UNITED STATES OF
AMERICA
FOOD AND DRUG
ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH
VACCINES AND RELATED
BIOLOGICAL PRODUCTS
ADVISORY COMMITTEE
MEETING
+ + + + +
THURSDAY, DECEMBER 15,
2005
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+ + +
The
meeting came to order at 9:00 a.m. in the Versailles Ballroom of the Holiday
Inn Select, 8120 Wisconsin Avenue, Bethesda, MD, Gary D. Overturf, Chairman,
presiding.
PRESENT:
GARY D. OVERTURF, M.D. Chairman
CHRISTINE WALSH, R.N. Ex. Secretary
MONICA M. FARLEY, M.D. Member
RUTH A. KARRON Member
DAVID MARKOVITZ, M.D. Member
WALTER ROYAL, III, M.D. Member
BONNIE M. WORD, M.D. Member
THOMAS FLEMING, Ph.D. Temp. Voting Member
BRUCE GELLIN, M.D., M.P.H. Temp. Voting Member
MICHAEL ROWBOTHAM, M.D. Temp. Voting Member
DANIEL SCHARFSTEIN, SC.D. Temp. Voting Member
MELINDA WHARTON, M.D., M.P.H. Temp. Voting Member
SETH HETHERINGTON, M.D. Acting Industry Rep.
This transcript
has not been edited nor corrected, but appears as received from the commercial
transcribing service. Accordingly, the
Food and Drug Administration makes no representation as to its accuracy.
AGENDA ITEM PAGE
WELCOME:
Gary Overturf................................. 3/6
CONFLICT OF INTEREST STATEMENT:
Christine Walsh................................. 3
INTRODUCTIONS:.................................. 6
SAFETY & EFFICACY OF ZOSTAVAX:
FDA BRIEF INTRODUCTION/QUESTIONS PRESENTATION:
Patricia Rohan.................................. 7
SPONSOR PRESENTATION:
David Gutsch................................. 9/63
Jeffrey Silber................................. 15
QUESTIONS...................................... 66
FDA PRESENTATION:
Patricia Rohan................................ 106
QUESTIONS..................................... 136
QUESTIONS ADDRESSED BY SPONSOR:
Jeffrey Silber................................ 151
FDA PRESENTATION OF QUESTIONS:
Patricia Rohan................................ 168
COMMITTEE DISCUSSION ON FDA QUESTIONS:........ 169
COMMITTEE RECOMMENDATIONS:
QUESTION 1.................................... 226
QUESTIONS 2 & 3............................... 248
POLL OF COMMITTEE:............................ 267
ADJOURN:
Gary Overturf................................. 269
P-R-O-C-E-E-D-I-N-G-S
9:03
a.m.
CHAIRMAN
OVERTURF: Good morning, I would like to
call the meeting to order and first of all, I'll turn it over to Christine
Walsh, the Executive Secretary, for some administrative issues.
MS.
WALSH: Good morning. I'm Christine Walsh, the Executive Secretary
for today's meeting of the Vaccines and Related Biological Products Advisory
Committee. I would like to welcome all
of you to this meeting of the Advisory Committee.
Today's
session will consist of presentations that are open to the public. I would like to request that everyone,
please, check your cell phones and pagers to make sure they are off or in the
silent mode. Due to a family emergency,
Dr. Pamela McInnes will be unable to attend the meeting with us today.
I
would now like to read into the public record the Conflict of Interest
statement for today's meeting.
"This brief announcement is in addition to the Conflict of Interest
statement read at the beginning of the meeting on December 14th and
will be part of the public record for the Vaccines and Related Biological
Products Advisory Committee meeting on December 15, 2005.
This
announcement addresses Conflicts of Interest for the discussions of Topic 2 on
the Safety and Efficacy of ZOSTAVAX manufactured by Merck and Company. Dr. Steven Self has recused himself from the
discussion of Topic 2, Safety and Efficacy of ZOSTAVAX. In accordance with 18 USC Section 208(b)(3),
waivers have been granted to Drs. Ruth Karron, Thomas Fleming and Daniel
Scharfstein.
Dr.
Ruth Karron for unrelated consulting with the competitor for which she receives
less than $10,000 per year. Dr. Thomas
Fleming for unrelated consulting with a competitor for which he receives less
than $10,001 per year. Dr. Daniel
Scharfstein for unrelated consulting with a competitor for which he receives
less than $10,001 per year and ownership of stock in the sponsor currently
valued at less than $10,001.
A
copy of the written waiver statement may be obtained by submitting a written
request to the Agency's Freedom of Information office, Room 12A-30 of the
Parklawn Building. Dr. Seth Hetherington
is serving as the industry representative acting on behalf of all related
industry and is employed by Inhibitex Incorporated. Industry representatives are not special
Government employees and do not vote.
In
addition, there are regulated industry speakers making presentations. These speakers may have financial interest
associated with their employer and with other regulated firms. The FDA asks in the interest of fairness that
they address any current or previous financial involvement with any firm whose
product they may wish to comment upon.
These
individuals were not screened by the FDA for conflicts of interest. This Conflict of Interest statement will be
available for review at the registration table.
We would like to remind Members and consultants that if the discussions
involved any other products or firms not already on the agenda for which an FDA
participant has a personal or imputed financial interest, the participants need
to exclude themselves from such involvement and their exclusion will be noted
for the record.
FDA
encourages all other participants to advise the Committee of any financial relationships
that you may have with the sponsor, its product and, if known, its direct
competitors." That ends the reading
of the Conflict of Interest statement.
Dr. Overturf, I turn the meeting back over to you.
CHAIRMAN
OVERTURF: Again, I would like to welcome
you to this meeting of VRBPAC for December 15th and I would like to
go around the Committee Members and ask them to introduce themselves again and,
please, tell us where you are from. Dr.
Karron, we'll start with you.
MEMBER
KARRON: Ruth Karron, Johns Hopkins
University.
DR.
FLEMING: Thomas Fleming, University of
Washington.
MEMBER
WORD: Bonnie Word, Baylor College of
Medicine.
DR.
SCHARFSTEIN: Daniel Scharfstein, Johns
Hopkins University.
DR.
ROWBOTHAM: Mike Rowbotham, University of
California San Francisco.
DR.
GELLIN: Bruce Gellin, National Vaccine
Program Office, HHS.
DR.
WHARTON: Melinda Wharton, National
Immunization Program, Centers for Disease Control and Prevention.
MEMBER
ROYAL: Walter Royal, University of
Maryland School of Medicine.
DR.
HETHERINGTON: Seth Hetherington,
Inhibitex in Alpharetta, Georgia.
MEMBER
FARLEY: Monica Farley, Emory University
School of Medicine.
MEMBER
MARKOVITZ: David Markovitz at University
of Michigan.
CHAIRMAN
OVERTURF: And I'm Dr. Gary Overturf from
the University of New Mexico. So we will
begin the meeting today which is to evaluate the safety and efficacy of
ZOSTAVAX and I'll ask Patricia Rohan to come forward and provide the introduction
from the FDA.
DR.
ROHAN: Dr. Overturf, good morning,
personnel from Merck, invitees, Committee, I would like to welcome you
all. I'm the medical officer and I'll be
speaking later for this presentation, but first we would like to as usual go
over the Committee's questions that will be considered later this afternoon.
Question
No. 1: "Are the available data
adequate to support the efficacy of ZOSTAVAX when administered to individuals
50 years of age and older in preventing herpes zoster, in preventing
postherpetic neuralgia, preventing postherpetic neuralgia beyond the effect on
the prevention of herpes zoster and decreasing the burden of illness and
decreasing the burden of illness beyond the effect on the prevention of herpes
zoster and, if not, what additional information should be provided?"
Question
No. 2: "Are the available data
adequate to support the safety of ZOSTAVAX when administered to persons 50
years of age and older, if not, what additional information should be
provided?"
Question
No. 3: "Please, identify other issues
that should be addressed, including post-licensure studies. In particular, please, address the use of the
vaccine in persons with co-morbid conditions.
For example, those who might typically reside in assisted living
residences and nursing homes. The use of
the vaccine among persons taking chronic immunosuppressive agents, such as
corticosteroids, the use of the vaccine in certain subjects of the sponsor's
proposed age indication. For example,
those 70 years of age and older, those 80 years of age and older. The duration of immunity and a sponsor's
proposed pharmacovigilance plan."
Thank you.
CHAIRMAN
OVERTURF: Thank you, Dr. Rohan. We will begin now with the sponsor's
presentation.
DR.
GUTSCH: Good morning, Mr. Chairman,
Members of the Advisory Committee, the FDA, ladies and gentlemen. My name is David Gutsch and I'm a Director in
the Department of Regulatory Affairs at Merck Research Laboratories. Today I'm going to start by introducing you
to ZOSTAVAX, the Merck vaccine, for the prevention of herpes zoster and its
complications including postherpetic neuralgia or PHN.
As
you will hear today, there is a medical need for a vaccine to prevent herpes
zoster and its complications. Herpes
zoster is common in those 50 years of age and older. There is no medical intervention to prevent
herpes zoster. The acute and chronic
pain associated with herpes zoster is often severe and debilitating. And with available therapies, management of
the acute and long-lasting pain complicating herpes zoster can be frustrating.
The
hypothesis for the ZOSTAVAX Program is that vaccination with the live
attenuated Oka/Merck VZV vaccine will meet an important unmet medical need by
reducing the incidence of herpes zoster, otherwise known as shingles, and by
reducing the frequency and/or severity of herpes zoster of the complications of
herpes zoster, including postherpetic neuralgia, the pain that can last for
months to years after a rash heals.
As
you will see in the following presentation, there are many definitions of
postherpetic neuralgia in the literature, including pain persisting beyond rash
healing through pain persisting beyond six months. Based on the literature and consultation with
experts for the purposes of the ZOSTAVAX clinical studies, PHN was defined as
the presence of clinically significant pain present 90 days or more after
herpes zoster rash onset.
ZOSTAVAX
is a live attenuated varicella-zoster vaccine, varicella-zoster virus vaccine,
that uses the same Oka/Merck strain that is present in VARIVAX, the licensed
vaccine for chicken pox, and the recently licensed ProQuad for measles, mumps,
rubella and varicella. And while VARIVAX
and ProQuad contain the same active ingredient, there are notable differences
in these products.
VARIVAX
is used for the primary prevention of VZV and, therefore, is administered to
younger VZV naive population. The
proposed use of ZOSTAVAX is for prevention of reactivation of VZV and the
subsequent complications of that reactivation.
So ZOSTAVAX would be targeted to an older population. ZOSTAVAX is a preservative-free lyophilized
product that is administered as a single subcutaneous dose.
ZOSTAVAX
is manufactured using the same process as VARIVAX and both vaccines contain the
same excipients. When reconstituted and
administered as instructed, ZOSTAVAX contains 19,400 plaque-forming units per
dose, which is about 14 times the dose present in VARIVAX in order to list at
the desired immune response.
The
proposed indications for ZOSTAVAX are as follows: ZOSTAVAX is indicated for the prevention of
herpes zoster or shingles, prevention of postherpetic neuralgia, reduction of
acute and chronic zoster-associated pain.
ZOSTAVAX is indicated for immunization of individuals 50 years of age
and older. As you will hear in more
detail, these three clinically meaningful indications are directly supported by
having met the success criteria for key Shingles Prevention Study efficacy
endpoints that were pre-specified and mutually agreed upon by the sponsor and
the FDA.
The
three endpoints that support the indications regarded the decrease incidence of
herpes zoster, decreased incidence of postherpetic neuralgia and reduction of
the pain burden of illness over a six month follow-up period after herpes
zoster rash onset. Although the Shingles
Prevention Study enrolled subjects 60 years of age and older, there is a strong
case for vaccination with ZOSTAVAX starting at age 50. The next speaker will take you through the
epidemiologic and clinical evidence supporting the proposed target age range.
In
the ZOSTAVAX vaccine license application there are eight clinical trials in
which ZOSTAVAX has been administered, including the Shingles Prevention Study
of Veterans Affairs, Cooperative Studies Program, Multicenter Placebo-Controlled
Study in which nearly 40,000 subjects were enrolled. And as you will see, these studies
demonstrated that ZOSTAVAX is efficacious in preventing herpes zoster and PHN
in reducing the overall burden of zoster-associated pain, including severe
pain, and in reducing the interference with activities of daily living due to
herpes zoster.
Furthermore,
you will see that ZOSTAVAX is immunogenic in the VZV experience vaccinees and
that ZOSTAVAX has an excellent safety profile.
Collectively, the efficacy, immunogenicity and safety that results
support a favorable risk/benefit assessment as an intervention to prevent
herpes zoster and its complications, including PHN, ZOSTAVAX represents a major
medical advance.
There
are several collaborators present who are associated with the Shingles
Prevention Study, the large pivotal study in support of ZOSTAVAX. Here today are Dr. Michael Oxman, Study
Chairman for the Shingles Prevention Study; Gary Johnson, a Shingles Prevention
Study Biostatistician; and Dr. Myron Levin, a key principle investigator. Also present as clinical consultants are Dr.
Ann Arvin, Dr. David Cornblath, Dr. Robert Johnson and Dr. David Weber. And our statistical consultants are Dr. James
Neaton and Dr. Janet Wittes.
A
detailed briefing document was previously provided to the Advisory Committee
Members. Dr. Jeffrey Silber from the
Department of Clinical Research at Merck Research Laboratories will now present
the highlights of the information provided in the briefing document. Following this, I will provide some
concluding remarks.
DR.
SILBER: Thank you, David, and good
morning. This morning I have the
privilege of sharing with you information on a number of topics. The epidemiology of herpes zoster and
postherpetic neuralgia, an overview of the Clinical Development Program for
ZOSTAVAX followed by a more detailed description of the study design and key
results from the Shingles Prevention Study.
I will also review available immunogenicity and safety data for the
product before providing an overall summary of the clinical trial results.
As
background, it is important to note that herpes zoster, commonly known as
shingles, is a clinical manifestation of the reactivation of latent infection
with varicella-zoster virus or VZV.
Primary infection with VZV typically in childhood causes chicken
pox. Thereafter, the virus establishes a
latent infection in the dorsal root ganglion of the spinal cord where it
remains quiescent for many years.
In
the United States nearly all adults have evidence of prior VZV infection and
therefore are at risk for shingles.
During prolonged latency, VZV-specific cellular immunity keeps the virus
in check. And for reasons that are not entirely
understood, but are clinically associated with advancing age or immunosuppression,
the virus reactivates.
The
virus travels down the nerve root, reaches the skin and develops into the
characteristic eruption of painful, erythematous, maculopapular lesions that
evolve into clustered fluid-filled vesicles that are shown on the right hand
side in a pathognomonic dermatomal distribution.
Herpes
zoster is a relatively common disease.
It is estimated that, approximately, 1 million cases of herpes zoster
occur each year in the United States, of which nearly two-thirds occur in persons
over the age of 50. And this number is
expected to rise due to the aging of the population. An estimated 50,000 to 60,000
hospitalizations each year in the United States include a diagnosis of herpes
zoster. And among these are an estimated
12,000 to 19,000 for which herpes zoster is the primary diagnosis.
Of
note, 85 to 90 percent of all herpes zoster cases and 70 to 80 percent of
hospitalizations occur in immunocompetent individuals. And it has been noted in recent studies that
the lifetime risk of developing herpes zoster may be as high as about 30
percent and for those who attain the age of 85, up to 50 percent will have
suffered one or more episodes of zoster in their lifetime.
Although
herpes zoster has been noted to occur after stressful life events or the site
of prior physical trauma, the only
clearly established risk factors for herpes zoster are increasing age and
immunosuppression. This figure is from a
classic paper by Hope-Simpson showing the age-related contributions in herpes
zoster and postherpetic neuralgia or PHN.
I'll be speaking much more about PHN in subsequent slides.
In
this figure, the X axis shows age in years and on the Y axis is the rate of
disease. And you will note that there is
a substantial increase in the incidence of postherpetic neuralgia beginning at
age 60, whereas the incidence of herpes zoster begins to rise fairly
dramatically at age 50. Similar findings
have been borne out from more recently conducted population-based studies.
This
slide shows the number and the proportion of all herpes zoster cases in the
United States across the different decades of life, based on the most recent
census data and the age-specific rates from the Hope-Simpson Study. And the results are generally similar when
results of other population-based studies are applied. Note the preponderance of herpes zoster cases
among the older adults with the number of cases among people in their 50s at
least as high as among people in their 60s, a phenomena that is expected to
continue.
The
next two slides show typical herpes zoster eruptions. The first shows a herpes zoster case in a
mid-thoracic dermatome. The lesions of
herpes zoster are typically unilateral, but can cross the midline slightly and
can also cross into adjoining dermatomes.
The skin lesions usually evolve over about 7 to 10 days and then heal
over the subsequent two to three weeks.
The
following slide shows an episode later in its course, an ophthalmic zoster in
the ophthalmic distribution of the fifth cranial nerve. After the thorax, the fifth cranial nerve is
the most common location for herpes zoster to occur. Herpes zoster ophthalmic represents 10 to 15
percent of all herpes zoster cases and about 50 percent of those have ocular
involvement. Sight threatening
complications can ensue and so prompt attention to these cases is essential.
Numerous
complications can result from an episode of herpes zoster. The most common neurologic manifestation is
acute neuritic pain, which affects over 90 percent of all episodes of herpes
zoster, and can be quite severe even in younger individuals. Postherpetic neuralgia, which is generally
defined as pain present following resolution of the rash, is a relatively frequent complication that
increases with age, and more on this later.
Other
neurologic complications include loader motor neuron palsies, which can affect
up to 5 percent of episodes, sensory deficits, autonomic dysfunction and more
rarely meningitis, myelitis or encephalitis.
A number of ocular complications can occur as a result of ophthalmic
zoster as shown on the previous slide.
Among the cutaneous complications of zoster are scarring and bacterial
superinfection most commonly with staph and strep.
In
immunocompromised individuals, visceral complications can occur, including
disseminated disease, which carries a mortality rate of up to 40 percent. Although the rash is the most characteristic
feature of acute herpes zoster, the most troubling symptom is pain. A majority of patients with herpes zoster first
experience prodromal pain of varying duration and the symptoms can also include
tingling, itching or burning.
As
shown here, the pain during both the acute herpes zoster episode and the
postherpetic phase can be quite severe.
Patients frequently compare it to the pain associated with child-birth
or passing a kidney stone. Early in its
course, herpes zoster can be mistaken for a number of other clinical diseases
that are common in older adults, including myocardial infarction,
cholecystitis, kidney stone, migraine or other CNS condition or severe
musculoskeletal pain.
Almost
half of all patients with herpes zoster experience pain on a daily basis during
the episode and a similar percentage described that pain as horrible or
excruciating.
Postherpetic
neuralgia is residual pain that is present after resolution of the acute
cutaneous eruption of herpes zoster. The
pain of PHN can be constant or intermittent, dull and achy, burning, sharp and
stabbing or shock-like. And most
patients with PHN describe more than one pattern of pain. A particularly common and distressing
symptom, which affects a majority of PHN patients, is allodynia.
The
exaggerated pain experienced in response to otherwise benign stimulus like the
breeze, a bedsheet or just the touch of clothing, often leads to sleep
disturbance, social isolation and depression.
Overall 10 to 20 percent of herpes zoster patients develop PHN, but the
incidence increases dramatically with age.
The impact of PHN can be profound leading to physical, psychological,
social and functional deficits as well as increased use of health care
resources.
Particularly
in older adults, PHN can last for months or even years. It is estimated that the prevalence of PHN in
the United States is as high as 500,000 or more, which is nearly as high as the
prevalence of diabetic neuropathy as a cause of neuropathic pain. As mentioned by Dr. Gutsch, the Pivotal
Efficacy Study for ZOSTAVAX implied a specific and rigorous definition of PHN.
This
slide from the era before the availability of antivirals looks at postherpetic
pain by age and makes several interesting points. The findings are not terribly different today
for older adults with herpes zoster.
First, note that postherpetic pain of at least a month's duration is
rather common, even in middle-aged adults, but that it is very common in the
oldest patients. Second, prolonged pain
of a year or more becomes more common among the oldest individuals.
Antiviral
medications have been shown to reduce the severity of acute herpes zoster and
in some patients the medications can shorten the duration of the acute episode
by a few days. However, the drugs need
to be started within the first 72 hours of onset to have maximum effect. Also, antivirals have only a limited effect
on the incidence or the severity of PHN once an episode of herpes zoster has
begun.
Corticosteroids
have often been used in acute herpes zoster, either alone or in conjunction
with antivirals, and the corticosteroids may ameliorate the acute episode, but
they have not been shown to affect either the incidence or the severity of
PHN. Once PHN develops, finding
effective treatment can be challenging, in part because of the wide variation
in the type and intensity of the individual's symptoms.
Among
the available therapies for PHN are a variety of topical and systemic
analgesics, including opiates, tricyclic antidepressants, drugs with
anticonvulsant properties and a number of invasive procedures. In general, these interventions have been
shown to have limited benefit for patients with PHN and some patients are
completely refractory to multiple interventions.
In
addition, these agents often have narrow therapeutic indices. They are often associated with limiting side
effects, particularly in elderly patients, that make their continued use
problematic. The published literature
shows that the risk of herpes zoster and PHN goes up substantially after age 50
and there are, approximately, 87 million people in the United States in this
age group, and this is a number that will only rise with time.
