The U.S. Food and Drug Administration's ( FDA ) Vaccines and Related Biological Products Advisory Committee agreed that the extensive data from clinical trials in more than 40,000 people support the efficacy and safety of Zostavax ( zoster vaccine live ) to prevent shingles in adults aged 60 and over.

The Advisory Committee did not agree that the data presented were sufficient to support the efficacy and safety of Zostavax in adults aged 50 - 59 as Merck had proposed.

Merck filed a Biologics License Application ( BLA ) with the FDA on April 25 for Zostavax to reduce the risk of shingles; to reduce the risk of postherpetic neuralgia, the persistent, often debilitating long-term nerve pain that is the most common complication of shingles; and to reduce the total burden of pain and discomfort caused by shingles.

Shingles is caused by the reactivation of latent varicella zoster virus - the same virus that causes chickenpox.
Shingles may first appear as abnormal skin sensations ranging from itching or tingling to severe pain on a single area of the body or face. It then usually progresses to a rash and fluid-filled blisters accompanied by pain in almost every case.
The pain varies in intensity and duration.
Shingles also can lead to severe complications, including long-term nerve pain ( postherpetic neuralgia ) that can follow an episode of shingles. This complication can last for months or even years after the rash has healed and can range from a tender, burning pain to a throbbing, stabbing pain.

Shingles can affect anyone who has had chickenpox -- more than 90 percent of adults in the United States -- and occurs most frequently in older adults. In fact, it is estimated that up to half of all people who reach age 85 will have developed shingles during their lifetime. A recent study estimated that up to 1 million cases of shingles occur every year in the United States. The number of shingles cases is expected to increase as the population ages.

Merck presented data from several studies conducted in more than 40,000 people, including data from the Phase III Shingles Prevention Study ( SPS ) of 38,500 adults age 60 and over.

The SPS was a Department of Veterans Affairs ( VA ) study conducted in collaboration with the National Institute of Allergy and Infectious Diseases ( NIAID ) at the National Institutes of Health ( NIH ) and Merck at 22 U.S. research sites over a period of five years.
Results from the SPS were published in the The New England Journal of Medicine.

Zostavax reduced the total burden of pain and discomfort caused by shingles by 61 percent.
In the study, Zostavax also reduced by 67 percent the incidence of postherpetic neuralgia, and reduced the incidence of shingles by 51 percent.

The randomized, double-blind, placebo-controlled study was conducted to determine whether vaccination with a single dose of a live attenuated investigational vaccine, Zostavax, would decrease the incidence and/or severity of shingles and persistent nerve pain in men and women age 60 and older who had no previous history of shingles.

In the study, participants were randomized to groups given either Zostavax ( n=19,270 ) or a placebo ( n=19,276 ) and followed for the development of shingles for a median duration of 3.1 years.
Suspected cases of shingles were assessed by polymerase-chain-reaction ( PCR ) assay, virus culture and clinically by an evaluation Committee consisting of five physicians with expertise in shingles. All subjects with clinically diagnosed shingles were offered antiviral treatment ( Famciclovir ) when indicated or as appropriate and were offered standard-of-care treatment for pain.

The primary endpoint of the study was the burden of illness ( BOI ) caused by shingles over the first six months after shingles rash onset, a measure affected by the incidence, severity and duration of shingles-associated pain and discomfort.
Severity of pain was evaluated according to a "worst pain" score on a 0-to-10 scale using a validated questionnaire ( Zoster Brief Pain Inventory ) with a zero being no pain and a 10 being worst pain imaginable. Those in the study who did not develop shingles were assigned a score of zero. The BOI score represented the average severity of illness among all subjects in the vaccine or placebo group.

The study also evaluated the incidence of persistent long-term nerve pain after shingles in the group that received Zostavax compared to placebo.
Postherpetic neuralgia was defined as shingles-associated pain ( rated as > 3 on a 0-to-10 scale, using the Zoster Brief Pain Inventory ) that persisted or appeared more than 90 days after the onset of the shingles rash. The incidence of shingles in the group vaccinated with Zostavax compared to placebo recipients was also evaluated in the study.

The study showed efficacy with Zostavax on all measured endpoints compared to placebo:

- Zostavax significantly reduced the incidence, severity and duration ( burden of illness ) of pain and discomfort associated with shingles - by 61.1 percent ( p<0.001 ); the overall BOI score was 2.21 for the vaccine group ( N=19,254 ) compared to a score of 5.68 in the placebo group (N=19,247);

- Zostavax significantly reduced the incidence of persistent nerve pain after shingles - by two-thirds ( 66.5 percent ) ( p<0.001 ); 27 cases of postherpetic neuralgia occurred in the vaccine group ( N=19,254 ) compared to 80 cases in the placebo group ( N=19,247 );

- Zostavax significantly reduced the overall incidence of shingles by 51.3 percent ( p<0.001 ); 315 cases of shingles occurred in the vaccine group ( N=19,254 ) compared to 642 cases in the placebo group ( N=19,247 ).

In the study, the rates of serious adverse events, systemic adverse events and hospitalization were low.
During safety evaluations conducted during the first 42 days following vaccination, the number and types of serious adverse events were similar in the vaccine ( N=255/19,270 ) and the placebo groups ( N=254/19,276 ) and the distribution of serious adverse events by organ system were also similar between the groups.
Only five subjects had serious adverse events that were assessed by site investigators as possibly vaccine related, two in the vaccine group ( exacerbation of asthma and polymyalgia rheumatica ) and three in the placebo group ( anaphalactoid reaction, polymyalgia rheumatica and Good Pasture's syndrome ).
During this period, varicella-like rashes at the injection site appeared more frequently in the vaccine group ( N=20/19,270 ) compared to the placebo group ( N=7/19,276 ). However, these rashes occurred at other sites at similar rates in the vaccine ( N=18/19,270 ) and placebo groups ( N=14/19,276 ).

. In an adverse events sub-study that included more than 6,600 subjects from all 22 research sites, significantly more people in the vaccine group ( N=1,929/3,345 ) had one or more adverse events compared to the placebo group ( N=1,117/3,271 ) reflecting a greater frequency of injection-site adverse events in vaccine recipients.
The most frequently observed injection-site adverse events among those in the vaccine group were erythema ( N=1,188/3,345 or 35.8 percent, compared to N=227/3,271 or 7.0 percent with placebo ); pain or tenderness ( N=1,147/3,345 or 34.5 percent, compared to N=278/3,271 or 8.5 percent, with placebo ); swelling ( N=871/3,345 or 26.2 percent, compared to N=147/3,271 or 4.5 percent with placebo ); and pruritus ( N=237/3,345 or 7.1 percent, compared to N=33/3,271 or 1.0 percent with placebo ).
Reactions at the injection site were generally mild.
No other adverse event at the injection site was observed in more than 2 percent of those in the vaccine group.

Source: Merck, 2005


XagenaMedicine2005