Merck's zoster vaccine Zostavax show decreasing efficacy for reduction of shingles pain and other endpoints three years after vaccination in the company's pivotal trial, FDA's clinical reviewer says.

The study "shows a trend of decreasing efficacy in all three major efficacy endpoints...over the first three years following vaccination," FDA Clinical Reviewer Patricia Rohan said in ¹ agency briefing materials for the Dec. 15 meeting of FDA's Vaccines & Related Biological Products Advisory Committee.

"Interpretation of data in the later years, i.e., more than three years post vaccination, is limited by the relatively small proportion of subjects with follow-up," Rohan added.

In ² company briefing documents, Merck acknowledged that the vaccine efficacy wanes but levels out over time. "The efficacy decreased somewhat shortly after vaccination, but stabilized thereafter," Merck said.

[Editor's note: To ³ watch a webcast or order a video/DVD of FDA's Vaccines & Related Biological Products Advisory Committee's review of Zostavax, visit FDAAdvisoryCommittee.com.]

Zostavax is a more potent version of the live varicella zoster vaccine (Oka/Merck) currently marketed as Varivax for chickenpox prevention. Merck is seeking indications for Zostavax in the "immunization of adults = 50 years for prevention of herpes zoster, post-herpetic neuralgia and reduction of acute chronic zoster associated pain."

In the pivotal trial of 38,500 healthy adults over the age of 60, a single dose of Zostavax reduced the incidence of herpes zoster by 51.3% and the incidence of post-herpetic neuralgia by 66.5% at the end of three years. The burden-of-illness score, a composite measure of herpes zoster pain incidence, severity and pain duration, was reduced by 61.1%, FDA noted.

The clinical reviewer found that the efficacy of Zostavax appears to vary according to age group. The incidence of herpes zoster was reduced by 63.9% in subjects ages 60-69 years compared to 37.6% in subjects over 70 years of age. Efficacy in post-herpetic pain and burden-of-illness score reduction were also lower in the older age group.

Rohan found that the "major treatment effect" associated with Zostavax vaccination was "the decrease in the incidence of [herpes zoster] by 51.1%." The other efficacy endpoints, incidence of post-herpetic neuralgia and herpes zoster burden-of-illness, "provide little additional information," the reviewer said.

FDA's analyses show that the incidence of post-herpetic neuralgia occurring or persisting at 90 days following rash onset was reduced from 12.5% in the placebo group to 8.6% in vaccine recipients; the result was not statistically significant (p-value=.08). Similarly, the burden-of-illness was reduced from a score of 87.75 in the placebo group to 82.50 in the vaccine group; however, the p-value was .25. A p-value of .05 is typically required for a statistically significant result.

⁴ FDA's statistical review also questions the separation of the different endpoint claims considering that the burden-of-illness index encompasses both post-herpetic neuralgia and herpes zoster incidence.

"Considering this lack of independence in the metrics used to evaluate efficacy, the appropriateness of separate claims of efficacy in reducing HZ BOI and in reducing the incidence of HZ (or the incidence of PHN of the duration of pain) may warrant consideration," FDA statistical reviewer Sang Ahm proposed.

While FDA did not raise significant safety concerns for Zostavax, the agency suggested that it is difficult to draw conclusions from the pivotal trial with regard to long-term safety.

"Given the lack of information on the proportion of subjects responding at the monthly [Automated Telephone Response System] contact and at study termination...it is difficult to draw conclusions as to the relative safety of Zostavax at this time," FDA's clinical review concludes.

Zostavax safety is bolstered by data from post-marketing surveillance of Varivax and the combination varicella/measles-mumps-rubella vaccine ProQuad .

-Mary Bruce

Merck Zostavax Shingles Vaccine Decreases In Efficacy Over Three-Year Period, FDA Review Finds

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