As
just pointed out, the handful of currently available therapies have only
moderate benefits and sometimes significant limitations. No intervention can reliably prevent shingles
or PHN. Because herpes zoster is more
frequent and more severe as age increases and because VZV-specific immunity is
known to decline with age, then if VZV-specific immunity could be boosted with
vaccination, herpes zoster could be prevented or ameliorated.
For
these reasons, ZOSTAVAX has been developed and is expected to have a dramatic
public health impact in the United States.
I would like to turn now to the ZOSTAVAX Clinical Development
Program. The hypothesis that vaccination
could prevent herpes zoster, ameliorate its severity and potentially prevent
PHN comes from two proof of concept studies that were conducted by Ann Arvin
and her colleagues at Stanford University using a heat inactivated formulation
of the Oka/Merck VZV vaccine to vaccinate immunocompromised patients in a multi-dose
regimen.
The
first study published in 1997 show that the vaccine had good biological
activity. Although the incidents of
herpes zoster was not reduced among those who were vaccinated, the vaccine did
reduce the incidence of PHN and significantly ameliorated the severity of
herpes zoster. Based on the results of
this study and other pilot studies, the efficacy trial was designed originally
with pain-related primary endpoints and so-focused on the age group 60 and
above in whom zoster-associated pain and PHN are most severe.
In
a follow-up study, the results of which became available when enrollment in the
pivotal study was complete and follow-up was continuing, Arvin's group found
for the first time that vaccination could significantly reduce the incidence of
herpes zoster outright.
The
licensed application for ZOSTAVAX includes a number of studies that are
outlined on this slide. The first two
were dose selection studies that established the safety of the vaccine over a
35-fold range of potencies and also explored immune responses using a number of
potential markers. Efficacy was
evaluated in the pivotal Shingles Prevention Study, which will form the bulk of
the remainder of my talk.
Other
studies in the program included evaluation of a two-dose regimen and a booster
study in individuals who received vaccine years earlier. Additional safety evaluations included
vaccination of a small number of VZV-seronegative adults and a study that
compared the vaccine at maximum potency with a potency similar to that studied
in other clinical trials. In all, about
21,000 subjects received one or more doses of ZOSTAVAX and nearly as many
placebo recipients were enrolled in well-controlled clinical trials.
I
would like to spend a moment discussing the potency range that was studied in
the program, and in particular, the prospect of assessment that led to the
potencies that were evaluated in the Shingles Prevention Study.
Across
the program, vaccine was administered across, approximately, a 100-fold range
of potencies. In addition to
demonstrating an adequate safety profile, the early studies suggested that
potencies of, approximately, 17,000 plaque-forming units or higher resulted in
a boost in VZV-specific immunity and thus formed the basis for selecting a
target minimum potency of 19,000 plaque-forming units for the efficacy trial.
ZOSTAVAX
has been studied in a large number of older adults reflecting the target
population for the vaccine. The vaccine
has been administered to individuals as young as 30 and as old as 99 with a
wide array of underlying medical conditions.
About 58 percent of the subjects enrolled were male. Over 95 percent of the study population was
caucasian, but the database also includes over 400 African Americans, about 300
Hispanic subjects and a number of subjects from other racial and ethnic
minorities. Except for some age related
findings that we presented in subsequent slides, no differences in the
efficacy, immunogenicity or safety of the vaccine were seen across demographic
groups.
I
would now like to turn to an in-depth description of the Shingles Prevention
Study. The Shingles Prevention Study,
the results of which were published in the New England Journal of Medicine
earlier this year was a double-blind placebo- controlled multicenter trial
conducted by the Department of Veteran Affairs Cooperative Studies Program in
collaboration with the National Institute of Allergy infectious diseases of NIH
and Merck.
The
study enrolled 38,546 individuals 60 years of age and older. Enrollment was stratified by age to ensure
that at least one-third of the subjects enrolled would fall in the 70 plus age
group. Nearly 90 percent of the enrolled
subjects had one or more underlying medical conditions, but those with known
immunocompromised were excluded. Nearly
half of the patients or subjects noted some limitations in their daily function
from their medical illnesses with about 10 percent moderately or severely
limited.
Enrolled
subjects were randomized 1:1 to receive ZOSTAVAX or a placebo injection that
was made up of the vaccine's stabilizer and uninfected cells. Most of the doses in the study were
administered near the proposed expiry potency and after enrollment, follow-up
to identify suspected cases of herpes zoster, monitor safety and ensure subject
retention was undertaken through use of monthly telephone contacts and a final
closeout interview.
As
shown on the slide, although a majority of the subjects enrolled in the study
were at VA medical centers, the overall enrollment was reasonably well-balanced
by gender. The mean age in both
vaccination groups was 69.4 years with 46 percent of the subjects at least 70
years of age and about 7 percent 80 years of age and older. And, as noted previously, the study
population was largely caucasian.
The
next two slides show the most common underlying medical conditions that were
reported by subjects in the Adverse Event Monitoring Substudy, the Shingles
Prevention Study. Of note, in a study
this size, even a 1 percent incidence rate reflects enrollment of a fairly
substantial number of patients with a given illness and these slides provide
one measure of the heterogeneity of the population enrolled, this slide showing
those conditions with an incidence rate of 5 percent or more and the following
slide with the conditions that were seen in at least 1 percent of the subjects.
Embedded
within the overall Shingles Prevention Study were a number of substudies. Among these were the Adverse Event Monitoring
Substudy, a Cell-Mediated Immunity or CMI Substudy and a Persistence of
Efficacy Substudy. The Adverse Event
Monitoring Substudy, which was conducted at all 22 study sites, enrolled over
6,600 subjects who underwent a detailed assessment of local and systemic safety
following vaccination.
The
CMI Substudy, which was conducted at only the Denver and San Diego sites,
enrolled almost 1,400 individuals who had blood specimens obtained at baseline,
at six weeks postvaccination and at subsequent time points.
The
Persistence Substudy, which is still ongoing at 12 of the original 22 study
sites, is following, approximately, 7,500 subjects who had been randomized to
the vaccine group. The substudy is
expected to provide information on the performance of the vaccine through,
approximately, 10 years postvaccination and the findings of this substudy will
be reported at a later date.
This
is a pictorial representation of the study and substudy enrollment. Randomization was quite successful with
nearly equal numbers randomized to vaccine and placebo in each of the age
cohorts and, importantly, the study enrolled nearly as many subjects in the 70
plus age category as in the 60 to 69 age category.
The
average duration of follow-up in the study was 3.1 years with a range of up to
4.9 years. Remarkably, only 0.6 percent
of the subjects in each vaccination group withdrew from the study or were lost
to follow-up. This incredibly high
degree of subject retention is a tribute to the effectiveness of the
protocol-specified surveillance and the tremendous tenacity of the
investigators and other study personnel at the 22 sites.
Over
95 percent of the subjects in each vaccination group remained in follow-up and
conducted a closeout interview at the end of the study after accrual of all
suspected herpes zoster cases was completed.
Shown
here is an overview of the 42 day safety follow-up that was undertaken for all
subjects enrolled in the study. More
than 70 percent of the subjects either completed a vaccination report card if
they were in the Adverse Event Monitoring Substudy or contacted the automated
telephone response system, which was available to them for safety follow-up
through day 51 postvaccination.
A
variety of other types of subject contacts with the study sites were
undertaken, including phone calls directly to and from sites, most of them
shortly after day 42. In all, about 97
percent of the subjects provided safety information following vaccination,
including 93 percent establishing contact by day 60 postvaccination.
The
active surveillance for suspected herpes zoster cases cast a very wide
net. Through monthly contact with the
automated telephone response system and/or the study sites, subjects with
findings at all suggestive of herpes zoster were asked to report to the study site
within 24 hours and if the investigator could not confirm an alternative
diagnosis, the subject was entered into six months of protocol-specified
follow-up.
The
study sites performed an initial clinical evaluation and were reminded to use a
low threshold for calling a rash illness a suspected case of herpes
zoster. Lesion and blood samples were
taken for laboratory analysis. The
digital photographs were obtained. A
number of shingles-specific questionnaires were administered in order to define
the impact of the illness on the subject, and treatment with famciclovir and
analgesics was initiated.
And
it's important to note that all of the enrolled subjects with suspected herpes
zoster were urged to seek medical care immediately. These highly motivated subjects,
well-educated about herpes zoster, received state of the art care by experts in
the field with aggressive pain management and frequent, attentive follow-up by
study personnel.
Thus,
the vaccine's efficacy was not evaluated in the setting of a placebo group that
received no treatment, but rather one that received optimal care for their
episodes of herpes zoster and PHN. The
study had three key efficacy endpoints, the incidence of herpes zoster, the incidence
of PHN and the herpes zoster burden of illness or BOI. Subsequent slides will describe each of these
endpoints further.
Pain
throughout the period of follow-up was scored on a 0-to-10 scale using a
validated instrument. The primary
efficacy analyses were based on a modified intention-to-treat approach that
excluded only those patients, subjects, who dropped out of the study or
developed a case of herpes zoster within the first 30 days postvaccination.
This
modified approach was employed to ensure that the primary efficacy analyses did
not include those vaccine-associated rashes, a primary safety concern in the
early days postvaccination, nor those cases of herpes zoster that may have
already been in the prodromal phase at the time of vaccination and before the
immune response could be elicited.
Although
I will be presenting the MITT analyses this morning, the analyses were also
performed using a full intention-to-treat approach, as were a variety of
sensitivity analyses with virtually identical results.
As
mentioned earlier in the presentation, the state of scientific knowledge when
the Shingles Prevention Study began indicated that vaccination could prevent,
might prevent PHN and lessen zoster-associated pain, but there was no evidence
that vaccination could prevent herpes zoster altogether. Thus, the study was designed with two
co-primary endpoints related to this important issue of pain, the herpes zoster
pain burden of illness and the incidence of PHN.
Incidence
of herpes zoster was considered a tertiary endpoint. Because of the age-associated increase in the
incidence of PHN, the study was designed to enroll subjects beginning at age
60. Following publication of the second
Ann Arvin Proof of Concept Study and prior to study unblinding, Merck and CBER
agreed to the elevation of herpes zoster incidence to a key secondary endpoint
with a prospectively designed and defined criterion for success.
Turning
now to the endpoint definitions.
Suspected herpes zoster was defined as any subject with a suggestive
cutaneous eruption. These subjects were
evaluated by the study physicians and underwent the six months of
protocol-specified follow-up that I just mentioned to monitor the presence and
the amount of pain and discomfort, development of PHN and the development of
any other possible complications.
Although
the study cast a very wide net to accrue the suspected cases of herpes zoster,
in the end the protocol utilized very strict definitions of herpes zoster and
PHN.
All
suspected herpes zoster cases were clinically adjudicated by a Clinical
Evaluation Committee made up of five independent, that is non-Merck, members of
the study's Executive Committee. The
Clinical Evaluation Committee adjudicated the cases in a blinded fashion
according to a detailed Standard Operating Procedure with all laboratory data
redacted from the clinical summaries.
Final
confirmation of the herpes zoster cases was determined by a hierarchical
algorithm that considered the results of PCR of skin lesions, viral culture and
the decision of the Clinical Evaluation Committee in that order and, in the
end, a large majority had final determinations based on PCR results.
For
the purposes of the primary analysis, PHN was defined as zoster-associated pain
with a score of 3 or higher on a 0-to-10 scale that was present for at least 90
days following herpes zoster rash onset.
During earlier validation of the pain questionnaire, it was found that a
pain score of 3 or higher was correlated with functional limitation on activities
of daily living.
The
co-primary endpoint, the herpes zoster burden of illness or BOI, was a
composite endpoint that was designed to capture the entire burden of pain due
to herpes zoster, a population measure that reflected the incidence, the
severity and the duration of zoster-associated pain and discomfort over six
months following onset.
This
slide includes a graphic that shows a curve representing the pain scores over
time for a hypothetical subject who developed herpes zoster. With time noted on the X axis and the 0-to-10
scale on the Y axis, an individual severity-by-duration score is thus generated
and the BOI represents the scores of all subjects in a particular group.
For
the BOI and the other efficacy endpoints, the primary analysis was performed on
the entire MITT population. So for each
subject who developed an episode of herpes zoster, a severity-by- duration
score was calculated and an area under the curve constructed.
Those
subjects who did not develop herpes zoster during the study were included in
the analysis. They were assumed,
however, to have had no zoster-associated pain and, thus, were given a
severity-by- duration score of zero.
Incidence
and severity-by-duration are both important to describing the overall burden of
herpes zoster on patients and the outcome measure needed to reflect both of
these components. And to help the
Committee get a better grasp of the concept of BOI, which is a bit abstract,
the following three slides give hypothetical examples of the BOI in action and
I would like to thank Dr. Oxman for providing these slides to me.
In
the first example, the putative vaccine reduces the incidence of herpes zoster,
but the severity of those cases that do occur in the vaccine group are no lower
than the severity in the placebo group, and the reduction in the BOI for the
vaccine group is reflected at the bottom of the slide to show the impact on
incidence but not severity.
Conversely,
here we show the vaccine reducing the severity of the individual herpes zoster
episodes, but no impact at all on the incidence of the disease. And the reduction in BOI once again shows
benefit from the vaccine. In this third
example, the vaccine reduces both incidence and severity-by- duration. And as you will soon see, this third example
most closely reflects the outcome of the Shingles Prevention Study.
Shown
here is a flow diagram of the 1,308 suspected herpes zoster cases that were
followed during the course of the study.
Of these, 481 were in the ZOSTAVAX group and 827 in the placebo group. Of note, across the two vaccination groups,
similar numbers of subjects were determined not to have herpes zoster, 156 in
the vaccine group, 161 in the placebo group, about 0.8 percent of the total
population in each group, a finding that reflects the comprehensive and unbiased
nature of case accrual.
Of
the 322 and 662 herpes zoster cases respectively in the full intention-to-treat
analysis population, nearly all were included in the primary modified
intention-to-treat population and of these about 93 percent in each vaccination
group were diagnosed by PCR, about 5 percent in each group by the Clinical
Evaluation Committee and the remainder by viral culture.
This
figure provides an overview of the key efficacy results from the study for the
three main endpoints, herpes zoster incidence, PHN incidence and the herpes
zoster burden of illness. The vertical
line at 25 percent efficacy reflects the pre-specified minimum criterion for
success that had been established for each of these endpoints in discussions
between Merck and the FDA.
The
blue bars reflect the vaccine efficacy that was observed in the study along
with the 95 percent confidence intervals for each endpoint. The slide shows that for each of three
endpoints, the efficacies exceeded substantially the minimum criterion
established for the study's success.
The
two key messages from these results are, one, that the vaccine was able to
significantly reduce the incidence of herpes zoster among the vaccine
recipients and, two, there was a significant impact on the severity of the
herpes zoster episodes. And I will go on
to discuss each of these endpoints in turn.
First,
for herpes zoster incidence, this slide shows a Kaplan-Meier plot for the
cumulative incidence of herpes zoster over time by vaccination group. The X axis indicates time of follow-up and on
the Y axis, the proportion of subjects developing herpes zoster. 315 herpes zoster cases occurred in the
ZOSTAVAX group compared with 642 cases in the placebo group.
The
curve demonstrates a vaccine effect soon after vaccination. The two curves continue to diverge throughout
the entire follow-up period. But note
that follow-up beyond four years is rather limited because only a small
fraction of the overall study population was followed for four years or longer.
One
can see here that the most common complications of acute herpes zoster occurred
at a lower rate among ZOSTAVAX recipients than among placebo recipients. The neurologic complications, as shown on
this slide, exclude the acute neuritic pain.
Complications
of sacral dermatome involvement include such findings as urinary retention or
incontinence, constipation or rectal incontinence and across these categories,
the vaccine reduced the frequency of complications by, approximately, 65 to 75
percent and the reduction in these complications reflects the vaccine's effect
on severe cases of herpes zoster.
Shown
here is another Kaplan-Meier plot for PHN incidence using the protocol
definition of pain greater than or equal to 3 present 90 days or longer after
herpes onset. There were 27 cases of PHN
in the vaccine group and 80 in the placebo group. Supportive analyses using alternative time
points to define PHN, 30, 60, 120, 182 days, showed generally similar results.
As
was the case with the herpes zoster endpoint, the vaccine effect was
demonstrated early and then throughout follow-up. And note again the relatively small
proportion of subjects with follow-up extending out to four years or longer.
I
would like to turn now to the herpes zoster pain burden of illness. As noted earlier, the BOI includes both the
incidence of herpes zoster and the severity-by-duration of zoster-associated
pain.
The
overall efficacy for this endpoint was 61 percent with the 95 percent
confidence intervals as shown. The BOI
efficacy that was demonstrated in the study reflects a combined effect of both
of these components. The 51 percent
reduction in the incidence of herpes zoster was already described. With respect to severity-by-duration scores
among those subjects who developed herpes zoster there was a statistically
significant 22 percent reduction in the scores among those in the vaccine
group.
Now,
to put a human face on this reduction, because again these scores are a bit
abstract, the reduction from a mean of, approximately, 180 to 140 creates a 40
point difference, which reflects nearly a two week reduction in the duration of
clinically significant pain at a level of 3 or a four day reduction in pain at
the maximum level of 10, the worst imaginable pain. This indicates a huge impact in preventing
suffering over and above the vaccine's impact and reducing the incidence of
herpes zoster.
This
slide gives another perspective on the impact of ZOSTAVAX beyond its ability to
prevent cases of herpes zoster. The slide
shows a histogram with the subjects who had the highest severity-by- duration
scores. The increasing scores are shown
on the X axis, the number of the cases on the Y axis. And for the purposes of illustration in this
exploratory analysis, the scores of 600 or higher are depicted.
To
obtain a score of 600 or higher, the subject would have to have the maximum
pain score of 10 for at least two months or a score of 3 to 4, that is
clinically significant pain, every day throughout the entire six month follow-up
period. So we're talking about very
severe cases of PHN.
The
slide overall shows that there were only 22 vaccine recipients of 600 or higher
compared with 40 recipients and that's a 73 percent reduction. And if one looks at the slide beginning from
the right and working toward the left, you can see the very dramatic effect of
the vaccine at the farthest end of the pain spectrum.
Among
those vaccine recipients who went on to develop PHN, the vaccine effect was
equally clear. In an exploratory
analysis, including those subjects who developed PHN that was in the license
application, it was found that through the end of the follow-up, there was a 57
percent reduction in the severity-by- duration scores among those who received
ZOSTAVAX compared with those who received placebo. This statistically significant benefit again
shows evidence of the substantial role that the vaccine can play even in
subjects who ultimately go on to develop PHN.
As
noted earlier, subject enrollment in the study was stratified by age and this
slide displays the vaccine effect for the three main study endpoints stratified
by age. For the herpes zoster endpoint,
there was 64 percent efficacy in the younger cohort and 38 percent efficacy in
the older cohort. Despite this difference
across the two age strata, vaccine efficacy for herpes zoster incidence
remained substantial even for the older age group.
Importantly,
since PHN frequency and pain severity increase with age, the vaccine efficacy
for PHN was comparable across the two age strata as shown. In fact, among subjects with herpes zoster
the vaccine reduced the risk of developing PHN by a statistically significant
38.5 percent, including 47 percent reduced incidence in the 70 and older age
group.
Because
the vaccine retains substantial efficacy for those subjects with more severe
pain associated with a zoster episode, the overall effect on burden of illness
was relatively well-preserved among the older age group. Although the point estimate for the burden of
illness was a bit higher in the younger group, reflecting the effect on the
incidence, there is wide overlap in the confidence intervals between the two
age strata because of the benefits on severity-by-duration in the older group.
ZOSTAVAX
also had an effect on the incidence of zoster-associated interference with
activities of daily living. These
analyses were based on the mean of the responses to seven ADL-related questions
on a validated questionnaire using a 0-to-10 scale. The vaccine reduced the overall interference
with activities of daily living by 66 percent in the overall population.
This
combined score for the overall population is sensitive to the incidence,
severity and duration of interference, and so it was analogous in many respects
to the burden of illness for the overall population.
The
vaccine also led to a 55 percent reduction in moderate-to-severe interference
with daily living. Now, this reduction
was of course influenced by the reduction in the incidence of herpes zoster. So in a pre-specified analysis to determine
the vaccine effect on ADL interference above and beyond the vaccine's effect on
the reduction of herpes zoster incidence, a reduction of 8 percent was seen,
which was not statistically significant.
The
duration of the vaccine efficacy was alluded to briefly in the prior
Kaplan-Meier curves for efficacy, and this slide presents the efficacy for
herpes zoster and PHN over 48 months of follow-up. After an initial decline in efficacy during
the first year, the point estimates for efficacy remain relatively stable
through 48 months postvaccination.
Now,
the confidence intervals do get wider over time reflecting fewer subjects with
long follow-up and few with clinical endpoints.
So the interpretation at the later time points becomes limited. However, the follow-up for the longer term
persistence of efficacy is currently being evaluated, as previously noted, at
12 of the 22 sites and so additional information will be accruing over time.
Thus,
the Shingles Prevention Study has shown conclusively that vaccination can
reduce the incidence of herpes zoster with better efficacy among the younger
age cohort, reduce the incidence of PHN and reduce the burden of illness
associated with herpes zoster pain.
For
the pain-related endpoints, the vaccine efficacy was very well-maintained in
the older cohort compared with the younger cohort. The vaccine also reduced the duration of pain
and the risk of substantial interference with activities of daily living and,
thus far, the efficacy has extended out to four years.
