Dengvaxia Submission Fails to Prove Efficacy in Adults

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Committee: Vaccines and Related Biological Products Advisory Committee (VRBPAC)

Indications: Dengue Tetravalent Live Vaccine (Dengvaxia) for the prevention of dengue disease

Question 1: Has the applicant provided adequate evidence to support the effectiveness of Dengvaxia in the prevention of dengue disease caused by viral serotypes 1, 2, 3, and 4 in people 9 to 45 years of age with laboratory confirmed previous dengue infection and living in endemic areas?

Vote Results:   Yes  6   No  7 Abstention 1

Question 2: Has the applicant provided adequate evidence to demonstrate the safety of Dengvaxia in prevention of dengue disease caused by viral serotypes 1, 2, 3, and 4 in people 9 to 45 years of age with laboratory confirmed previous dengue infection and living in endemic areas?

Vote Results: Yes  7   No  7

Drug/Device: Drug

Sponsor: Sanofi Pasteur, Inc.

FDA Documents:

Background:

Sanofi Pasteur, Inc. submitted a biologics license application (BLA) for a live tetravalent vaccine (Dengvaxia) to be used in prevention of dengue disease in individuals 9 through 45 years of age with previous dengue infection.  In support of the BLA, the applicant submitted 16 studies in an attempt to collectively demonstrate efficacy, immunogenicity, and safety of Dengvaxia.  Nine of the submitted studies were considered by the agency as less applicable (i.e. small sample size and early phase) therefore were excluded from the review. Data from two phase 3 and one phase 2b studies were considered by the agency for the assessment of clinical efficacy.  Safety and immunogenicity were evaluated based on three phase 2 studies.  While the committee voted that the evidence supported Dengvaxia's safety and effectiveness in children and adolescents between 9-17 years of age, it was less convinced with the evidence presented for its use in adults.

Unique Challenges:

Study design and efficacy assessment via bridging studies:

Two phase 3 and one phase 2b clinical studies conducted among children and adolescents aged 2 to 16 years were selected for assessment of vaccine efficacy. Additional trials that included adult participants (18-45 years) assessed safety and immunogenicity only and were intended to support immune bridging from children to adults.

Two of the three clinical studies (CYD14, CYD15) satisfied pre-specified primary efficacy criterion, while the phase 2b study (CYD23) did not.  Serotype specific immunogenicity data, as measured using geometric mean titres (GMTs), from trials of the adult participant (CYD47, CYD28, CYD22) were compared with a subset of CYD14 and CYD15 where efficacy was demonstrated in children/adolescents.  Although descriptively, immunogenicity of studies from Vietnam (CYD22) India (CYD47) were similar to that of CYD14 and 15; the agency questioned the validity of CYD47 (Singapore) where the participants’ baseline GMTs were significantly lower than Vietnam and India, despite being characterized as a Dengue endemic region.  WHO recommends demonstration of non-inferiority when bridging study is used to estimate efficacy of a vaccine product.  However, the applicant provided no prespecified statistical criteria for assessing comparability of GMTs from adults to GMTs of clinical efficacy studies.

Safety:

The applicant pooled safety data from subjects aged 9 to 45 for safety evaluation of Dengvaxia.  The dataset included safety outcomes for over 20,000 subjects up to at least 6 months after each dose.  There was no significant difference in rate or patterns of SAEs between Dengvaxia and placebo groups.

The applicant successfully demonstrated safety and efficacy of the indication among children and adolescents 9 to 17 years of age through randomized trial studies.  However, for safety and efficacy in adult patients aged 18 to 45, the applicant was unable to establish similarly due to criticisms raised around results of the bridging studies.  The advisory committee therefore voted against Dengvaxia’s efficacy in adult patients, and was uncertain of its safety. 

In summary：

None of the studies submitted for review was conducted in the United States.  Of the three clinical efficacy studies conducted in children and adolescents, two met the primary efficacy endpoint.  Unlike previous studies that also conducted clinic trails out of US, the agency did not request evidence of generalizability to the U.S. population.  The most likely reason could be that although dengue is endemic to island territories of the U.S. such as Puerto Rico and the Virgin Islands, the disease is extremely rare on the continental US primarily due to infrequent contact of vectors with people, rendering the majority of the U.S. population unaffected though in the U.S., there are no approved vaccines or antiviral treatments for dengue.   

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