influenza/country/en/
4. AAP and TFAH Pandemic Influenza: Warning, Children at Risk, Oct 17, 2007;
5. Guidance for Industry: Clinical data needed to support the licensure of pandemic influenza vaccines http://www.fda.gov/cber/gdlns/panfluvac.htm.
7. Rappole JH and Hubálek Z;
Birds and Influenza H5N1Virus Movement to and within
8. World Health Organization. Epidemiology of WHO-confirmed human cases of avian influenza A(H5N1) infection. Wkly Epidemiol Rec. 2006;81:249–60.
9. Nguyen Duc Hien et al.; Human Infection with Highly Pathogenic Avian Influenza
Virus (H5N1) in