I
would like to turn now to the immunogenicity results. Declining VZV-specific immunity most
frequently associated with age is thought to be a precursor for the development
of herpes zoster and, as such, the immune response to vaccination is thought to
be reflected in efficacy.
The
ZOSTAVAX clinical studies evaluated immune responses using two key validated
assays of VZV-specific interferon-gamma enzyme-linked immunospot assay and a
glycoprotein enzyme-linked immunosorbent assay that has been used to measure
antibody responses in the varicella vaccine programs for many years. The VZV-specific antibody measured through
the gpELISA is known to be T-cell dependent and is, therefore, felt to reflect
the cellular immune response to vaccination.
In
the pivotal efficacy study, the primary endpoints for immunogenicity by these
assays and also for the responder cell frequency assay were assessed at six
weeks postvaccination. And on the next
few slides, these endpoints, the endpoints that will be shown, are the ratio of
the geometric mean titers or counts in the vaccine and placebo groups, as well
as the geometric mean fold increases from baseline.
At
six weeks postvaccination in the Shingles Prevention Study, immune responses were
seen for both of the key validated assays.
Of note, of course, these are previously VZV experienced individuals and
so even at baseline, rather high levels of preexisting VZV immunity were seen. And, as you can see, relative to the day zero
levels, the VZV antibody measured by gpELISA increased 1.7-fold and the ELISPOT
counts increased 2.0-fold, both of which were statistically significant
increases.
In
a regression model that looked at each of these immune markers as possible
correlates for prevention of herpes zoster, both the gpELISA and the VZV
interferon-gamma ELISPOT assay correlated with protection. However, the gpELISA correlated best with
efficacy, as shown in the slide, with each log unit increase associated with a
larger risk reduction.
Note
importantly that this is a correlation for values across the population. No specific value in either assay can
reliably predict whether an individual subject is protected from herpes zoster,
and so the study was unfortunately unable to define a true surrogate.
Looking
at the different age cohorts, one sees immune responses that are generally
similar with slightly higher geometric mean fold rises from baseline and
postvaccination geometric mean titers for the younger group. Immunogenicity in adults has been evaluated
in the VARIVAX and ZOSTAVAX Program, including both seronegative and
seropositive individuals, and the vaccine has been shown to be immunogenic in
adults.
To
lend further support to the utility of the vaccine, this slide provides a preliminary
summary from a subset of subjects who were enrolled in a recently completed
study that was not included in the original license application. And with all studies that have been initiated
since 2003, this protocol, Protocol 010, enrolled subjects beginning at age 50.
The
slide shows preliminary results for 113 subjects, 45 of whom are 50 to 59 years
of age, 68 of whom are 60 to 69 years of age or, I'm sorry, 60 years of age or
older. Note that in this study the
postvaccination blood sample was obtained at four weeks postvaccination. Not surprisingly, the immune responses in the
50 to 59 group were as good as those in the 60 and older group.
So
in summary, in the face of often high levels of preexisting immunity, ZOSTAVAX
elicits an immune response by both gpELISA and ELISPOT. The VZV antibody response measured by
gpELISA, a T-dependent phenomenon that reflects cellular immunity, correlates
best among the assays evaluated with protection against herpes zoster.
I
would like to move on now to the safety profile of the vaccine. It's important to remember that ZOSTAVAX is a
high potency Oka/Merck VZV vaccine that builds on an extensive VARIVAX safety
database. More than 56 million doses of
VARIVAX have been distributed mostly in VZV naive individuals since the initial
licensure of the product in 1995.
VARIVAX has demonstrated an excellent safety profile in the ensuing ten
years.
Within
the ZOSTAVAX Program, the clinical evaluation includes over 20,000 subjects who
receive vaccine and importantly over 19,000 placebo controls. So this assessment of safety was performed in
a rigorous comparative setting that permitted a reliable enumeration of both
common and uncommon adverse experiences.
As shown here, the studies that were conducted had 97.5 power to detect
an event with a rate of 1.8 per 10,000 and 80 percent power to detect an event
with a rate of 0.8 per 10,000. The
studies have demonstrated that ZOSTAVAX was generally well-tolerated in these
older adults.
With
regard to the safety evaluation in the Shingles Prevention Study, the following
safety evaluation was undertaken for all enrolled subjects. Adverse experiences occurring day 0 to 42
were to be reported and assessed.
Vaccine-related serious adverse experiences occurring at any time during
the study were also to be reported, as were deaths at any time following
vaccination.
As
previously noted, all subjects enrolled in the study were to have contact
shortly after day 42 postvaccination to ensure complete ascertainment of
serious adverse experiences in the full cohort and 93 percent of them did by
day 60 and 97 percent overall. The
Adverse Event Monitoring Substudy again conducted at all of the sites and
including over 6,600 subjects added two additional measures over and above the safety
evaluation that was done for the overall population in the Routine Safety
Cohort.
In
addition to the standard safety evaluation that was on the prior slide, the
subjects completed a diary, a vaccination report card through day 42
postvaccination. And in addition for
this cohort, hospitalizations for any cause were to be reported through the end
of the study. For the overall study
population, the incidence of serious adverse experiences in each vaccination
group was identical with a rate of under 1.4 percent.
In
the Adverse Event Monitoring Substudy shown in the hash marks here, more
serious adverse experiences were reported in the ZOSTAVAX group than in the
placebo group, which was offset by a corresponding increase in the serious
adverse experiences reported among placebo recipients in the Routine Safety
Cohort.
Now,
this table reflects the distribution of serious adverse experiences in the two
safety cohorts. A review of the serious
adverse experiences in the substudy found that no body system, no clinical
syndrome, no diagnosis was responsible for this difference and there was no
temporal clustering of these serious adverse experiences relative to
vaccination.
Given
the follow-up for and distribution of these serious adverse experiences in the
overall population, the conclusion of the detailed review was that the
imbalance and serious adverse experiences in the substudy was chance
event. In further support of the safety
profile of the vaccine, in the entire cohort of nearly 40,000 vaccinated
subjects, there was a total of only five possibly vaccine-related serious
adverse experiences reported. Two in the
vaccine group and three in the placebo group.
The number of deaths during both the first 42 days postvaccination as
well as during the entire study were the same in the two vaccination groups and
there were no vaccine-related discontinuations at all in the study.
In
the Adverse Event Monitoring Substudy, the data recorded in the vaccination
report cards demonstrated, not unexpectedly, that injection-site adverse
experiences were more frequent in the ZOSTAVAX group than in the placebo
group. The recording of intensity
demonstrated that most of these, approximately, 85 percent were scored as mild
by the subjects.
In
this double-blind experience, the overall proportion of subjects with systemic
clinical adverse experiences was the same in both groups, just under a
quarter. An increase in vaccine-related
systemic adverse experiences was observed in the vaccine group, but the rates
in both the vaccine and placebo groups were low, about 6 percent in the
ZOSTAVAX group and about 5 percent in the placebo group.
Among
the vaccine-related adverse experiences only headache was seen more frequently
in the vaccine group than in the placebo group. Hospitalization rates at any time during the
study for any reason were comparable at 107 per 1,000 person- years.
I
would like to turn now to Protocol 009, the safety study that was conducted at
the estimated maximum vaccine potency.
This double-blind controlled multicenter trial, which enrolled subjects
50 years of age and older, evaluated two lots of the vaccine that were
administered at 58,000 and 207,000 plaque-forming units per dose. About 700 subjects were enrolled with nearly
200 of them 50 to 59 years of age. The
vaccine was generally well-tolerated at both potencies as shown in the next
slide.
Here
we have the overall safety findings of the study by potency group and age
cohort. The proportion of subjects with
local adverse experiences was higher at the higher potency and the younger age
cohort reported these local reactions more often than the older cohort, but
these events were viewed almost exclusively as mild or moderate in intensity
and of relatively brief duration of just a few days.
Importantly, the frequency of systemic
adverse experiences was similar in the higher and lower potency groups and
overall the vaccine was generally well-tolerated at both of the potencies
administered. A relatively small number
of VZV- seronegative adults has been identified and enrolled through our
clinical trials. No seronegatives at all
were seen among the 1,400 subjects in the CMI Substudy of the Shingles
Prevention Study.
A
different study, Protocol 003, was conducted in tropical countries specifically
to enhance the potential for identifying VZV-seronegative adults, because
published literature suggests that VZV-seroprevalence is lower and
seropositivity obtained at a later age than in temperate climates. Despite screening over 1,100 individuals, few
VZV- seronegative adults were found and enrolled.
In
Protocol 049, from the VARIVAX Program, varicella history negative adolescents
and adults were enrolled. Among these,
17 VZV-seronegative subjects 30 years of age and older were identified. In this small subset from the two studies, it
appears that local and systemic adverse experiences as well as elevated
temperatures occurred frequencies that are similar to those seen in VZV
experienced individuals.
Importantly
though, despite concerted efforts to identify such individuals, VZV-
seronegativity is very rare among persons over the age of 30. Based on these findings, the criteria for
enrollment in the ZOSTAVAX studies which did not screen for VZV-serostatus,
there is no need to screen or otherwise assess pre-vaccination immune status in
individuals who are otherwise candidates for ZOSTAVAX.
An
adverse experience of particular interest in the ZOSTAVAX Program, as it has
been in all of the varicella vaccine programs, was the development of rash within
42 days after vaccination. In that time
frame, within ZOSTAVAX clinical trials, approximately, 0.3 percent of subjects
reported a VZV- like rash across the database.
A rate that is roughly 10-fold lower than that seen following
administration of VARIVAX.
Those
who developed VZV-like rash were requested to have sample lesions obtained for
PCR analysis. Across the entire clinical
database, two subjects with VZV-like rash were found to have the Oka vaccine
strain in their lesions. Among the
subjects in the Shingles Prevention Study, the Oka/Merck strain was not
identified in any suspected herpes zoster case or in any postvaccination rash
at any time point early or late in the postvaccination period.
So
in summary, compared with placebo those who received ZOSTAVAX had a higher
incidence of injection-site reactions, but a similar overall incidence of
systemic clinical adverse experiences.
The incidence of vaccine-related and systemic experiences was slightly higher
among ZOSTAVAX recipients than among placebo recipients. Following a dose of ZOSTAVAX
vaccine-associated rashes were uncommon and so we conclude that overall the
vaccine had a very acceptable safety profile in those 50 years of age and
older.
So
to summarize, ZOSTAVAX is proposed for vaccination of individuals beginning at
50 years of age. Although the pivotal
efficacy study enrolled subjects beginning at 60 years of age, the
epidemiological data and the limitations of currently available therapies argue
that there is a strong medical need to prevent herpes zoster and its
complications starting at age 50.
Over
100,000 additional cases of herpes zoster and an additional 8,000 to 15,000
additional cases of PHN could be potentially prevented each year in a group of
individuals who suffer as much acute zoster-associated pain as those 60 to 69
years of age. With the additional
societal burden of being an age group in which a majority of the population is
still employed, the data indicates that substantial benefit could accrue from
vaccination beginning at age 50.
Efficacy
for ZOSTAVAX had been demonstrated directly for those 60 years of age and older
with a very high degree of efficacy against herpes zoster, 64 percent, among
those 60 to 69 years of age. Efficacy in
this age group should predict well the efficacy in persons 50 to 59 years of
age. The vaccine has been shown to be
immunogenic with generally comparable responses in the 60 to 69 and 70 plus
cohorts in the Shingles Prevention Study.
Similar
age-related findings were observed in other ZOSTAVAX studies. Most recently in the form of the supportive
data that have recently become available from Protocol 010 for those 50 to 59
years of age. The vaccine has been
administered in clinical studies to individuals 50 years of age and older and
has been shown to be well-tolerated with only a moderate increase in transient
injection-site reactions of mild to moderate intensity.
To
conclude, in a very large clinical database ZOSTAVAX has been shown to reduce
herpes zoster by one-half, reduce PHN by two-thirds and to reduce herpes zoster
pain burden of illness by over 60 percent in older adults. The vaccine elicits a VZV-specific immune
response, demonstrates efficacy that persists for four years postvaccination
and has an excellent safety profile.
At
this point, I would like to turn the podium back to Dr. Gutsch for a few
concluding remarks.
DR.
GUTSCH: In addition to the large and
comprehensive database that went into the application for licensure, there are
ongoing and future plans for further study of ZOSTAVAX that will shed light
onto the vaccine performance. To answer
the question what is the durability of ZOSTAVAX efficacy? There is continuation of the Shingles
Prevention Study at 12 of the 22 original sites involving 7,500 subjects.
In
addition, up to 18,000 of the placebo recipients in the Shingles Prevention
Study and Protocol 007 are in the process of receiving vaccination with
ZOSTAVAX and this will then provide further safety follow-up.
A
clinical study is being conducted to assess a new formulation of ZOSTAVAX that
allows refrigerator storage to increase the settings in which the vaccine will
be available. Another study is being
conducted to show that ZOSTAVAX can be administered concomitantly with
inactivated influenza vaccine.
Pharmacovigilance planning is important for a vaccine as it enters the
postmarketing period.
A
pharmacovigilance plan was developed that builds on the extensive VARIVAX
experience with over 56 million doses distributed to the market and ZOSTAVAX
for which a robust database has been provided in a licensed application. Proposed plans include extension of the
postmarketing surveillance activities that are well-established at Merck for
vaccines to monitor adverse events after licensure.
In
addition, the VZV Identification Program determines by a preliminary chain
reaction if wild type or vaccine strain, varicella zoster virus, is present in
clinical specimens, such as vesicle fluid or cerebral spinal fluid from
individuals with adverse experiences.
Finally,
the Pregnancy Registry that was initiated with the VARIVAX Program in 1995 will
also be applied to ZOSTAVAX in the postmarketing period. Collectively, results from our program
indicate that the benefit/risk ratio for ZOSTAVAX is favorable. Herpes zoster and PHN are often debilitating
diseases in need of better management.
ZOSTAVAX would be the first intervention when licensed to prevent herpes
zoster and its complications, including postherpetic neuralgia.
Beyond
the benefit from preventing these two diseases, ZOSTAVAX also reduces the
severe pain associated with herpes zoster and PHN. ZOSTAVAX has been studied in subjects 50
years of age and older and has demonstrated an excellent safety profile with no
clinically important safety risks identified from a very large database of
placebo-controlled clinical trials. So
overall, the benefit/risk ratio is favorable and ZOSTAVAX, when licensed, will
meet an important unmet medical need.
In
closing, the proposed indications for ZOSTAVAX supported by the clinical data
just presented are: ZOSTAVAX is
indicated for prevention of herpes zoster, prevention of PHN, reduction of
acute and chronic zoster-associated pain.
ZOSTAVAX is indicated for immunization of individuals 50 years of age
and older. Thank you very much. We can now entertain your questions.
CHAIRMAN
OVERTURF: Are there questions from the
Committee for the sponsors at this time?
Dr. Wharton?
DR.
WHARTON: I have a couple of questions
about safety monitoring. I'm a little confused
about the group who were in the safety substudy. Did they participate in the 42 day automated
telephone call? From the first slide it
seemed as if they didn't and then later it was stated that the supplemental
safety monitoring was on top of other safety monitoring being done.
DR.
SILBER: The question relates to the type
of safety follow-up for the subjects in the Adverse Event Monitoring
Substudy. And as initially designed, all
subjects were to have the day 42 contact by phone or through other contact with
the sites. And the vaccination report
card was used for that subset of 6,600 individuals. It became apparent through frequent phone
calls to the sites that the subjects found it a bit of an annoyance to have to
go through all of this redundancy having already completed a 42 day diary card,
so that the protocol through an operations memorandum permitted either of those
contacts to be a suitable completion of the 42 day contact.
So
the majority of those subjects who were enrolled in the Safety Monitoring
Substudy had the vaccination report card in lieu of the phone call. But for those who didn't turn in the
vaccination report card or for some who did both, there may have been, and
actually in other respects, more than one form of contact. In the pie chart that was shown any given
subject was only counted once with the vaccination report card and the ATRS
being prioritized.
DR.
WHARTON: Okay. And I want to follow-up to that. For the subjects who didn't have contact with
the investigators within 60 days of vaccination, which I think were about 7
percent on your pie chart, when was information on those subjects attained and
how was it obtained?
DR.
SILBER: Yes, that was variable. First, I should say for the persons who were
involved in the Adverse Event Monitoring Substudy, about 97 percent returned
those vaccination report cards. For the
remaining individuals, the small subset who had follow-up beyond the day 60, it
was highly variable. Many of those were
in contact by day 90, but some went on longer.
I
recall that after this initial follow-up period for safety, the monthly
contacts for efficacy were continuing and so there were reminders to the
subjects on a monthly basis. Despite all
of these efforts and despite the very careful attention to follow-up for
efficacy and safety by the investigators, we still had 3 percent who ultimately
had no follow-up for safety.
CHAIRMAN
OVERTURF: Dr. Hetherington?
DR.
HETHERINGTON: How are the patients in
the Safety Substudy selected and recruited and how do they compare to the
general population in the study?
DR.
SILBER: Yes, thank you. That's a question about the selection of
subjects in the AE Substudy. What
happened was, as you can imagine, this was a very huge endeavor to undertake to
have a study of this size at 22 sites.
And the way that the Adverse Event Monitoring Substudy was conducted was
that basically after the first several months that allowed the sites to sort of
settle in with their procedures and do the routine activities, each of the
sites was then asked to consecutively recruit the next 300 individuals into the
Adverse Event Monitoring Substudy.
And
so there was no cherry picking or preselection that happened. And then at the time when that cohort was
filled, the routine cohort continued.
And so that through the randomization and through the way that the
timing intervals occurred, there were no differences, overall differences
demographically or in other ways between the two cohorts.
DR.
HETHERINGTON: Did the patients have a --
were they able to elect whether to participate or not? Could they decline the long-term or the
Safety Substudy participation? And if
so, what was the rate?
DR.
SILBER: I believe I'm going to have to
turn to Dr. Levin for confirmation. But
my understanding is that subjects could opt out of the Adverse Event Monitoring
Substudy and remain in the routine cohort, but the communications that I have
heard from Dr. Oxman and Dr. Levin and others over the years is that it was a
very small number who did so.
DR.
HETHERINGTON: Could we get that exact
number some time this morning?
DR.
SILBER: We will certainly try.
DR.
HETHERINGTON: And did you ever compare
the demographics and the age distribution in that subgroup versus the general
population?
DR.
SILBER: They were similar.
CHAIRMAN
OVERTURF: Dr. Farley?
MEMBER
FARLEY: I have some questions about what
is known about the more detail of the epidemiology in the 50 to 59 year-old
group that has sort of been added into this expanded request. And do you know whether those who develop
herpes zoster in that decade are more likely to be immunocompromised, more
likely to be HIV with reconstitution syndromes or people on steroids or with
malignancies and therefore might not be in the targeted group, at least
initially for this vaccine?
And
also, do you know anything about the epidemiology of zoster in the last decade
of general use of the varicella vaccine?
Has that had an impact not having natural chicken pox out there as much
by far as previously and in terms of if there is a boosting effect of exposure
as adults?
And
finally, do you have any information about the durability of the immune
response that you showed us the small numbers of 50 to 59 year-olds, because,
of course, the issue will be will they not have the benefit when they are at
maximum risk later?
DR.
SILBER: Okay. So there were at least three questions there,
so I'll try to take each of them. I'll
start with the VARIVAX question and influence of varicella vaccination on the
incidence of herpes zoster. In fact, the
few population-based databases that have been available long-term suggested the
incidence of herpes zoster has been increasing for at least the last 50 years. Both in terms of absolute numbers and in
terms of age adjustment.
The
data that are available thus far, realize are only 10 years out from onset of
varicella vaccination and only about seven years out from widespread use of the
vaccine. And so it may be too early to
see anything, but the fact is that the studies that have been completed to
date, some of them at CDC, at Group Health Cooperative out in Seattle have
indicated that thus far there does not appear to be any differences in the
incidence of herpes zoster with the use of varicella vaccine.
Now, there are mathematical models that
have predicted that this will happen over time and that with less boosting from
exogenous exposure, assuming that there is not endogenous boosting to make up
for that, that the incidence of herpes zoster may increase. And, in fact, that the age of zoster may
shift to an earlier age. But, at this
point, it remains speculative and the available data do not indicate that this
is happening as yet.
With
respect to the demographics and characteristics of persons 50 to 59 years-old
who develop herpes zoster, the fact is that the population has a higher
percentage of immunocompromised with age.
And so in terms of the overall population, there were fewer
immunocompromised individuals in their 50s than in their 60s, 70s and
later. There are few data looking
specifically at immune status in the 50 to 59s, but such that is available
suggests that the large majority of the cases of herpes zoster among people in
their 50s are in the immune-competent population.
Your
third question had to do with the durability of the immune response and the
durability of protection that would ensue.
And what we have seen with vaccination in terms of the CMI Substudy that
went out to three years and also following an episode of herpes zoster actually,
that there is an early and large increase, but that within six months the
markers of immunity tend to decline and head back toward baseline, as one might
expect even with silent exogenous or endogenous boosting.
And
it appears that following an episode of zoster and following vaccination,
people sort of settle out at a level and this is what one might expect when we
are dealing with a memory response in the face of prior immunity. And so in terms of the actual immunologic
markers, they do head back toward, but still remain above the baseline
values. However, in terms of the vaccine
efficacy, as one looks at year two, year three, year four, there was no decline
seen in the point estimates for efficacy.
So
at least from the clinical protection standpoint, even for those 60 and older,
a decline in durability has not yet been observed. And one would expect that vaccination of an
even younger adult cohort 50 to 59 durability would be at least as good as is seen
with other vaccines.
CHAIRMAN
OVERTURF: Dr. Markovitz?
MEMBER
MARKOVITZ: Yes, I have two
questions. The first one is in terms of
safety in the 50 to 59 year-old group, unless I missed it, the only slide we
saw was with these higher doses. And of
course, there is a lot of reactogenicity, you know, systemic reactions around
40 percent in all age groups. But yet,
it is stated that the vaccine was "well-tolerated." Can we have some elaboration on that? And then I have a second question.
DR.
SILBER: Sure. If we can pull up the safety table?
MEMBER
MARKOVITZ: 74.
DR.
SILBER: Across the ZOSTAVAX Clinical
Development Program, most of the studies were placebo- controlled. And as you might recall from the Adverse
Event Monitoring Substudy in the Shingles Prevention Study, roughly a quarter
of those individuals receiving placebo had one or more systemic adverse
experiences. And so just to sort of put
a frame of reference around it, that's what is seen after placebo injection.
And
across ZOSTAVAX studies, we tend to see systemic adverse experience rates in
this range. And as you see, we can look
at it both ways across the potencies horizontally across the age groups
vertically. There was really not a large
difference across the potencies. In
fact, in the younger age cohort, the rate of reporting of systemic adverse
experiences was actually lower in the higher potency than it was in the lower
potency.
And
in this study the reporting rate was within a couple of percentage points of
those for the 60 plus. And again, other
than a slightly higher incidence of headache in the younger group, there were
no differences seen by body system, by clinical syndrome, by any other
diagnostic criteria and a very small percentage of any of these adverse
experiences were rated as severe in intensity by the subjects.
CHAIRMAN
OVERTURF: Just a point of clarification
before Dr. Markovitz asks the second question.
Both the higher and the lower potency dose in the 50 to 59 year-old age
group are considerably higher than the overall dose that you are asking for
approval. Is that correct or am I
confused on that issue?
DR.
SILBER: I'm sorry, the potencies
administered?
CHAIRMAN
OVERTURF: Yes, the potencies.
DR.
SILBER: Is that what you are
asking? Yes, the question is about the
potencies administered here. The lower
potency within Protocol 009 was 58,000 plaque-forming units and doses of around
50,000 plaque-forming units were the highest potencies administered within the
Shingles Prevention Study, which had 12 different lots, and 50,000 was also the
potency that was administered in several of the other clinical studies.
And
so we selected a lower potency within this study really to help us benchmark to
the other studies, because we didn't have a placebo control here. And prior to Protocol 009, the highest
potency we administered in any prior clinical trial was 67,000 plaque-forming
units, and so the higher potency group here was about a 3-fold higher potency
that had been administered previously.
And we don't expect that very many people would ever receive a potency
this high out in clinical practice.
CHAIRMAN
OVERTURF: In fact, I was wondering --
PARTICIPANT: I don't think that answered the Chair's
question. The Chair asked a very
important question here and I just --
CHAIRMAN
OVERTURF: Yes. To me what you're asking for is approval of
licensure for the 50 to 59 year-old age group, but you're asking for approval
for a dose that is considerably lower than either one of these. Is that correct?
DR.
SILBER: Well, the specification for
this, as for other live virus products, is built around a minimum expiry, a
minimum potency that would be observed at expiry and so the clinical experience
from the time the vaccine is manufactured and released would be at a variety of
potencies higher than that, and so there would be a spectrum of potencies
administered.
And
so much as the Shingles Prevention Study evaluated efficacy at the lowest,
largely at the lowest potency, so we are looking at safety at the highest
potency to provide a buffer, if you will, for what might be seen in terms of
the efficacy experience on the one hand and the safety experience on the other
hand when a vaccine might be administered in practice. Did that answer it not?
CHAIRMAN
OVERTURF: We may come back to this issue,
but let Dr. Markovitz ask.
MEMBER
MARKOVITZ: Yes. Actually, that's what I was trying to get to
also because, essentially, most of the data you showed us for the older people,
meaning 60 and over, were based on I believe a 19,000, was it, plaque-forming
unit dose and here it's much higher.
So
I guess what I'm really asking or suggesting is you have no data that deals
with the actual vaccine going into 50 year-olds in terms of safety, is that
right, or you haven't presented it?
DR.
SILBER: No, this -- I'll take a step
back on this. The Shingles Prevention
Study included 12 lots of vaccine that ranged in potency from roughly 20,000
plaque-forming units up to roughly 60,000 plaque-forming units. The dossier included a number of other
studies, including but not limited to Protocol 009, that also used vaccine at a
range of potencies up to 67,000 plaque-forming units.
Across
that dose range, let's take it separate from Protocol 009 for a moment, across
the dose range seen and actually reflecting what has been seen for many years
with VARIVAX across a wide range of potencies for seronegative individuals is
that other than a potency-related increase in injection- site reactions, no
difference was seen in the safety profile.
So
that is what was seen for all of these other studies and, in fact, the dose
selection studies prior to the Shingles Prevention Study were looking at
whether there was any dose-related effect.
Jump
now to Protocol 009 and, again, to create the highest hurdle, if you will, for
safety because it is at the maximum potency that someone might expect, this is
what was seen. And, again, with systemic
safety consistent with what was seen in other trials with local reactions at a
somewhat higher reporting rate.
MEMBER
MARKOVITZ: But these other protocols
actually dealt with 50 to 59 year-olds before, too?
DR.
SILBER: No. The shingles?
MEMBER
MARKOVITZ: When you talk about that you
tested a wide range of doses of the vaccine, what I'm trying to understand is
what percentage of those people who got vaccine, what's in the range of what is
going to actually go into people in a clinical setting, were in the 50 to 59
year-old range?
DR.
SILBER: Right. The data that were included in the original
dossier included, approximately, 200 to 300 subjects, most of them from
Protocol 009, some of them from Protocol 049 that was alluded to, which was
actually a VARIVAX protocol but included what for VARIVAX is a high potency lot
that was actually used in the Shingles Prevention Study at, approximately,
50,000 plaque-forming units also.
And
so in terms of the database within the dossier, again because enrollment
starting at age 50 only began in the studies in 2003, that is what is in the
dossier. The studies that have been
conducted since, including the Refrigerated Vaccine Bridging Study and the
Influenza Concomitant Use Study, both of which are at or near completion, also
included the vaccination of individuals beginning at age 50 and has gone
through a range of safety doses.
And,
again, younger individuals in general seem to report adverse experiences more
often than the elderly. And so with this
population and with the highest maximum potency, we consider that the data here
provide comfort that vaccine administered at lower potency than that maximum
would be with an acceptable safety profile for the age group.
MEMBER
MARKOVITZ: What will be the actual dose
of the vaccine going into people in a clinical setting if license is granted?
DR.
SILBER: Do you want to answer that
one? I think I will turn to Dr. Gutsch
for a moment to answer that.
DR.
GUTSCH: Just for clarification, this is
a live virus vaccine so there is a shelf life during which the vaccine has a
decaying potency that occurs over time just due to storage conditions. And so there is not one dose that anyone is
going to get at any given time.
What
we want to assure is that at the expiry potency, the potency at the very end,
that it never goes below that so that we have an efficacious vaccine. But we have to put sufficient virus in there
of this live virus to ensure that at the end of this shelf life, there is
sufficient left over. And in order to do
that we need a little bit of a range there and, therefore, we test the lower extreme
for efficacy and the upper extreme for safety.
So
we can't really say that you're going to get one specific dose, but the label
indicates that you will get greater than 19,400 plaque-forming units. Does that clarify things?
MEMBER
MARKOVITZ: Yes, thanks, that does.
CHAIRMAN
OVERTURF: Dr. Karron?
MEMBER
KARRON: So I have three sets of
questions, one related to dose and potency, one related to safety and then
finally to the gpELISA. So, first, I
just wanted to know in terms of understanding about dose, actually really two
sets of questions, one to follow-up on Dr. Markovitz'.
So
in the VA study, were there multiple lots of vaccine used and were they of
different potencies? And in terms of
looking at efficacy, did you stratify by potencies to see if there was any
difference in efficacy according to potency of vaccine?
DR.
SILBER: Shall I answer that one first?
MEMBER
KARRON: Yes, yes.
DR.
SILBER: Okay. The question had to do with the lots that
were used in the Shingles Prevention Study.
In all there were 12 lots that were used, as I mentioned previously, at
release potencies ranging from 20 some odd thousand up to about 60,000 with
doses administered going from about 18,700 up to close to 60,000.
Included
within those 12 lots was a three lot consistency series. What we found, what was found across the lots
and across the potencies, and the trial was not powered based on the efficacy
endpoints to demonstrate formally consistency, but when one looks at the lots
by potency across the 12 lots and, in particular, when one does a comparison
pair-wise within the three consistency lots, in both cases there were no
differences observed with respect to efficacy for any of the three endpoints
and with the potencies.
MEMBER
KARRON: Okay. And then to follow-up on that issue, when the
original studies, the dose ranging studies, were done to choose a dose to go
forward with, had you done that looking over an age range?
Did
you look at the young elderly and the very elderly in terms of making that
decision?
DR.
SILBER: Yes. The early dose selection studies that included
the immunogenicity assessment were done in individuals 60 years of age and
older. There were a couple of earlier
pilot studies that enrolled people beginning at 55, but Protocols 001 and 002,
which were the ones that were alluded to in the Clinical Development Program
overview slide that I gave, included individuals 60 years of age and older.
At
that point, the interferon-gamma ELISPOT assay was not operative. There were a number of cytokine ELISAs, the
responder cell frequency. A number of
candidate markers were used with slightly different patterns in terms of when
immunity developed, but across the assays that were being used at that time it
was in the range of 17,000, 19,000 for two of the potencies that we did
administer that we started to reliably see across the different markers that
there was an immune response.
MEMBER
KARRON: Okay. And I just want to understand better the
rationale for the high dose study in the younger individuals, so somewhere
between 5 and 10 times the dose, the minimum dose, the minimum 19,000 PFU dose.
I
mean, is that because there are potentially future plans to try to have a
higher potency vaccine? What was the
rationale for that higher dose?
DR.
SILBER: The question surrounding the
rationale for Protocol 009 was really just to frame at the very highest end of
what might be manufactured, because the manufacturing will be targeted, again,
to ensure that all doses administered within human certainty will be above a certain
minimum potency, that there will be a target and variable potencies, as Dr.
Gutsch had alluded.
And,
again, this is really just to frame what could be acceptable at the very high
range. If you're asking if we're
specifically targeting 200,000 plaque-forming units as a dose for this or
future studies, the answer is no.
MEMBER
KARRON: Okay. Okay.
So those were my potency questions.
Safety questions. I was actually
wondering if we could look at that slide 36 again, which is the pie
diagram? I don't know if it's possible
to pull up.
DR.
SILBER: Sure. Can we get 36? Thank you.
MEMBER
KARRON: Okay. So I think if I understood the briefing
documents correctly -- so, first of all, I want to clarify. The blue are the individuals in the detailed
Safety Substudy?
DR.
SILBER: That is correct.
MEMBER
KARRON: Is that right? Okay.
If I read the pie, the briefing documents, correctly, I think that there
are about 25 percent of the people in this large study for whom I would say
that safety data collection was not absolutely optimal. It was after day 42. In some cases is was well after that
time. It had to be sort of sought by study
personnel and such.
And
my question is for those people not in the blue and the green --
DR.
SILBER: Sure.
MEMBER
KARRON: And I would sort of like
detailed information about this. Are
they comparable in terms of age, in terms of underlying conditions, in terms of
whatever demographics we can measure to the people in the blue and green?
DR.
SILBER: Sure.
MEMBER
KARRON: Whom I do think we have good
safety data on.
DR.
SILBER: Okay. So the question has to do with the
characteristics of those people who had other than an ATRS contact by day 50,
other than a vaccination report card.
Before
answering that, I would just like to turn attention to particularly this
magenta or purple and gray. These two
bars or two pieces of the pie represent over 20 percent of the individuals in
each group, and these represent either the staff calling ATRS, basically on
behalf of the subject, due to some contact or the staff following up on an ATRS
fax, because again at day 50 or 51 it is shut down.
And
just as with the vaccination report cards, not everybody comes in exactly on
day 42. It might be sometime later. Out of these 21, 22 percent of individuals in
the gray bars, the timing of when those contacts took place is known and
roughly 80 to 90 percent of those additional subjects also had that contact
prior to day 60.
So
it could have been for any number of reasons.
Without going to the ATRS, a subject may have called the site directly
to say, hey, I had this really bad sore arm or, hey, I remember that I was
supposed to check in six weeks later and I'm calling you or I have this rash,
maybe it's shingles, can I come in?
There are going to be all different ways in which this sort of contact
might have occurred, and so been done in lieu of the green or the blue.
So
having said that, I don't have at my fingertips any of the demographics or the
characteristics of the persons in the bars, in the pieces other than green or
blue, but we could check on that.
MEMBER
KARRON: I think that would be very
helpful. My last question actually just
has to do with the gpELISA and the comment that that's the best correlate protection. And my question is really so when we look at
responses in the sort of younger, the under 70s and the older 70s, in fact,
over 70s have higher titers.
So
what my question is is so does it correlate best, say, with protection against
postherpetic neuralgia or burden of illness as opposed to incidence because, in
fact, the incidence efficacy is much less in the over 70 group?
DR.
SILBER: Sure, yes. The question has to do with the surrogacy of
or, I'm sorry, the correlation, there is no surrogacy, the correlation of the
gpELISA.
Now,
recall that these assays were conducted just on the CMI Substudy representing
1,400 of the 38,000 individuals enrolled in the study. And so there were relatively few clinical
endpoints among the primary efficacy endpoints that occurred among the
individuals within the substudy.
Unfortunately, there was no blood collected from the other 37,000.
And
so based on that, and I can't recall, I think there were only one or two or
just a handful of PHNs at all across either of the treatment groups within the
substudy. So the analysis looking at the
correlation with protection was built on the protection against the incidence
of herpes zoster.
CHAIRMAN
OVERTURF: Dr. Fleming?
DR.
FLEMING: I'm trying to pare down questions
here. There are three areas of questions
I would like to pursue, the first relating to generalizability, the second
relating to safety, the third relating to the BOI for efficacy.
Starting
on generalizability, your label is very broad.
You're asking in slide 5 for immunization of individuals over age 50 and
then note in the EpiData that the only known risk factors are age and
immunosuppression. And, yet, you
completely excluded patients, for example, that were on regular use of inhaled
corticosteroids.
You
have also excluded other high risk patients, patients that are homebound or
non-ambulatory or have cognitive impairment and your representation of those
patients over the age of 80 is only 2,500, a very small fraction, a fraction
that in fact shows very little efficacy when you look at the age relationship
to efficacy, and a group that shows on slide 71 to have a particularly higher
excess rate of SAEs.
So
the first of the generalizability questions is why such an under-representation
of those very groups that your risk factor analysis says are the people in
greatest need?
DR.
SILBER: Okay. That was a dense question. Can I answer that one before any other
questions? Okay. The clinical studies for ZOSTAVAX, as for the
other live virus vaccines, have routinely systematically included or excluded,
excuse me, those with known immunosuppression.
And
so with respect to generalizability, the studies were conducted in this way and
the proposed package circular that has been submitted would contraindicate the
vaccine in those with known immunodeficiency, as is consistent with a label as
it had been for VARIVAX. And
particularly because of the high potencies administered, there were potential
safety concerns with using a high potency vaccine in individuals with known
immunodeficiency.
Having
said that, there were a small number, a handful, of subjects who did enter the
clinical trials with cancer or on steroids and one cannot infer anything
definitive, obviously, from just a handful of subjects, but no safety concerns
accrued.
The
second, there were a number of individuals in the Shingles Prevention Study and
in the other studies who developed immunocompromising conditions or required
corticosteroids or other immunosuppressors shortly after vaccination, and no
adverse experiences were noted there over and above what was seen in the
general population.
Third,
I would like to go back again to VARIVAX where the vaccine has been used in a
very large experience over many years.
Recall that although not indicated as such in the United States, the
vaccine was initially developed for use in leukemic children and through
studies that have been conducted by ACTG and others, the vaccine has
demonstrated a very acceptable safety profile in immunocompromised populations.
And
so in terms of that particular aspect of generalizability, what we are
proposing for our initial package circular is consistent with what we have
studied. In fact, we will, beginning in
2006 now that we have analyzed the full safety database for immunocompetent
individuals, be looking judiciously to expand the populations for whom the
vaccine would be developed, but those are for future studies. That is not for now.
In
terms of the other exclusions from the Shingles Prevention Study, those were in
some cases due to the immunodeficiency exclusion criteria, but several of the
other criteria were more practical considerations for that study only given the
fact that people needed to have frequent contact with sites, needed to have long-term
follow-up, needed to get back and forth.
And
so the enrollment for that study was built around largely ambulatory
subjects. There were two sites that did
some recruitment and enrollment at nursing homes. We went back and tried to verify exactly how
many and who these were, could not get exact numbers.
But
separate from the ambulatory issue, per say, I want to go back to the
functional status that was evaluated and, based on a functional status measure
taken at baseline, there were, approximately, half of the enrolled subjects who
were mildly, moderately or severely limited at baseline, about 10 percent
moderately or severely limited at baseline, and the profiles that were seen
were largely the same across those groups.
DR.
FLEMING: Let me ask for maybe more
concise answers, because I have got several questions and I know time is
limited. But the bottom line is it's
unfortunate not to have more data on these particularly important high risk
groups.
I
am confused about the exclusion of the 50 year-olds. When you were giving slide S-13 and S-39 you
were justifying their exclusion logically when the study was designed in part
because, as your data do show, PHN risks are very low until you're age 60. But your closing slide, S-79, then says EpiData
strongly established the clinical need above age 50. It seems inconsistent.
DR.
SILBER: Yes. The question is about age 50 and the decision
to not enroll or not target age 50 initially, but to target age 50
subsequently, is actually consistent with the scientific data knowledge
regarding --
DR.
FLEMING: Well, basically, you only
thought you were going to affect pain at the beginning and then you actually
more affected zoster risk and, hence, now you believe that 50 years-olds are
going to potentially benefit? Is that
the concise answer?
DR.
SILBER: Let's separate out the medical
need on the one hand and then the ability of the vaccine to meet that need on
the other hand.
Several
population-based epidemiologic studies suggest that on the order of 200,000
episodes of herpes zoster occur each year in this country among people 50 to 59
years of age. The acute episode for
people in their 50s is as severe, requires as much medical therapy, requires as
many doctor visits and results in on average five work days lost. So based on the magnitude of that, the need
is there.
DR.
FLEMING: Could you put up S-13? I need a much more quick answer, S-13. As you were describing when you designed the
trial and you were focusing on PHN and severity of zoster cases --
DR.
SILBER: Correct.
DR.
FLEMING: -- you noted that risk is small
below age 50, below age 60. That is
still, in fact, what you would view to be the truth, correct?
DR.
SILBER: That is correct, that the risk
of PHN begins to rise substantially at 60.
DR.
FLEMING: Next question. Why only 2 percent blacks?
DR.
SILBER: 2 percent blacks? Is that what --
DR.
FLEMING: Right. Why are there only 2 percent in the study
population, blacks?
DR.
SILBER: Yes. The Shingles Prevention Study was open to the
general population and was advertised in the general community, and this is
something that we acknowledge and have been making efforts to increase
enrollment of minority populations in studies.
It was a bit of a surprise to us as well, I must admit, and the recently
completed studies have included substantially more minority individuals.
DR.
FLEMING: Two more very quick
questions. One safety question and to
make it short, I will just ask for some data we can be presented later on. When we look at the Safety Substudy, there is
a 60 percent relative increase in SAEs and it's an 80 percent relative increase
in SAEs when you're above age 70.
Could
we get a summary of what those SAEs are?
And, secondly, could we get a summary of overall hospitalization by arm
for the entire cohort of 38,000 and, specifically, zoster-related
hospitalization by arm and serious morbidities by arm? If we could get those data, that would be
helpful.
My
last question up front here relates to the burden of illness score. My understanding is you're looking at, in
essence, the average. You look at that
burden of illness score and the duration of time that you have that score and the
product then, in essence, gives you that total burden.
So
if somebody had a score of 4 and somebody had a score of 3 and they were the
same duration over 182 days, then that would be a ratio of 4:3. If somebody has a score of 3 and somebody
else has a score of 2, it should be 3:2.
But
if, in fact, someone has a score of 3 over the 182 days and someone has a score
of 2 over the 182 days, does that come out as 3:2 or is the 3 counted for all
182 days and the 2 only counted for 30 days, in which case you're getting a
radical misrepresentation of that 3:2 ratio?
DR.
SILBER: The question relates to the use
of the BOI and the BOI was designed to look specifically at pain scores of 3 or
higher because of the validation that suggested that pain scores of 1 or 2 were
not clinically meaningful in terms of daily activity. So, yes, scores below 3 --
DR.
FLEMING: So is what I'm saying correct?
DR.
SILBER: -- were not included in the
scores, the overall scores for the vaccination or placebo groups.
DR.
FLEMING: So you impute a score of zero
after day 30 for people whose scores aren't above 3. Is that correct?
DR.
SILBER: That is correct.
DR.
FLEMING: And could you show us on S-52,
you come up with a P of 008 for the contribution, in essence, of this burden of
illness beyond the actual reduction in incidence of herpes zoster cases.
What
is your statistical test here that you're using? Is it one that, in fact, exaggerates emphasis
of the right hand tail and how do you justify that you have integrity of
randomization since it appears this is an initial analysis?
DR.
SILBER: Sure. Okay.
I would like to call Dr. Chan, our biostatistician, to talk about the
statistical methodology here.
DR.
CHAN: So the question is relating to the
supplementary analysis result, the severe duration among zoster cases as shown
in slide 52. First of all, all the
pre-specified analysis would support the indication based on the
intention-to-treat analysis. So we did
this pre-specified analysis just as a way to quantify the -- a second component
about the duration of pain. And this,
obviously, was done based on post-randomization comparative --
DR.
FLEMING: What's your test statistic?
DR.
CHAN: The test is based on a normal
approximation stratified by age based on comparing the mean between the two
groups. And in that comparison, we also
adjust for the age between the two groups.
DR.
FLEMING: And how do you address the fact
that this is not based on all people?
This is based on a conditional sub-cohort of people that, in fact, had
diagnosis of HZ. Integrity of
randomization doesn't hold here. What's
the validity of your P-value?
DR.
CHAN: That's true. So what we have done is also done a couple of
the sensitivity analyses that, one, are based on the bootstrapping techniques
and that sort of doesn't take into account the distribution of some things.
DR.
FLEMING: Well, that doesn't address the
issue of integrity of randomization.
Dan, did you want to comment?
DR.
SCHARFSTEIN: Do you have data showing
the --
CHAIRMAN
OVERTURF: Please, identify yourself and
use the mike.
DR.
SCHARFSTEIN: Sorry. Do you have data presenting the demographic
characteristics or health status characteristics of these two groups?
DR.
CHAN: Yes, we --
DR.
SCHARFSTEIN: So you can present?
DR.
CHAN: Yes. The question is whether we have demographic
data about the zoster cases and we do.
CHAIRMAN
OVERTURF: I'm going to ask that we
suspend discussion after he answers this question. If you want to wait until this afternoon when
we have time to address it, that would be fine.
DR.
SCHARFSTEIN: Yes.
DR.
CHAN: Can we -- can I have slide
1015? This slide shows the demographic
characteristics by trimming group among the zoster cases that developed. And as you can see, there is slight imbalance
in the age distribution between the two vaccine groups. Apart from there, all the other
characteristics are very similar across the trimming group. And one thing to know, obviously, the age
imbalance, actually what you can see is there are about 61 percent of older
individuals in the vaccine group that have zoster compared to 48 percent.
So
that in effect, there is actually in the comparison that was performed that is
reflected in the other slide that comparison takes into account the age
differential in there.
DR.
SCHARFSTEIN: Are there other clinically
relevant factors that you are not including on this slide that could explain
differences between populations?
DR.
CHAN: The questions are there in the
clinical characteristics.
DR.
SCHARFSTEIN: But relevant
characteristics you're not including on this slide that could explain
differences between these two cohorts.
DR.
CHAN: We haven't identified any other
characteristics that are different between the two groups.
DR.
SCHARFSTEIN: Can I just ask one more
important question about this? I'm
sorry. You considered cases as being
evaluable or non-evaluable. The rate at
which you considered cases as being non-evaluable was much higher in the
ZOSTAVAX group as opposed to the placebo arm.
Can you explain?
DR.
CHAN: Yes. For that question, I would probably turn to
Dr. Silber.
DR.
SILBER: Now, this question relates to
the rate of non-evaluable or cases that were not found to be evaluable cases of
herpes zoster in the Shingles Prevention Study.
And I think that it would be useful to turn quickly to slide 45,
please. What one sees is that the
fraction of cases that turned out not to be herpes zoster is the same in the
two groups if one uses as the denominator the entire population who would come
in with anything.
The
ones who develop suspected herpes zoster, in fact, were more likely to be in
the placebo group than in the vaccine group.
So the fact that the rate of non-evaluability is higher in the vaccine
group reflects the smaller denominator, because the vaccine was, in fact, efficacious.
CHAIRMAN
OVERTURF: I'm going to ask that we go
ahead and take a break, because we're a little bit limited on time, I ask
everybody to be back at 15 minutes after the hour for the FDA presentation. Thank you.
(Whereupon,
at 11:09 a.m. a recess until 11:24 a.m.)
CHAIRMAN
OVERTURF: I would like to ask the
Committee Members to, please, take their seats, members of the audience,
sponsors, please. Dr. Rohan will provide
the FDA presentation.
DR.
ROHAN: Good morning again. I would like to just give you a brief
overview of my presentation. We will
discuss the proposed indication, a little bit about the introduction and
background behind this disease, the ZOSTAVAX Clinical Development Program and
particularly we will discuss Protocol 004, the pivotal study and Protocol 009,
finish with a summary and then presentation of the questions, which will be
discussed later today.
I'm
going to kind of skip over some of the slides, Dr. Gutsch, Dr. Silber did a
great job in presenting a lot of the background, the indication as well, and
just point out that, you know, the very serious problem with postherpetic
neuralgia, the pain that can be debilitating and it can last for months or a
year or longer, particularly in the oldest age cohorts and that pain control
may often be inadequate in those with the most severe cases and there may be
complications or side effects from the treatments as well.
VARIVAX
was licensed in 1995 and I might be able to answer some of the questions here,
but I know that we have some CDC colleagues as well present in the
audience. By 2003, the United States had
achieved an 85 percent vaccination rate nationwide in the population for whom
this vaccine is recommended. At the same
time, CDC had been monitoring varicella zoster virus disease and had seen a
decrease of primary varicella infections over that same period by,
approximately, 85 percent.
And
I would like to point out that the epidemiology of this disease may be changing
and that future adult populations, these young people that are coming up that
have had vaccination and we don't have circulating varicella zoster vaccine,
chicken pox, out there, they may be relying on vaccination for protection from
primary VZV infection.
In
addition, the CDC has been interested in rates of herpes zoster. Again, we discussed earlier that there is a
concern that if circulating varicella zoster virus is not out there in the
community, we may see some impact on the HZ incidence as well as its manifestations. We saw that from 1999 to 2003, age
standardized rates for overall herpes zoster have increased in the adult
population and that upward trends in both the crude and adjusted rates were
both statistically significant with P-values of less than .001 in specifically
the 25 to 44 year age group and the 65 year and older age groups.
And
this is from Dr. Yih and Dr. Seward, who I believe is here today, too. This is just a schematic you've seen before
that older age groups have higher rates.
This is a bar graph of some of the data that Merck presented
earlier. I'm showing the large number of
elderly subjects with pain with duration of at least one year or 6 to 12
months, 1 to 6 months and at least one month.
And I would say that, you know, this data is derived from a study that
was published, it was noted earlier, in 1957.
And I don't think you will see this high rate of pain with long duration
from the studies that we will be discussing later.
This
is an overview of the ZOSTAVAX clinical development. As I mentioned, VARIVAX was licensed in
1995. Lydick published an article in
1995 comparing subjective responses to area under the curve based on the brief
pain inventory measure. The ZOSTAVAX IND
was actually submitted in the fall of 1996.
The last vaccination in the pivotal study Protocol 004 was administered
in September of 2003.
The
last case of herpes zoster was accrued in that pivotal study in the fall of
2003. We would note that the PHN
definition was changed from at least 30 days to at least 90 days in December of
2003. Protocol 004 was completed in
April of 2004. The incidence of herpes
zoster, the duration of herpes zoster pain and the interference, significant
interference with activities of daily living were all endpoints that were elevated
from tertiary to secondary endpoints and success criteria were provided in June
of '04.
Protocol
009 was completed in June of '04. The
publication validating the use of the HZ BOI instrument was published in August
of 2004. And in April of this year, the
ZOSTAVAX BLA was submitted. This is a
comparison of the dose ranges for VARIVAX, which is licensed for primary
infection versus ZOSTAVAX. A summary of
the clinical trials that are included in the BLA and again the focus will be on
the pivotal study, 004. That's the study
that has efficacy data.
I
can probably go through this quickly, but the Committee can stop me if I'm
going too quickly to try to not be too redundant with the previous
speakers. The primary objectives were to
reduce the incidence and severity of herpes zoster in those at least 60 years
of age as measured by the BOI and to reduce the incidence of PHN.
Secondary
objectives included reduction in the incidence of herpes zoster, reduction in
the duration of HZ pain and reduction in interference with activities of daily
living in subjects with HZ.
The
ZBPI was published, as I mentioned, in 2004.
It was based on 121 subjects who were enrolled within 14 days of the
onset of their rash and showed that the ZBPI severity duration associated with
severity duration as measured by ADLI and worsening of quality of life
measurements, also that a score of at least 3 on a 10 point scale occurring at
90 days or more after the HZ rash had high agreement with pain worse than mild
using a modification of the present pain intensity scale taken from the McGill
Pain Questionnaire.
As
you can see, there were nearly equal randomization in the older and younger age
cohorts. Although, the majority in the
older age cohorts were in the younger range of that, 70 and above. There were 12 clinical lots. Nine were accelerated-aged to mimic
end-expiry potency.
Pertinent
exclusion criteria included any subject that had more than intermittent use of
topical or inhaled corticosteroids, life-expectancy less than five years,
bed-ridden or homebound, cognitive impairments or severe hearing loss and those
two latter criteria were not specifically defined and weren't specifically
measured or tested.
This
is to point out that this study employed the 12 clinical lots. When you entered the study, you weren't
necessarily randomized to one of the 12 lots.
They were ruled out in sort of a dose de-escalation fashion, if you
will. However, I would point out that
the group 2, 3 and 4, which each include three of the clinical lots, these were
the accelerated-aged.
We
don't really know how the parental lot and the aged lot compare. So by saying that the nominal potency was
50,000 to 62,000 PFUs in group 1 versus 21,000 to 26,000 in group 4, we don't
know whether the effect of what the parental lot was measured at may have an
impact, because these are measuring live virus, but there is also a proportion
of no longer living virus in the lots.
You
can also see that the follow-up time is different. That the number of subjects enrolled in each
of these different sort of dose ranges are different. The CMI was combined to the last group 3 and
group 4. And there were different
proportions of subjects in each of these groups across the dose ranges enrolled
into the Adverse Event Monitoring Substudy as well.
We
talked about the vaccine report card, the automated telephone response
system. We also talked a little bit
about the HZ rash onset, which then triggered additional follow-up,
immunogenicity and other test instruments, particularly the IZIQ and ZBPI, which
measured the pain severity, which was used to calculate the BOI.
We
talked about the populations used and analyses as well. I would point out that one of the very nice
aspects of the study is that all potential HZ cases were evaluated by the
Clinical Evaluation Committee and then the analyses were compared using these
different populations and that the results were very similar. So that subjects that were evaluated and
determined to have HZ by clinical laboratory methods, PCR or culture, were also
evaluated in a blinded fashion by the CDC and the results were really quite
similar.
We
can see that the groups were balanced in terms of gender, race and age,
although it says previously mentioned, there are very few non-white subjects in
this group, in this study. There was a
high proportion of follow-up. Only 0.3
percent and 0.2 percent respectively of the subjects were lost to follow-up at
the end of an average of three years of follow-up.
The
PCR detected not only wild type VZV, but it also could detect the Oka/Merck
attenuated strain in the vaccine and HSV.
And as previously was mentioned, no Oka/Merck attenuated strain was
isolated from any of the lesions in this study.
You can see that the majority of the cases that were determined to be
evaluable HZ were determined by PCR and very few by viral culture and the
remainder by the Adjudication Committee.
The
co-primary endpoint, co-primary is used in the study not meaning as might be
thought that you would have to win on both endpoints. It's really an alternative endpoint so that
you could win on this endpoint or you could win on the other co-primary
endpoint and the study would be declared a success.
There
was a decrease in the HZ burden of illness of 61.1 percent in the ZOSTAVAX
group. There was a decrease in incidence
of PHN of 66.5 percent in the ZOSTAVAX group.
And as I pointed out, the definition of PHN was changed after the last
HZ case. The secondary endpoints
included a decrease in incidence of HZ of 51.3 percent. And this endpoint was elevated from a
tertiary to a secondary endpoint after the last HZ case was approved, but prior
to formal unblinding.
The
duration of clinically significant pain was found to be 20 days in the vaccine
group. 22 days in the placebo. It was using clinical scores of at least 3 on
a 0-to-10 point pain scale. The P-value
was less than 0.001 in the MITT group overall.
The P-value was 0.041 in evaluable cases only. And again, this was an endpoint that was a
tertiary endpoint, but was elevated to a secondary endpoint after the last case
of HZ, but prior to formal unblinding.
And
this is a statement from the Clinical Study Report and I think this to me sums
up the issues, the impact, all the endpoints.
This is related to the secondary endpoint substantial interference with
activities of daily living or SADLI.
"Because Substantial ADLI can only occur among HZ cases, the
benefit of vaccination in reducing the incidence of Substantial ADLI was
confounded by the benefit of vaccination in reducing HZ incidence."
As
you can see, the rates were 36.2 percent in the ZOSTAVAX group versus 39.4
percent in the placebo group with an 8.2 percent reduction beyond the reduction
in HZ incidence with a non-significant P-value.
And as I mentioned in the last slide, this is the one endpoint that does
not include the impact of HZ incidence on the vaccine effect of this
endpoint. It was also elevated from
tertiary to secondary endpoint after the last HZ case was accrued.
The
sponsor did a number of sensitivity analyses and modeling very nice to develop
more information about something we don't know enough about yet. And as you can see, the thing that stands out
is that age is the big factor in the severity-by-duration scores. Obviously, analgesic use, but that's sort of not
considered causal and that the vaccine versus the placebo group had a
significant P-value as well.
There
was a question about immunosuppression in the two groups. And as you can see, they were fairly
well-balanced as far as difference, causes of potential immunosuppression. I think if you look at the rates at the top,
this is sort of the flip side, the issue with looking at rates when you already
have a big difference in the incidence of HZ.
You have a higher rate of subjects that are immunosuppressed getting
zoster, herpes zoster in the ZOSTAVAX group.
It doesn't mean that the vaccine is causing that, it's just that you
have fewer cases, so the rate is higher in this case, in this group.
This
is a table showing some analyses by the sponsor looking at the efficacy for the
major endpoint of HZ BOI by year. And,
obviously, up to the first year, the subjects aren't randomized, but you can
see that there is a decrease in the differential between the placebo and the
ZOSTAVAX groups over time. You can also
see that after year three, year four, half of the subjects are no longer in the
population and the follow-up is maybe about half a year or a little over half a
year. And then in the fifth year, there
are even relatively fewer subjects and even relatively less follow-up.
You
can see with PHN again a decrease over time in the comparison between the two
groups for this endpoint. And finally,
you can see HZ efficacy, which was the secondary endpoint, you see a decrease
after the first year, but then it seems to not be dropping, just from a
non-statistician's perspective, as much as the others.
This
is a somewhat truncated summary of the mean worst pain in both of the groups
over time. And you can see that the
numbers are fairly similar. On day one,
the rash onset there are not too many subjects in that group relative to the
other time points. Most people were seen
relatively rapidly after the onset of their rash. But you can see that day 2, 3, 4, 5, 9 to 11,
week 4, 6, 8, 12, 16 and 26, there are not huge differences on that 10 point
pain scale.
This
is looking at the effect of age on efficacy.
We can see that there is some decrease in the 70 and above age group in
terms of the BOI endpoint. The incidence
of PHN is similar, but the incidence of HZ appears much lower in the group
that's 70 years of age and older.
FDA
did a number of exploratory analyses. We
wanted to try to see if we could understand further this difference in the
incidence of HZ efficacy endpoint. And
this is exploratory and the numbers as you get into the oldest ranges are very
small, but you see a consistent decrease, a trend towards decreasing efficacy
as you increase age.
We also looked at the major endpoints looking
at the impact of the vaccine beyond its affect on the incidence of herpes
zoster. The median HZ BOI score among
the HZ cases were fairly similar and didn't appear to be statistically
significant. The percent of HZ cases
with PHN slightly higher in the placebo group, but did not appear
significant. And the duration of
clinically significant pain did not appear significant, either.
This
is a graph looking at the rates of the BOI among the HZ cases, not the rates,
excuse me. And you can see that among
cases those in each -- instead of looking at numbers, you are looking at
proportions of subjects with HZ among each of the treatment arms and they look
relatively similar.
Comparison
of the BOI between a vaccine and placebo group, I would like to point out that
the median HZ BOI among the HZ cases is very similar and not significant. And using a variety of approaches, the
comparison of the BOI between the placebo and ZOSTAVAX group among the HZ
cases, except for the Log-Rank, the age-adjusted P-value, the other P-values
don't appear significant.
Comparison
of the PHN incidence between the vaccine and placebo groups, the percent of PHN
among HZ cases 8.57, 12.5, this was presented in an earlier slide. And this is looking at the distribution of
the BOI scores between the placebo group and the ZOSTAVAX group. To get an idea, very few people had high
scores. Very few people had scores, you
know, as time went on. Most of the cases
resolved. So, you know, when you are
looking at 90 or 120 days, you are looking at a relatively small proportion of
subjects.
Comparison
of the BOI among the PHN cases, you can see that the median HZ BOI among the
PHN cases again is not that different and it's not statistically
significant. Comparison of the BOI
between the placebo and ZOSTAVAX groups among the PHN cases using a variety of
approaches, the P-values, even age-adjusted, don't appear significant.
Now,
I would like to switch gears and look at the immunogenicity. There was a lot of very interesting
data. The sponsor used three different
assays, but it didn't seem the Responder Cell Frequency or the gamma interferon
ELISPOT provided any additional data, at least at this point, compared to the
gpELISA. So I'm going to focus and limit
my comments to the gpELISA data.
Here
we can see the various -- these are the clinical lots that were -- then the
data were pooled between two of each of these lots to represent the parental
lot from which these age lots were derived.
Then the efficacy data from the paired lots were then combined and then
compared pair-wise representing the three parental lots for the lot
consistency.
No
differences were seen. There were based
on clinical efficacy endpoints. As well,
this was not part of the endpoint analysis, but you can see that the geometric
mean fold rises were similar between these accelerated-aged lots.
Looking
at the gpELISA by HZ status, you can see that in people that developed HZ,
whether you are in the ZOSTAVAX group or the placebo, the GMTs at 6 weeks were
much lower than the people who did not develop HZ. Even among the placebos there is a difference
in the gpELISA levels. Looking at the
geometric mean fold rise from day 0 to week 6, you can see that there is a 1.7
GMFR in the ZOSTAVAX group in those subjects who didn't develop HZ and that
that's much different than the GMFR seen in people that went on to develop HZ.
We
then wanted to look at the GMTs that were observed and look at the risk of HZ
by 6 week gpELISA titer. And as you can
see, once you reach about 400, there are very few cases. There are three. I did go back and look at those three cases
and at the end of the study they were not considered to have been
immunocompromised. During the study
there were no adverse events reported with these subjects. So there wasn't any particular explanation,
but it looks like the majority of the cases are occurring about that level, on
the chart below as far as in terms of the quantitation of the gpELISA titers.
There
were no clear differences in the rates of the various reported complication
among the HZ cases in the treatment groups.
Again, when you account for the difference in the incidence of HZ. Also, there didn't appear to be any HZ
association with immunosuppression differentially seen between the two
treatment groups. The absolute numbers
were similar. And as was previously
mentioned, there were three subjects, two placebo and one ZOSTAVAX, who
developed two cases each of herpes zoster, evaluable cases, but data from the
first case, data were used in the analysis.
Comparing
the immune response in terms of gpELISA in subjects who were vaccinated to
people who developed HZ on study, whether they received ZOSTAVAX or placebo, if
you look, the GMT 6 weeks after vaccination in the ZOSTAVAX recipients compared
to the GMTs seen 6 weeks after their onset of herpes zoster rash in the two
groups are quite different, as well as the GMFR.
The
safety follow-up was quite a huge undertaking in such a large group. Most of the subjects were randomized and that
were randomized to the two treatments were followed in the Routine Monitoring
Cohort. However, a subset were in the
Adverse Event Monitoring Substudy. As
well, the CMI Substudy, this is really the immunogenicity subgroup, they were a
subgroup of the routine monitoring. So
you couldn't be in both. They were separate.
The
Adverse Event Substudy, I have to watch where I'm leaning, involved 6,600
subjects who used vaccine report cards, which specifically queried for
solicited adverse events on day 0 to 4, specifically queried for temperature
day 0 to 21 and allowed for subjects to report other complaints on that vaccine
report card.
The
automated telephone response system, which was to be conducted on or around day
42, specifically queried for the occurrence of rash, any unusual reactions,
hospitalizations, disability, life-threatening events, new diagnoses of cancer,
overdose of any medication. ATRS
follow-up was conducted monthly for surveillance of suspected HZ and in the AE
Monitoring Substudy for hospitalization.
In
addition, investigators could review available medical records on or around day
42 to look for other information related to adverse events or possible herpes
zoster.
The
Routine Monitoring Cohort, which is the remainder of the study, basically
relied on the ATRS monitoring for 42 day safety follow-up, the same questions
asked as I have mentioned before, available medical records could be reviewed
for adverse events or herpes zoster, and otherwise the safety monitoring in
this cohort was basically passive and, as I mentioned before, the monthly ATRS
monitor for HZ in this group and monitor for HZ and for hospitalizations in the
AE Monitoring Subgroup.
Looking
at the day 42 ATRS data set that was submitted to us, we note that there were
38,546 subjects enrolled. However, there
are only 25,613 subjects accounted for in the day 42 ATRS subsets. 66 percent of the subjects. We saw that there were 55 percent of the
total cohort who called in or either called or called the ATRS as was planned
by the protocol. We also see that an
additional 11 percent of the total study population had data answered by the
staff for the subjects into the ATRS system.
We
also noted that only 9 percent of the subjects from the AE Monitoring Cohort
had data included in this database. And
in addition, although subjects were to have a report on or around day 42, there
are subjects, there are 1,240 additional reports for subjects that already have
data in this data set and the data were entered sometimes one, two, three years
after the initial report.
In
looking at the source and time course of reporting, you can see that most
subjects called in on or around day 42 and that their reporting rates dropped
over time. After this point, we have
been told that subjects -- the system was disconnected or unplugged and so
subjects couldn't call in. You can see
also that staff were calling for the subjects over time and that after this
point, over 4,600 subjects are having data entered by the staff. This can go out two and three years
afterwards for the day 42 safety reporting.
In addition, you can see that some of these, not very many, are entered
well before day 42.
This
is a table showing the AE rates based on the vaccine report card
monitoring. You can see that
temperatures didn't seem to be wildly different between the two groups as far
as high temperatures or even feeling like your temperature was abnormal, even
if the documented temperature was less.
The
statistically significant differences were seen in erythema, pain and
tenderness and swelling. And I would
point out those were three things that were specifically queried for on the
vaccine report card. All had P-value for
the difference of less than 0.001.
Regarding unsolicited adverse events, I would note that there was a
higher rate of pruritus in the ZOSTAVAX group and some increase in reporting of
warmth.
This
is looking at systemic adverse events reported in the AE Monitoring Substudy
between 0 and 42 days. And you can see
that in the different body systems, they are fairly similar. Now, looking at serious adverse events, in
the Routine Monitoring Cohort, the group that was more passively monitored, the
large portion of the study subjects, there is a slightly higher rate of SAEs
reported in the placebo versus the ZOSTAVAX group.
If
you look in the Adverse Event Monitoring Substudy, there is a higher rate of
serious adverse events reported in ZOSTAVAX versus placebo. And although this difference is not as marked
in the younger group, it is even more notable in the older age group. The rate of deaths reported in the first 42
days were similar between the two groups.
These
are the report causes of death.
Obviously, things could be coded in multiple ways, so something that was
coded, reported to us as a myocardial infarction sometimes it would also say
heart arrest or cardiovascular disease.
So these are sort of in a hierarchial, if you will, exploratory,
obviously for safety. There were similar
rates of serious adverse events resulting in death in the first 42 days. The cardiovascular causes appear fairly
similar.
So
we didn't really see a difference as far as cause. I know that was a question that had come up
earlier. But I would note that of the
deaths that are reported, 26 of these are coming from the Routine Monitoring
Cohort. They were more intensively
monitored in that first 42 days, but not afterwards. We also had a question about hospitalization
and you can see that the overall rate of hospitalization was similar and didn't
seem to be a huge difference in the rate for HZ-related causes as well.
Deaths
overall for the entire study period appeared similar in both age cohorts and
overall. There is no information that
has been submitted to date on the proportion of subjects with ATRS contact at
each month overall by group and by site.
And this is important in terms of safety follow-up, because the AE
Monitoring Cohort were being queried for hospitalizations. Also, "Due to the passive and
inconsistent nature of the safety data collection in the Routine Monitoring
Cohort from day 43 through the study end, caution should be exercised when
interpreting these particular data."
Looking
at the AEs that occurred at rates of at least 1 percent in either group from
day 43 to study end, again we don't see huge differences in all the various
body systems that were being monitored.
And
now, I'm going to have a few comments on Protocol 009. The objectives, comparison of the safety and
tolerability of a higher potency ZOSTAVAX vaccine with that of a lower potency
dose. And also, that among adults 50
years of age and older, the higher potency ZOSTAVAX will be generally
well-tolerated as compared to the lower potency of ZOSTAVAX. And I think most of this was already
reviewed.
The
endpoints were, the primary endpoints included the difference between the higher
and the lower potency vaccine groups in the risk of investigator-determined
serious adverse experiences occurring up through day 42, postvaccination, and
the other primary endpoint is that the upper bound of the 95 percent confidence
interval for the incidence rate of moderate or severe injection-site pain,
tenderness, soreness or swelling, composite endpoint of those events occurring
on days 1 through 5 postvaccination would be higher -- in the higher potency
vaccine group would be less than 21.5 percent.
And this is based on the historical rate reported for PNEUMOVAX23.
Secondary
endpoints included monitoring varicella, varicella-like rashes, HZ and HZ-like
rashes and fevers as well. The primary
endpoints, there were no investigator-determined vaccine-related serious
adverse events. The rate of the
composite local adverse events in high potency group was 17.2 percent. The upper bound being 21.0, which met the
pre-specified criteria that it be less than 21.5 percent.
The
secondary endpoints, there were no occurrences of varicella or varicella-like
rashes. The zoster or zosteriform rashes
were similar in the two groups and temperatures were similar as well. These are a listing of the serious adverse
events that were reported day 0 to 42.
You can see that there was one in the low potency group. There were four in the high potency
group. And these two were in the lower
age cohort. These two were in the 60 and
above age cohort.
There
were no deaths reported in comparing the injection-site reactions based on the
composite endpoint. You can see that
there was a higher rate in the high potency group, not surprisingly. And also that higher rates of injection-site
reactions were seen in the younger cohort compared to the older cohort, but
this was particularly notable in the higher potency vaccine comparing the two
age ranges.
So
in summary, the ZOSTAVAX issues and summary of the data. Reduction in HZ incidence is 51 percent in
relatively healthy adults age 60 years and older, postvaccination. 64 percent in those 60 to 69 and 38 percent in
those 70 years and older. There is a
reduction in the PHN incidence of 67 percent at 90 days following HZ rash
onset. There is a reduction in the HZ
BOI score of 61 percent over the six month period following HZ rash. And the effect on PHN incidence and BOI
appear relatively small after accounting for the affect of the vaccine on the
incidence of HZ.
In
persons with HZ, there is no clear correlations seen between the reduction of
BOI scores and measures of clinical benefit.
For example, things like mortality, serious morbidity, hospitalization,
use of pain and medication of or interference with activities of daily
living. In the completeness of the
safety, the ATRS and study termination follow-up is unclear at this point.
And
age appears to be the strongest factor in determining vaccine effect and in an
exploratory analysis, efficacy appears minimal starting in around the 75 years
of age and older, which I would suspect would be the age group with potentially
the largest burden of disease as far as prolonged and severe pain.
The
relative increase in the rate of serious adverse events seen between day 0 and
42 in the AE Monitoring Substudy was most notable in subjects age 70 and
above. However, there was no specific
pattern of serious adverse events seen.
Exclusion criteria, those not expected to live at least five more years,
not ambulatory, chronic use of corticosteroid use, cognitive impairment, make
it difficult to draw conclusions as to the generalizability of Protocol 004
efficacy and safety analyses to a typical population aged 60 years and older.
Protocol
009, this includes a younger cohort of subjects 50 to 59 years of age, but
there is no comparison of the older age strata to previous age groups based on
ZOSTAVAX studies, particularly the pivotal study. The vaccine dose is four times higher than
any previously studied, but again there is no comparison or bridging to the
previous ZOSTAVAX studies.
The
clinical relevance of the study endpoints that were chosen, the primary
endpoints are not clear. And I wanted to
also acknowledge there are too many people to thank that have made this project
what it is, but I would like to specifically thank Dr. Ahnn, the statistician,
Dr. Pratt, Dr. Finn, who I wouldn't be here without their help, Dr. Goldenthal
and Captain Matrakas.
So
I would like to go back to the questions for the Committee to reiterate from
earlier today. Are the available data
adequate to support the efficacy of ZOSTAVAX when administered to individuals
50 years of age and older in preventing herpes zoster; in preventing
postherpetic neuralgia; preventing postherpetic neuralgia beyond the effect of
the prevention of herpes zoster; decreasing the burden of illness; decreasing
the burden of illness beyond the effect on the prevention of herpes
zoster? And, if not, what additional
information should be provided?
Are
the available data adequate to support the safety of ZOSTAVAX when administered
to individuals 50 years of age and older?
If not, what additional information should be provided?
And
finally, please, identify any issues which you feel should be addressed,
including post-licensure studies and, in particular, please, address the use of
the vaccine in persons with co-morbid conditions. For example, those who might typically reside
in assisted residences, excuse me, assisted living residences and nursing
homes; use of the vaccine among persons taking chronic immunosuppressive
therapies including corticosteroids; use of the vaccine in certain subsets of
the sponsor's proposed age indication, for example, those 70 years of age and
older, those 80 years of age and older; the duration of immunity and the
sponsor's proposed pharmacovigilance plan, which we really didn't discuss in our
presentations, but we could expand on during the discussion this afternoon.
So
that concludes my presentation. Thank
you.
CHAIRMAN
OVERTURF: Are there questions from the
Committee Members for Dr. Rohan at this time?
Yes?
DR.
SCHARFSTEIN: The follow-up of the pain
data says that it's measured day zero through 182 after the occurrence of the
rash. How was that data collected and
can you comment on the completeness of those data?
DR.
ROHAN: Well, the sponsors might want to
answer that.
DR.
SCHARFSTEIN: Yes.
DR.
ROHAN: Because they probably would be
able to do a better job, but subjects, once they had suspected HZ, were
seen. And, as I pointed out, Dr. Oxman
and his colleagues did a phenomenal job in the surveillance, evaluation,
treatment, determination of the HZ cases.
So within usually a couple days within the onset of the rash, subjects
were seen and that's like two or three days a lot of the subjects were seen.
Then
they were followed. There were a couple,
maybe about every several days, there were some windows for the time points
that they were asked again and again how is your pain? You know, there were a number of instruments
that were involved. I think in my
briefing document I have a list of those.
But
then they went out after the first week or two to weekly evaluations for
several months, and then they went to monthly evaluations. If that's -- you know, if people had pain,
they continued to have weekly follow-up.
After
day 30 if their scores fell below 3 at two consecutive time points, then they
weren't followed again, but they did then have the monthly follow-up so that
should they have pain that increased or recurred or occurred, then they would
be captured in the area under the curve with those monthly time points and
again go back to the weekly follow-up to capture the full burden of the
disease.
CHAIRMAN
OVERTURF: Dr. Royal?
MEMBER
ROYAL: I also have a question concerning
the pain data. It was said earlier that
significant postherpetic pain was that which was scored as 3 or worse on the
pain scale. And going back to the BOI
data, if you calculate those numbers using just those patients who had that
severity pain or worse, what do your comparisons show?
Also,
it was stated that the frequency of neurologic complications was decreased in
the immunized group. And could you speak
to whether that -- what the complications were that were seen and whether there
was an even decrease across that list of complications or whether some were
lower than others within the vaccinated group?
DR.
ROHAN: I don't know if the sponsor wants
to answer the question about the neurologic complications?
DR.
SILBER: Yes, one point of
clarification. The surest way to prevent
a complication of herpes zoster is not to get herpes zoster. And so I think our presentation and Dr.
Rohan's presentation basically said the same thing in two different ways in
that there was, indeed, across the population a reduction in the neurologic and
the other complications of herpes zoster.
What
Dr. Rohan was presenting was that once the herpes zoster developed, the
fraction of cases that went on to develop the neurologic complications was
neither higher nor lower. And so the
reduction in complications is from the reduction in the case outright.
DR.
ROHAN: You had a second, actually your
first question. Could you repeat that?
MEMBER
ROYAL: It concerns the group of patients
with significant postherpetic neuralgia with pain scores of 3 or better. When one does the severity duration
calculations and compares the two groups, do you see the same, especially if
you take away the most severe pain duration scores?
DR.
ROHAN: When you're saying when you take
away the most severe pain duration scores, can you clarify?
MEMBER
ROYAL: Well, a bar chart was shown of
those individuals who had the most severe with the highest pain duration
scores. If you take that group away and
look at those who are left who had significant postherpetic neuralgia, do you
see a difference between the treated and placebo groups?
DR.
ROHAN: I don't know if a subset
analysis, if you will, was done looking at different ranges of pain.
DR.
AHNN: I think he is mentioning page 47.
DR.
ROHAN: Slide 47?
DR.
AHNN: Yes, slide 47. Yes, that's just the comparison of the distribution
of area under the curve only among the PHN cases. So it's -- the comparison is in a non-random
subgroup, so it's hard to make any conclusion statistically, but it's just for
the exploratory purpose that we just want to show the distribution of the area
under the curve.
MEMBER
ROYAL: Right, but --
DR.
AHNN: Between the two groups.
MEMBER
ROYAL: Theoretically, those values could
represent individuals with low pain scores and long severity duration, so it
represents a mixture.
DR.
FLEMING: Can I comment on that, because
I think this is an important point that I wanted to pursue as well, and I would
like to walk through a few slides in progression to amplify this point.
If
we start with slide 45, what we're looking at here is an alternative attempt
from what the sponsor presents to get a sense about whether, given that you
have an HZ case, is there a difference in the BOI? So is there a difference in severity? And while the sponsor had a P-value slightly
below 01, these P-values predominantly are showing little association or a
fairly comparable balance.
Whenever
you see a Log-Rank P-value lower than the other P-value, it's suggesting if
there's a difference it's in the right hand tail, these are importantly
rank-based analyses where the sponsor had a parametric analysis that is going
to be heavily sensitive to this difference in the right hand tail.
So
if you go to slide 47, what we're seeing is the difference between the FDA
analysis showing really no meaningful difference in distribution and the
sponsor claiming that there is, I suspect is driven by these cases here in the
right hand tail.
And
I suspect that it's an artifact or it's a result somewhat of the definition,
because the definition if someone is 3 versus 2, but the 3 is only counted for
-- the 2 for 30 days and the 3 for 180 days, then it's really giving the 2
versus 3, not a 3 to 2 weighting, but a 10 to 1 weighting. So my read on this is that the BOI really
becomes tantamount to is there a difference in the fraction of people who have
sustained level 3 or higher and not something more general than that.
So
if you go ahead to slide 40, the question is is there a difference in the
message in BOI from the message in HZ, and the answer is at least in part. When you're below age 70 where more than half
the patients were, there is no difference, but there is a suggestion that there
may be, in fact, more benefit than just prevention of HZ when you're looking at
those people above age 70.
Then
if you could go to slide 41, what we're seeing here is there is strong evidence
that there is an age effect of HZ. It
dwindles as you get older. Now, to the
extent that the BOI data are interpretable, and it's complicated by this oddity
and the way BOI is calculated, but if you put any interpretation on it, it
seems to me it's in there. Beyond
preventing HZ, is there some added evidence that the most severe prolonged
cases are occurring less frequently?
If
you put that interpretation on from the analysis on page 40, if the answer is
no, not at all in the age 59 to 69 categories, but above age 70 maybe, so could
we go back to 41, could someone produce this slide for the BOI by age? If we go back a slide, you have pooled
together all the people above age 70 to suggest there is some difference.
It
would be interesting to see how this breaks out by half decades, next slide, as
you do for the HZ. Does that slide
exist?
DR.
ROHAN: It doesn't exist. I also wonder whether the right hand tail is
the older age group or not.
DR.
FLEMING: That's exactly a rewording of
my question. That's exactly what I'm
trying to get at. I suspect if we go
back to slide 40, that it must be predominantly at least people above age 50 --
above age 70, excuse me, because you don't see any difference between the HZ
and the BOI for ages 60 to 69.
It's
showing up for people above age 70. That
is suggesting to me that if you go back to slide 47 that these people might be
the older people. Where are they in that
distribution of older people?
MEMBER
ROYAL: I would still like to see the
data for those, the BOI data for those with significant postherpetic neuralgia
pain only, given someone with lesser pain with longer duration would be scored
equally as someone who has more severe pain and shorter duration.
DR.
ROHAN: So your comment is based on this
10 point scale, scores of 3 and above were included, but your question is what
about people 8, 9 and 10. Is that what
you're asking?
MEMBER
ROYAL: Well, this chart shows
individuals with pain scores of 0-to-10.
I would like to see those with pain scores from 3-to-10.
DR.
SCHARFSTEIN: Can we get a figure that
demonstrates the completeness of the data for day zero, you know, the
evaluation times for pain and how it differs between treatments groups because
I --
DR.
ROHAN: I think it's small and I don't
think we have analyzed it, but I think there might be some small differences,
but there are small numbers of subjects in the follow-up not -- in the
proportion of subjects who had follow-up for the whole 182 days, the numbers
are fairly similar, but there appears to be slightly less follow-up in the
ZOSTAVAX arm in sort of the mid range versus the placebo group.
DR.
SCHARFSTEIN: I think there is a lot of
imputation going on here.
DR.
ROHAN: Right.
DR.
SCHARFSTEIN: And there is probably a
fair amount of missing data along the way and then there is some impute, you
know, trapping in these lines between time points and I would be interested to
look at the distribution of the number of people who showed up at each visit
or, you know, provided data at each of those post-rash evaluation points.
DR.
ROHAN: Right. But I guess it's also sort of confounded by
the design in which if you fell below a score of 3, you weren't going to be
asked again the way people that had 3 or above will be asked every week until
they went below for two times points. If
you were below 3, you wouldn't then be asked until the next monthly, whenever
that occurred, sort of protocol-mandated follow-up for everyone with PHN.
DR.
SCHARFSTEIN: Right. So there is sort of structural missingness
and then there is unstructural missingness.
I'm really interested in the unstructural part of that.
CHAIRMAN
OVERTURF: Dr. Markovitz?
MEMBER
MARKOVITZ: Yes. I would like to ask some advice so we can
ruminate properly over lunch. I don't
know, Gary, if you want to tell us or FDA, but it seems like we're heading
towards having to decide. There may be
people who are in favor of 60 plus and not 50 to 60.
So
one question is are we going to be able to separate those out on the vote? And then the second thing is what is the
precedence for accepting an argument based on logic rather than data?
I
know we have rejected things based that way, but they were going the other way,
and my previous experience on the Committee was not wanting to extend things to
older people, but this question of extending it to younger people is somewhat
different.
And
I'm wondering does the FDA or you, Gary, have anything to tell us to guide us
as we think about this?
CHAIRMAN
OVERTURF: I think if the discussion this
afternoon generates concern and controversy about various age groups, then I
think we may need to split it out and we'll probably split the vote on that. The other issue, I would make a strong
recommendation based upon the consensus of the Committee for approval of the
vaccine at a given group.
Now,
the other issue is that I'm not sure that there is going to be sufficient
agreement also on the way the question is currently read, is it's we're
actually -- the question is whether efficacy is supported by at least three
parameters and I'm not sure that there is support for all those
parameters. But that may not affect the
discussion as much as the issue of the age.
So we could get clarification of that during the lunch period. Dr. Hetherington?
DR.
HETHERINGTON: One other issue that might
help when we try to deliberate on that point is the persistence of immunity by
age group. I realize that it's rather
short in duration, what you have now, but to look at whatever data there is
available.
Between
the 50 and 60 year group, 60 to 70, 70 to 80, etcetera, what is the data that
we have today on persistence particularly with regard to titers above 400 or
500, which was a cutoff that I think was implied in the FDA presentation, and
also by geometric mean fold rise. If we
had those data after lunch, that might help us a little bit.
CHAIRMAN
OVERTURF: I think I'm hearing also
everybody is in favor of taking a break for lunch, so we'll break for lunch at
this point and reconvene at --
DR.
FLEMING: Should we ask the additional
questions for the FDA after lunch then?
CHAIRMAN
OVERTURF: Yes. There will be time for additional questions
for both the FDA and the sponsor after lunch.
So we'll reconvene at 1:30.
(Whereupon,
the meeting was recessed at 12:21 p.m. to reconvene at 1:33 p.m. this same
day.)
A-F-T-E-R-N-O-O-N
S-E-S-S-I-O-N
1:33
p.m.
CHAIRMAN
OVERTURF: I would like to ask the
Committee Members, members of the audience and the sponsors to, please, take
their seats. I would like to call the
afternoon session to order at this time.
At this time, we have time slotted for an open public hearing, so I will
turn the meeting over to Christine Walsh.
MS.
WALSH: Good afternoon. As part of the FDA Advisory Committee Meeting
procedure, we are required to hold an open public hearing for those members of
the public who are not on the agenda and would like to make a statement
concerning matters pending before the Committee.
I
have not received any requests at this time.
Is there anyone in the room who would like to address the
Committee? I see no response. Dr. Overturf, I turn the meeting back over to
you.
CHAIRMAN
OVERTURF: Thank you. We'll proceed further with the FDA presentation
and the questions after we give some allotted time to the sponsors to address
some of the questions that were asked this morning. So I will ask the sponsors to come forward
now and address those questions.
DR.
SILBER: Thank you, Mr. Chairman. I would like to just spend a few minutes
touching on several points that were recurring themes in the questions this
morning in the hopes of bringing some clarity and closure to them.
I
would like to preface the comments by reminding the Committee that at the
primary analyses on the modified intention-to-treat population of subjects
enrolled, in those primary analyses for the key endpoints for support of the
labeled indications that the sponsor and CBER are in agreement on the primary
endpoints and where the different analyses and cuts of the data are leading to
sometimes different interpretations comes on the conditional supportive
analyses specifically among subjects who developed herpes zoster.
And
so it's important to remember also that the burden of illness is a composite
that includes the incidence and severity-by-duration. Once incidence is removed, it's still a very
clinically important issue to deal with, severity of illness or
severity-by-duration or area under the curve as we call it, but we need to make
sure that we don't call that burden of illness, because the way that the study
was set up from the outset was with an understanding that both incidence and
severity-by-duration were important clinical components of the disease.
And
so with that in mind, I would like to touch on five points quickly that have
come up and I would like to first address this issue of whether there was a
benefit of the vaccine over and above the incidence of herpes zoster and
particularly for the severe cases.
You
will recall that in the presentation this morning, I showed a histogram
starting with those individuals with scores greater than 600. I would like to show slide 1026 now, which
uses different cut points. And so, as
you see here, 600 is what we looked at this morning.
What
we have now is using different cutoff scores from 400 out through 1,000,
meaning with each cut we are dealing with successively smaller subsets, but
those people with the more severe cases were out at the tail. And what we see here, if we go to the right
hand column, the relative reduction in the likelihood of having this high score
goes steadily up as the bar gets raised.
The more severe the case, the greater the percentage reduction.
So
I would like to go then to 1028 because, as Dr. Fleming pointed out this
morning, in the younger age cohort a lot of what we are seeing is based on
incidence. In the older cohort it's the
issue of pain. And so if we look
specifically in the older age group, what we are dealing with here is, again,
increasing benefits with the increasingly severe cutoffs. I would like to turn next to slide 654.
DR.
FLEMING: These are nested, so when you
say increasing benefits, what you really have is--
DR.
SILBER: It's a relative reduction.
DR.
FLEMING: -- a signal at the highest
level and then, of course, lesser, in fact, imbalances as you then increment
next down scores.
DR.
SILBER: That or, alternatively, the more
severe the case, yes. Okay. And in terms of the reduction in the
incidence of PHN among those subjects who developed herpes zoster, what we see
here is a 38.5 percent reduction. So
this is among those with zoster, 38.5 percent reduction. In those 70 and older in whom the incidence
of PHN is greater, it is a 47 percent reduction in the incidence of PHN among
those who have developed herpes, excuse me, herpes zoster. So that is point number one.
Point
number two is an issue that Dr. Fleming had raised about the scores less than
3. And in the presentation this morning
I had commented on the fact that a number of sensitivity analyses had been
conducted and that those were virtually identical to the primary, and so I
would like to put up slide 630 which gives the sensitivity analyses on the
herpes zoster burden of illness and I would like to focus specifically on the
third line here, the MITT using the full AUC scale over the six month
follow-up.
And,
again, you see a point estimate of 61.2 percent, the same as what we had
overall. It does not address all of Dr.
Fleming's points, because the frequency of follow-up was less when pain was
less. Nobody was lost to follow-up, but
the frequencies were different. But in
terms of taking all of the scores that were obtained, there was no impact on
burden of illness.
The
third point that I think got lost was a question from Dr. Fleming on the 80
plus population. And we agree with Dr.
Fleming that there were 2,500 subjects enrolled, which was actually a fairly
sizeable population in this age group, and I would like to focus first on the
efficacy in this population because there had been questions about efficacy in
the older age group. So if we could
start first with herpes zoster on slide 248.
We
have the age stratification at 60 and 70.
We have further split this out not in five year increments, but at least
60s, 70s and then 80 plus. And what we
see here for the herpes zoster analysis is the 64 percent efficacy that we saw
earlier today and among the individuals 70 to 79, roughly 40 percent efficacy with
a lower bound of 27.6 percent.
And
for those over 80, the efficacy for herpes zoster did fall to 18.3 percent,
some reduction, but a confidence interval now below zero. We're dealing with a relatively small
percent, again about 7 percent of the overall population, and the study was not
powered to observe efficacy at this level.
But,
again, as you get older it's the pain that becomes more severe and adds even
more to the burden. And so if we could
pull up slide 250, please, which is on the herpes zoster burden of illness,
first we see that with the 61 percent overall, we have got 65.5 percent for the
60 to 69s, 59 percent, very well-preserved in the 70 to 79 group, and a point
estimate of 38 percent. So still
preservation on a very clinically meaningful and clinically important endpoint. Although, again with the small numbers, the
confidence interval going below zero.
Lastly,
on the PHN endpoint, slide 252, we have very good preservation of efficacy in
the older group, 74 percent, and with increasing numbers, tight confidence
intervals in the 70 to 79 group. Again,
somewhat lesser efficacy, point estimate 39 percent, with the wide confidence
intervals.
So
the conclusion from all of this is that whereas the incidence of disease and
the prevention of the herpes zoster is the critical parameter for the younger
cohort, in the older group who suffers disproportionately with severe and
long-lasting pain, the vaccine's effect is strong and persists for these
endpoints.
With
respect to safety, there is a question that also came up, and I would like to
put -- we have a question about the serious adverse experiences. So if we could get to slide S-2, please? This is the overall cohort and the split in
serious adverse experiences was 27 versus 21.
In
this slide we have it broken out by body system and it's a fairly symmetrical
mix here. I will get to the
cardiovascular in a second. The skins
were a couple of skin cancers. The
metabolic/nutritional were a couple of dehydrations. But, in general, for many of these serious
adverse experiences it was just one in one or the other groups.
Slide
S-1 gives the specific breakdown among the cardiovascular events, so if I could
get S-1. Oh, it's S-3 now. Okay.
What we have here is, again, a mix of different events. There were three atrial fibrillations, three
myocardial infarctions, but then there is a coronary occlusion in the other
group and one MI. So it does not look as
though there is any particular specific serious adverse event.
There
was among the individuals 80 years of age and older one possibly
vaccine-related serious adverse event.
It was an 80 year-old male who developed some symptoms shortly after
vaccination, was not diagnosed ultimately until about day 80 with polymyalgia
rheumatica. This is a fairly common
condition in older adults, often takes a long time until diagnosis, but that
was the only possibly vaccine-related event in that group.
The
next question is on persistence. The
question on persistence came up shortly before lunch. As I had mentioned, after zoster and after
vaccination, the immune markers tend to fall back toward baseline relatively
quickly and I would like to refocus the discussion for a moment on persistence
of efficacy, which in the end is what we really need to be thinking about.
So
if we could start with slide 704. There
is an analysis in the study report that was submitted in the dossier looking at
efficacy by year. We detected a drop, as
I pointed out in the presentation this morning, a drop in the first year
followed by steady decline. And so I'm
going to be showing you some tables now showing year-on-year, but also
splitting out the first year into months 1 through 6 and months 7 through 12.
So
here for incidence of herpes zoster, and we'll focus ourselves on the right
hand column of these slides for the vaccine efficacy, what we find is that in
the first six months postvaccination an observation that will recur in the next
several slides, which is 75 percent efficacy in that early time period.
In
the second half of year one we're at 51 percent, which by chance was exactly
the estimate that we saw over the entire period of follow-up and, as I think
you saw earlier in the day, that we have got point estimates of 47, 43, 51
throughout. So, really, from month seven
on there is no indication from the trend that there was any decrease or any
waning of the efficacy of the vaccine.
Now,
I would like to split this out by the two age cohorts, so if we could go to
708. This is the year-by-year efficacy
for herpes zoster in those 60 to 69 and you will note that there is actually no
drop-off at all in this younger cohort.
So this is, again, part of the 64 percent overall and persistence that
we think will be predictive of vaccination in the adult population under 70.
And
then for age 70 and up, slide 709, please, here we do, in fact, see a decline
from year one, 60 percent efficacy, relatively flat point estimates. We're dealing with smaller cuts of the
data. These confidence intervals do get
wider, but at least the trend among the point estimates is for stable efficacy
over time. So that is for herpes zoster.
Now,
if we could turn to 714, please, and we'll get to the PHN endpoint. Again, you'll recall 66.5 percent overall, 93
percent efficacy in the first six months following vaccination. Remember, smaller numbers here, fewer cases
of PHN, but again dropping somewhat in the second half of the first year. No clear pattern or suggestion that there is
a waning of efficacy. Directionally,
there is still a reduction in the vaccine group.
So
if we could then split this out by age.
718, please. Among those less
than 70 years of age, there were relatively few cases of PHN. You see very high point estimates the first
two years, small numbers, 4411 thereafter, but again getting to the important
point. In the older individuals, slide
719, where there is much more PHN, again very high efficacy in the first year,
83 percent, with very stable point estimates in excess of 50 percent from year
two and thereafter.
Lastly,
on the burden of illness, slide 724, 92 percent reduction in burden of illness
over the first six months dropping to 70 percent. And, again, you will recall the 61 percent
overall. From that point forward, one
sees again no indication of clear waning over time and we can cut this by age
also.
Slide
727, please. Burden of illness beginning
at 83 percent in the first year for the younger cohort and then the percentages
as shown, again not reflecting any clear waning. And, lastly, for 70 plus, a similar pattern
after year one, stable estimates at 40.
So
the last point that I would like to address refers to some of the safety
follow-up. There were a lot of questions
about that. I would like to call back
slide 36, the pie chart, from the main presentation.
You
will recall a number of 66 percent that was offered by CBER, which I think
reflects the green and the magenta, but the fact is that if we combine the
different means of follow-up, we come back to the fact that by one or another
of the methods, 93 percent of the subjects did have follow-up.
There
was a comment that these staff calls began or were clustered after day 50, and
that is because the ATRS was open to the subjects until day 50. When that day came and went, the sites
received faxes to inform them that the patients, the subjects, had not called
ATRS. And within virtually a week or 10
days thereafter, a large majority of the calls were made to follow-up where the
subjects had not.
Importantly,
the information that was captured, the script that was used by the sites in
their discussions with the patients, with the subjects, was exactly the script
that was used from the ATRS. And so the
follow-up was comprehensive and it was consistent across the population.
In
terms of timing, I would like to turn to slide 407, and this is the
distribution of staff calls for the routine cohorts, so these are the calls to
the ATRS. You will see that it was about
13 percent of the subjects overall, but a very large majority of these happened
before day 60.
And,
again, these would be clustered from day 51 to day 60 because of the way the
ATRS was structured, and it was a relatively small percentage of the overall
enrollment of 31,000 subjects who had any follow-up that was after day 60.
For
slide 408 we have got the follow-up to the faxes and, again, you see that a
large majority of these were occurring before day 60 shortly after the ATRS was
turned off for the subjects, only a little over 1 percent of the subjects
beyond that.
There
was a question about the demographics of these people who had the later
follow-up.
DR.
FLEMING: Could you go back a slide just
before we lose the thought?
DR.
SILBER: 407, is that --
DR.
FLEMING: I think it was the previous
slide to this.
DR.
SILBER: I'm sorry. I can't see who is even asking. Oh, okay.
DR.
FLEMING: Are these to be -- basically,
are the bottom five rows mutually exclusive as they appear to be and should
they add up to the staff called ATRS line?
DR.
SILBER: These --
DR.
FLEMING: I mean, I'm sorry, into the
placebo? Should the bottom five lines
add up? I think they do. The percentages don't add up.
DR.
SILBER: Should be.
DR.
FLEMING: Okay. All right.
DR.
SILBER: Should be.
DR.
FLEMING: Go ahead. The percentages don't add up, but go ahead.
DR.
SILBER: Maybe some rounding. Okay.
There was a question about the demographics and that is still being
looked at, but in terms of gender and age, and we are looking now at functional
status and other health markers, we have seen no differences at all yet among
any of these parameters for those who followed-up for safety in the various
different ways.
The
last point briefly was about opting out of the Adverse Event Monitoring
Substudy and we have Dr. Levin who could speak for the Shingles Prevention
Study investigators on this point.
DR.
LEVIN: Dr. Silber is correct in that
there was a delay until the sites got started, but once they were set and ready
to go, that the patients who were offered sequentially the opportunity to be in
the substudy, they were not selected.
And all I can report is in my experience and that of Dr. Oxman, who I
was in close contact with, that roughly 95 percent of people accepted it at
that time, and there was no bias in individuals not being in the study. Everybody who was offered it, essentially,
was willing to be in it. Questions?
DR.
FLEMING: You said everybody that was
offered was willing to be in it?
DR.
LEVIN: Well, 95 percent, and we had no
reason to believe that a select group of people were choosing not to be in, but
we don't --
DR.
FLEMING: And that choice was made at
time zero, at the very beginning?
DR.
LEVIN: At the time that they were
offered it.
DR.
FLEMING: And remind me, that time was?
DR.
LEVIN: At time zero. When they entered the larger study, they were
asked if they would be willing to be in the special substudy. I'm sorry, I can't speak for --
DR.
FLEMING: And people didn't drop out
beyond that point based on willingness to participate. So at time zero, 95 percent agreed to be in?
DR.
LEVIN: Now, that is my experience and
Dr. Oxman's. I can't speak for the other
sites and we do not have records on that, but that's our perception.
DR.
FLEMING: And once somebody was in, you
had or you retained them for long-term safety assessments in what fraction of
cases?
DR.
LEVIN: They were retained the way all
the other subjects were retained for the long-term assessment. Actually, they had more. They had additional follow-up and then all
hospitalizations as well were reported in that specific group. They were actually looked at more carefully.
But
I think your question was were they demographically different. We don't have specific records to that, but
there is no reason to think that they were selectively chosen or they
selectively chose to be in the substudy.
CHAIRMAN
OVERTURF: We can address further
questions to industry as we begin to discuss the questions, so I think I will
ask the FDA to come back and re-present the questions to us again.
DR.
SCHARFSTEIN: Could we ask a couple
questions of -- wait?
CHAIRMAN
OVERTURF: Let's wait a minute.
DR.
ROHAN: Once again, questions for the
Committee's consideration. No. 1. Are the available data adequate to support
the efficacy of ZOSTAVAX when administered to individuals 50 years of age and
older in: (a), preventing herpes zoster, (b), preventing postherpetic
neuralgia, preventing postherpetic neuralgia beyond the effect on the
prevention of herpes zoster, (c), decreasing the burden of illness, decreasing
the burden of illness beyond the effect on the prevention of herpes
zoster? If not, what additional
information should be provided?
Question
No. 2. Are the available data adequate
to support the safety of ZOSTAVAX when administered to individuals 50 years of
age and older? If not, what additional
information should be provided?
And
Question 3. Please, identify any other
issues that should be addressed, including post-licensure studies. In particular, please, address: (a), the use of the vaccine in persons with
co-morbid conditions, for example, those who might typically reside in assisted
living residences and nursing homes, (b), use of the vaccine among persons
taking chronic immunosuppressive therapies, including corticosteroids, (c), use
of the vaccine in certain subsets of the sponsor's proposed age indications,
for example, those 70 years of age and older, those 80 years of age and older,
(d), duration of immunity and, (e), the sponsor's proposed pharmacovigilance
plan.
CHAIRMAN
OVERTURF: So we will actually begin the
discussion and, at this time, if there are additional questions that the
Committee Members want to address to either the FDA or the sponsors, we have a
few more minutes to do that. Dr.
Markovitz?
MEMBER
MARKOVITZ: Yes. I would still like to get the take of the FDA
on, if there is someone who can speak to the idea when we addressed the 50 to
60 group in lieu of data, what considerations are there from an Agency point of
view, if someone can answer that.
CHAIRMAN
OVERTURF: Dr. Baylor?
DR.
BAYLOR: Norman Baylor, FDA. We would like you to try to address the
questions based on the data presented.
We really need the advice based on your interpretation of the data. I don't think you should use logic or gut
feelings so, please, use the data.
CHAIRMAN
OVERTURF: Yes, Dr. Word?
MEMBER
WORD: I just want to go back to the
issue with duration again. I know the
sponsor showed a slide, but I guess one of the questions I had, you know, if
you looked efficacy and they said in the 60 to 69 age range I think it was like
73 percent and maybe it dropped down to 38 percent in those older, so then I'm
looking at, well, that's when it was administered at 60.
If
they are proposing to administer at 50, do they anticipate that there is going
to be a change, that suddenly those numbers are going to drop or is there going
to be a point where you think that do I need a booster?
And
I guess the other part of the question I have is right now for individuals who
are born, I think it's after 1965, the adult immunizations recommend that they
all get varicella vaccine if they haven't had it. And so then do you have any information about
if they receive varicella and then you want to offer them this, because they
are close to that age group, what would you give them?
CHAIRMAN
OVERTURF: I'll let the sponsors answer
that. My own personal feeling on that
issue would be that, obviously, we need data in that regard. I mean, if we -- and, actually, I don't think
it's restricted to the population less than 50, because we only have data that
we're being presented today that is really, essentially, a four year period.
So
the issue, well, this obviously has to be part of the pharmacovigilance issue,
is to continue to look at that in order to justify the vaccine. Does the --
DR.
SILBER: Okay. I think I heard three questions, so I will
take them in turn.
In
terms of the expectations of what might happen at the age of 50, again, for the
herpes zoster incidence endpoint as we went out over time, we were at roughly
65 percent efficacy and stayed pretty much right there throughout the period of
observation. With the younger
individuals, younger immune system, we would expect that the durability of the
response should be at least as good, let us say as good, in the 50 to 59. So 60 to 69 experience we think will be
predictive in that regard.
With
respect to the possible need for a booster vaccination, which I think was your
second question, which is really a question whether one vaccinates at 50, at
60, at 70 or at any other age, that is not known at this time.
One
of the really critical questions that we're answering or hope to answer in the
persistence substudy of the Shingles Prevention Study is to take these people
out to 10 years, is the target right now, and to determine whether there is any
waning of efficacy at any point. Again,
after the initial drop, we have not seen that yet.
But
should that happen, what could be explored certainly is to define when or if a
booster is needed and then, if we use this population basically as a
bellwether, then we would be able to assess the potential benefits of booster
vaccination ahead of those populations who would be receiving vaccine in the
general marketplace later. So we don't
know but the persistence substudy, we hope, will give us that answer.
Lastly,
with respect to varicella vaccination and what advice -- I think the question
was what would the advice be if someone had varicella vaccine?
MEMBER
WORD: Right now in the adult
recommendations, now they point blank just put it in as a recommendation if you
didn't have varicella or if you were born after 1965, that you have to -- to
immunize them. So they are in your 50
year-old age range now.
DR.
SILBER: Right, yes. And what we know from the VARIVAX experience
is that the very large majority of the cases, of the doses of VARIVAX, have
been administered in childhood. We do
not have -- other than as part of our booster studies, we don't have data that
speak to the benefits of someone with prior varicella vaccination, but even in
that these were seropositives. And so it
will be some time until there will be a body of data really to be able to
answer that question.
CHAIRMAN
OVERTURF: Do you have a predefined
signal for lack of efficacy of the vaccine in those that you continue to follow
beyond? At this time, is there any
predefined signal or are you simply going to --
DR.
SILBER: This is something that will be
looked at by annual summaries and other than a signal of a lower bound of
efficacy falling below zero, there are no specific criteria at this time.
CHAIRMAN
OVERTURF: Dr. Fleming?
DR.
FLEMING: Could I have the FDA slide 47
which I will get to in a moment, but at least we can pull it up. My sense is you have shown us after the break
now quite an array of additional slides and I am not sure that too much of it
is what we hadn't already seen.
You
showed us a lot of slides on persistence of effect, which I don't think was
something we were challenging as controversial.
As your slides point out, in fact, your curves that you presented
earlier, S-48 and S-50, were very descriptive of how effect occurred over time
and did, in fact, show that it was a larger relative efficacy in the first six
months. In fact, what you didn't show is
it's probably even larger in the first three months and then after six months,
it seems to be fairly constant.
The
controversial issues are age, how is that an effect modifier for effect, and is
the BOI, which is intended to look at severity-by-duration beyond incidence,
telling us something beyond what just the incidence is telling us?
And
what your data seem to be showing us as it relates to age is that while we had
pooled ages 70 and above before, now when we're looking separately at 70 to 79
and greater than 80, there does seem to be a gradient for PHN by age as well as
for BOI. And we also see, as we had
already seen before, that at age 60 to 69, the BOI relative efficacy is the
same as the HZ relative efficacy.
In
terms of the explanation of the BOI, I don't contest what you were showing, but
it seems to be entirely consistent with what the FDA already showed in slide
47, which is that there is, in fact, the appearance of this number of people
that had very high scores that are more prevalent or predominant in the placebo
group.
Although,
if we go to the next group that you didn't go to, then there is a bit more of
those in the intervention arm, which is part of why a Log-Rank analysis is
going to be a little more sensitive than a Wilcoxon analysis. I actually -- oh, go ahead.
DR.
ROHAN: I wanted to make a comment at
this point. We had talked about the
PHN. The duration of follow-up was 182
days and there were equal proportions of the subjects followed in either the
vaccine or the treatment arm out to 182 days.
But
if you look at other increments in more the mid range, and I don't have those
data with me, there is some difference in the proportion of subjects being
followed and I think it would be important to look at the pain scores that had
been accrued at that point.
Obviously,
it's in an exploratory manner, but to look at the pain scores in the subjects
that were then lost to follow-up, didn't have complete follow-up, because if we
see, for example, half a dozen subjects in the zoster group that don't have that
sort of mid range follow-up that had scores in the hundreds and only one in the
placebo group or if we see a number of subjects in the placebo group that had
zero or very low scores and very few in the zoster group, that would also skew
this because the vast majority of the postherpetic neuralgia cases even in the
older subjects, they resolve after several weeks and a smaller proportion are
carried out --
DR.
FLEMING: Right, yes.
DR.
ROHAN: -- to 60 or 90 days.
DR.
FLEMING: Yes. Could you go to slide, your slide, 68, FDA
slide 68? You did answer one of the
questions I had asked the sponsor this morning and that is to give us
information on hospitalization and HZ-related hospitalization.
DR.
ROHAN: This is the sponsor's data
though, I will point out.
DR.
FLEMING: Okay. But you showed it so I'm asking you about
it. It's interesting to me how few of
all hospitalizations are HZ-related, so that at least as we look at what might
be an anticipated effect on something as significant as hospitalization
mediated through a vaccine effect on reducing HZ-related hospitalization, we
would expect almost no effect. And, of
course, we see almost no effect.
Hospitalizations in total are 22 in excess, which is entirely consistent
with random variability.
But,
basically, what this is telling me is we didn't reduce any HZ-related
hospitalizations but, then again, they are so incredibly infrequent I don't
suppose it really matters so much.
DR.
ROHAN: Well, I think that sort of speaks
to two different, I guess, factors. I
think, first of all, the question of the subjects that were enrolled and the
exclusion criteria, etcetera, I don't know if the burden in very ill subjects
that might not be candidate for this vaccine that might not be -- had been
enrolled might be a factor, but I also think it also speaks to Dr. Oxman and
his colleagues and the care that they have provided, keeping people out of the
hospital.
So
I think it's the investigators, as well, that deserve -- you know, maybe they
are sort of a victim of their own success in that respect, as well, and you
might not have seen this low hospitalization rate out in the general
community. You might have seen more
people hospitalized.
DR.
FLEMING: Well, they weren't keeping them
out of the hospital, 1,115, 1,137, but at least those people that would have
been HZ-related hospitalizations on placebo didn't --
DR.
ROHAN: That's what I was talking
about. I'm sorry.
DR.
FLEMING: So I take more your first point
to heart and that is we didn't look at a cohort here where in the placebo arm,
there was very much prevalence or incidence of HZ-related hospitalization and,
in turn, we didn't decrease it at all either.
DR.
ROHAN: I probably wasn't clear, but what
I meant was that I think that the health care that was provided in HZ-related
disease may have kept subjects out of the hospital, been more effective than
you might have seen in a community setting.
MEMBER
FARLEY: I would make a comment on that,
too. As a clinician, I think that the
idea that they were highly educated on the signs and symptoms of zoster and
that they were instructed to immediately consult their study physicians and
then they were given antivirals within this window, and I think these people
were cared for at a higher level at an earlier point on average for sure than
the general population.
DR.
FLEMING: But what all that would mean is
we can, in fact, do something about HZ-related hospitalizations. We don't need this vaccine to do it. We just need the kind of surveillance and
quality care that you have referred to.
Either
that is the conclusion or the conclusion is we didn't look at a sufficiently
high risk group. We excluded a lot of
the people that really would have been at risk and we never found out what the
efficacy was in that group.
CHAIRMAN
OVERTURF: Actually, that addresses one
of the subsets of the questions under Question 3, which is obviously the
patients. The vaccine use in patients
with co-morbid conditions and those taking corticosteroids has really not been
answered by this study and clearly is an issue that has to be addressed in any
post-licensure procedure, because it's clearly not asked. And it's actually the dilemma that we
actually still face somewhat with the varicella vaccine. Yes, Dr. Hetherington?
DR.
HETHERINGTON: I just want to come, I
think, to closure on some questions we had earlier about dosing and I'm sure
you have the information, but I'm not sure that we have finally come to
resolution.
And
that is, and I will try to ask it very specifically, what are your release
specifications going to be for the upper limit, if any, for the potency of
this? And I ask the question to try to
get some idea of what is the potential range of doses that one might get once
this is approved, assuming it's approved?
And in that range of potential doses that one would receive, would you
expect to see a difference in immune response?
Another
way to ask the same question is do you have any dose ranging data on immune
response over different plaque-forming unit doses and, in particular, how did
you come up with 19,000 as a minimum for your dose?
So
there's a number of questions in there, but I think it tries to get to the same
sort of understanding about the dose and the immune response.
DR.
SILBER: Well, I think there were two
main questions, so I will go to the second question first, which was with
respect to dose ranging and immune responses.
What
we saw in the early studies is that at the low end, basically the varicella,
the VARIVAX-type potencies, less than 10,000, that there was not a
response. We ended up getting a dose
response going up to about that 17,000/19,000 level that I had spoken to with
very little dose response beyond that.
In our studies conducted since then, there was likewise little dose
response over the range once you get into a range above what has been defined
as the expiry.
With
respect to specifications, the lower specification just is defined by the
efficacy study. The upper specification
would certainly be no higher than 207,000 plaque-forming units but will be an
ongoing discussion between us and the FDA.
DR.
HETHERINGTON: All right. So just a two pointed edge on it. The pharmacodynamic response, if I can borrow
that term, for immunogenicity, once you hit about 20,000 it's flat going above
that. And what you showed in your
high/low dose study shows that the relative safety and adverse event rates were
similar across the range that you just described.
DR.
SILBER: Yes. And perhaps even more importantly than immune
response over the range that was studied is the fact that the vaccine efficacy
appeared to be relatively flat over the ranges that were studied in the
efficacy study.
CHAIRMAN
OVERTURF: A somewhat related
question. What about the relationship
between pre-immunization antibody and adverse events? Was there a relationship between that,
particularly local reactions? Actually,
you implied that when you commented on the studies when there was a comment
made in patients who were 50, the 50 to 59 year-old age group, that there might
be a relationship.
DR.
SILBER: I'm not sure that we have
specific safety tables related to baseline titer, but in three of our studies
we had second doses, one at an interval of six weeks, one at an interval of
about two years, one at an interval of about eight years.
In
all of those the baseline titers were higher than we see in a typical
population receiving a first dose, and the second doses had safety profiles in
each case that were really the same as was seen with dose one.
CHAIRMAN
OVERTURF: Dr. Rowbotham?
DR.
ROWBOTHAM: I have a question that I
think would be good for Dr. Levin to comment on, and that is that it relates to
the hypothesis behind this as a treatment, and it doesn't seem to me that it
would be mutually exclusive for younger subjects who have younger immune
systems to have primarily a zoster prevention effect, but then in older
subjects who have greater immunosenescence to have less of a change in the
incidence of zoster, but a change in the natural history of zoster once they
get it, such that they might have a change in the burden of postherpetic
neuralgia.
DR.
LEVIN: So the question is why do we see
this difference between the young-old people and the old-old people? Well, I don't know the answer, but the way I
look at it is that in the younger people, they have a more vigorous immune
response and actually you can show that and, therefore, they have a memory
component, a T-cell memory cell response to VZV, that when they reactivate it
quickly comes to the fore and the reactivation is often subclinical. You don't see anything. If they do have disease, it will tend to be
mild because they have responded so quickly.
In
the older individual, there is a delay or they don't mobilize their memory
response to reactivation so quickly. The
virus takes hold. It does
reactivate. You do have some zoster, but
then it comes to the fore more quickly than in someone not vaccinated and it
limits the disease or attenuates it. And
I think that concept fits perfectly with both the efficacy and the immunologic
data that we have.
CHAIRMAN
OVERTURF: Would any other Member of the
Committee like to address any of the specific questions? Dr. Wharton, you had a question.
DR.
WHARTON: This is not related to FDA-specific
questions, but I have two questions I would like to ask the sponsor.
Was
the information collected on the vaccine safety card and in the 48 day
telephone call follow-up comparable since they are apparently being used
interchangeably as far as safety follow-up is concerned and, specifically, do
they both collect information on hospitalization and medical encounters during
that 42 day period?
The
second question I have has to do with postmarketing surveillance. Once this vaccine is in use in an older
population with a high level of co-morbidity, I can anticipate that there will
be deaths that occur among recently vaccinated persons and would like to know
what plans the sponsor has that will help evaluate such episodes when they
occur.
DR.
SILBER: Okay. I will address the first question and someone
else will get up to address the second question with regard to postmarketing
safety.
With
respect to the follow-up information, again, the follow-up information for
those events that were defined by the typical -- by the ICH and in GCP as
serious adverse experiences were collected uniformly, consistently the same way
from everybody.
So
those questions were asked in the vaccination report card. They were part of the script. They were part of the follow-up, in fact did
not have to happen and it was encouraged not to happen at the end of 42 days,
but all serious adverse experiences were to be -- were asked to be reported as
soon as possible after onset.
So
in terms of that sort of safety follow-up, the mechanisms were the same in all
types of follow-up, whether diary or otherwise.
And I think Dr. Gutsch will get up to talk about the post-licensure.
DR.
GUTSCH: Yes. Our post-licensure plans build upon the
experience that you have all heard about today with the Zoster Program and upon
the experience with the VARIVAX Program using the same active component in over
56 million subjects.
In
the placebo-controlled trial for ZOSTAVAX in which no specific adverse
experience was identified as being clinically significant for follow-up, we
have a great safety profile and we have reasonable power, 97.5 percent power,
to detect an adverse experience with a frequency of about 5,500. So this trial gives us a good backdrop going
into the postmarketing period.
In
addition, we're going to have an additional opportunity to look at the safety
in another 17,000 or 18,000 when you combine the Shingles Prevention Study and
Protocol 007 in which the placebo recipients are going to be vaccinated.
In
addition, we plan to conduct surveillance in the marketplace looking for
signals as they are developed and in those instances where some signal might
arise from our surveillance systems that are in place, we plan to evaluate
those, discuss those with the Agency and, where necessary, adjust the label
accordingly.
I
think that other than the other things that I mentioned about the
identification program to try and get a handle on any AEs and whether they
might be related to vaccine and placebo constitutes the package of what is
coming up.
And
then there's a few other studies that are in place, which we mentioned earlier
the Concomitant Use Study and the Bridging Study for a new formulation, which
are ongoing. In those studies we are now
enrolling subjects 50 to 59 in addition to the older age cohorts so that we'll
get additional data in those groups.
And
I might add we have also made an effort and are having some success in
increasing the minority representation in those studies. So that constitutes the plans that we have.
CHAIRMAN
OVERTURF: What is the cohort size over
80 in that placebo group? Do we know,
have an estimate, since that was a specific previous question?
DR.
SILBER: I think that the number enrolled
in the study over 80 was about 2,500 and so it's about 1,250 additional vaccine
recipients now through this follow-up.
CHAIRMAN
OVERTURF: Dr. Fleming, you had a
question.
DR.
FLEMING: A question for the FDA. Could I get FDA slide 60, please? And while that is coming up, a quick question
for the sponsor. I am pleased that you
had a Data Monitoring Committee in place.
I am concerned, if not disturbed, that they didn't routinely
automatically have unblinded data from the beginning of the trial.
My
question is was this a fully independent committee? Were the members of the DMC fully independent
of the sponsor?
DR.
SILBER: The DSMB met periodically
throughout the course of the study.
DR.
FLEMING: That's not my question. Just simply, were they independent?
DR.
SILBER: I'm sorry? They were completely independent.
DR.
FLEMING: Completely independent.
DR.
SILBER: In fact, you are here today
because of one of the independent people, I think, who served on the committee.
DR.
FLEMING: Okay. So all members of the committee were independent?
DR.
SILBER: Everybody. Yes, they were all external, independent
members.
DR.
FLEMING: Then a question for the sponsor
relating to slide 60 or, excuse me, a question for the FDA for slide 60. In the FDA presentation, you don't have to
show it, in slide 83 you say the completeness of safety ATRS and study
termination follow-up is unclear.
And
I find myself still struggling to understand the level of completeness that we
can be assured has been achieved by the nature of the surveillance, so I think
it's slide 60 that you have that I wanted to go to. And I always think of a threshold or a
tolerance level for safety in a benefit to risk fashion.
And
so what is the benefit here? The benefit
appears to be per 1,000 person-years a reduction of 5.7 HZ cases and a little
less than one per 1,000 person-years PHN cases, none translating at least in
this study into something as significant as reducing hospitalization. So clinically meaningful events, quite infrequent
in their occurrence, are being reduced something on the order of 50 percent.
It
makes me, from my perspective, believe that understanding safety with great
thoroughness is important to make sure that benefit to risk is favorable and,
as you have noted here on this slide as well as on the slide that I was quoting
from, 83, that were reliant on a fair level of what we might call passive
surveillance.
The
sponsor again just echoed the rule of 3, i.e., assuming that you look at 19,000
people, we can rule out events that would occur in one in 5,500. Assuming we didn't see any such events, then
we can rule out rates at that level under the assumption that were such an
event to occur, we would capture it and that subtle, if not not-subtle,
assumption is there.
How
confident are you? You know the data
better than I. You know the system
better than I do. How confident are you
that this system that has a non-trivial amount of passive surveillance with a
fairly low threshold level for safety, given the nature of efficacy, can be
reliably capturing events that, if they were occurring, would in fact
meaningfully impact benefit to risk assessment?
DR.
ROHAN: I guess one of the issues is
looking at the vaccine report cards versus the ATRS safety data. The ATRS specifically queried for these things.
The
vaccine report card, and this is part of sort of human nature, if you will, as
well, specifically asked for local reactions through day 4, specifically
queried for temperature through day 21, and then if subjects felt that they
were feverish or felt their temperature was abnormal, they could record their
temperature and it also allowed them to record unusual or other events, but it
didn't specifically ask were you hospitalized, I don't believe.
I
don't believe that it asked these specific questions. So I would think that -- I would be concerned
that subjects will be focusing on the first four days of local reactions and
temperatures for 21 days every day and that what they reported in the vaccine
report card, the rates, etcetera, might differ from the data in similar
subjects reporting to the ATRS follow-up, and I am not sure.
I,
you know, saw the slides that the sponsor put up. This is from the data set that they provided
with us and, as I said, the 4,639 are not all clustered between day 51 and 60,
but they go out for several years and there are hundreds and hundreds of people
in the second and the third year being added into the database and I don't know
what to make of that.
The
sponsor has told me that there is no window for the day 42 safety follow-up
and, as you can see, people are being enrolled before they were vaccinated,
which I take day minus 5 in the first couple weeks, and I don't know if that
data is the same as data at two years or three years involving the 42 day
follow-up period. So that is an issue.
I
don't know how many people are actually calling in on the monthly phone calls,
how many of the subjects are having data entered by the investigator, the
investigator's site, by month. And,
obviously, subjects were followed for an average of three years but many were
followed for about two. Some were
followed out to five, so there is a variety of issues.
DR.
FLEMING: And this is just about three
quarters of the study, i.e., when you add up all these numbers this is about
three quarters. This is about 28,033.
DR.
ROHAN: 66 percent of the total
population.
DR.
FLEMING: Okay.
DR.
ROHAN: 55 from the subjects calling.
DR.
FLEMING: Plus 11 percent.
DR.
ROHAN: 11 from data being entered.
DR.
SILBER: Can I clarify?
CHAIRMAN
OVERTURF: Yes, please.
DR.
SILBER: First to Dr. Fleming's
comment. This was active safety
follow-up of all subjects through day 42, all subjects in the AE Monitoring
Substudy, all subjects in the routine monitoring cohort.
The
passive surveillance for vaccine-related serious adverse experiences and deaths
is as is done in all studies. It does
become passive beyond that point. The 66
percent figure, again, does not include the 16 or 17 percent with vaccination
report cards and again --
DR.
FLEMING: Plus the gray region, right,
your 11 percent?
DR.
SILBER: Well, the magenta and the gray
were some of these that -- again, as I showed right after the lunch break,
about 80 to 90 percent of the magenta and the gray were between day 51 or at
least prior to day 60. And the total
before 60 was, again, 93 percent across the entire study of both cohorts.
With
respect to these calls that may have gone out beyond day 60 or day 90 or the
ones that came before day 42, this table is not one per subject. These are all contacts. So if somebody called the ATRS or there was
some other contact for an AE on day 6 and then there was another one on day 44,
this would show up twice.
DR.
FLEMING: That's why this is only 66 and
not 75 percent.
DR.
ROHAN: Right. And, in fact, many subjects had two or more,
up to six additional entries, so some people had seven entries in the day 42
safety data set and this could occur at day 42, a year later, two years
later. There are additional entries
being put into this data set for a particular subject.
DR.
FLEMING: With, approximately, 1,600
people who died. Certainly, that also
impacts the nature of safety information we would get from those. Can you comment on that?
DR.
ROHAN: Because there was an anticipated
relatively high rate of deaths in this particular population, deaths were
monitored but narratives and further details weren't necessarily
collected. They were collected in the
first 42 days with the follow-up of serious adverse events, so we have more
confidence, more knowledge about that time period.
But
overall deaths and I guess you could also say that deaths that occurred within
the day 42 day period might take longer to be reported since the subject
themselves had died, you know, that kind of thing.
CHAIRMAN
OVERTURF: Dr. Farley?
MEMBER
FARLEY: Can I ask a quick follow-up to
this? Can you tell us what the study
termination follow-up was to be? And I
think if I remember your report, it was missing in a high proportion. How important is that? What was that going to provide us and should
we be concerned at all about that?
DR.
ROHAN: Well, we recently actually have
gotten a little bit of clarification on the termination procedures. Subjects were contacted. There was a determination of whether the
subject had been immunocompromised during the study or at study termination,
whether they had developed herpes zoster or PHN, whether they had died and, if
so, there were additional data elements that were included at that point.
MEMBER
FARLEY: But was it, in fact, missing in
the very high proportion of cases?
DR.
ROHAN: We recently became -- I guess
were in discussions. I guess it was
clarified why those elements were not filled in and that the data resides in a
different -- in a column rather than in the row that is left blank, that the
actual date is actually in a column that is not called date of last contact.
It's
called exam date. So even though the
question with when was the subject last contacted is left blank in the majority
of the cases, the information is in a column that is termed exam date, but we
just were informed of this a couple of days ago.
CHAIRMAN
OVERTURF: Yes, Dr. Rowbotham?
DR.
ROWBOTHAM: I have a couple of
questions. One is related to the issue
of vaccinating patients in the 50 to 59 age group. So from the earlier discussion and Dr.
Levin's comment, one would expect that in that group you would primarily see an
effect on preventing zoster and perhaps even less of an effect on zoster pain
or development of postherpetic neuralgia.
And
the other thing that came out of the data presented earlier is that if you get
zoster, the amount of immune response, the ELISA titers, is much, much greater
than what is achieved with the vaccination.
So
if you are vaccinating people in the age 50 to 59 category and at this point
don't know how long that protection is going to last, especially compared to
getting zoster in your 50s when the risk of postherpetic neuralgia is lower, we
may not be doing the patients that much of a favor by shifting their zoster
episode from the mid 50s to their mid 60s or into their 70s without knowing
when would be an appropriate date to give follow-up vaccinations.
The
other aspect is that in the younger population, since there is a lower risk of
zoster in the first place, the issue of risks and the vaccination becomes more
important and that you make it closer to the risk of the vaccination being
close to the risk of just having zoster during that decade, and we don't have a
lot of information about that.
CHAIRMAN
OVERTURF: That actually begins to
address the first question, but I would echo that I think there is considerable
issues concerning immunization of individuals 50 to 59 without -- and I think
it's clear that there are not data that clearly support that. And, although I appreciate what the sponsor
has initiated, I think there are problems in trying to make a recommendation
for that group.
DR.
SCHARFSTEIN: I would like to come back
to an issue I raised before and maybe I can just get a yes or no answer to this
regarding PHN and both BOI depend upon the quality of the pain data.
Can
you assure me that the pain data is of high quality and there is not a lot of
missing data, so that we're actually getting proper measures of PHN and BOI?
DR.
ROHAN: I believe that there was about 91
percent 182 day follow-up in the PHN cases, so follow-up over that period, but
in the intermediate periods, which I don't have that data, there are some
differences. Whether they are clinically
significant, etcetera, this is obviously going to be exploratory but, you know,
it would be, I think, important to look to see if there were more cases in the
ZOSTAVAX group with higher AUCs, up to the point where they were missing and at
what point they became missing versus the placebo.
DR.
SCHARFSTEIN: All right. So to define AUC, you have to have --
DR.
ROHAN: A time.
DR.
SCHARFSTEIN: -- to be following. Keep a complete follow-up.
DR.
ROHAN: Right.
DR.
SCHARFSTEIN: So there's probably very
few people who have complete follow-up over that time period. I don't know.
We haven't seen any of the data.
So two of our endpoints critically depend upon the quality. Yes, you have the data? Do you have it?
DR.
SILBER: Yes. Actually, I would like to just clarify one
other point. Again, in terms of the
termination interview, 95 percent of the subjects enrolled in the study
completed a termination interview. 4 percent
died. Less than 1 percent were lost and
so did not have follow-up. Month by
month, a very large majority had ongoing follow-up throughout.
So
now, if I could turn to slide 1501. I
think this speaks to the issue of follow-up.
And I think it's important to realize people were not lost to follow-up. What happened was the pain fell below a
certain level, so the frequency of visits decreased. At any given time point for a particular
visit, about 90 percent were at a visit and the BOI does cover the entire
period.
What
we see here, again, is that 91 percent completed. Another 5 percent were within a stone's throw
of 182 days by having at least 175 days.
We're talking about roughly 5 percent who had incomplete follow-up and,
among the 33 out of the 950 or so, there were 11 deaths. And, as you can see here, among the individuals,
several of them had a healed rash and a score of 1 or lower at the last visit
and then there were just a little handful who had no follow-up.
DR.
SCHARFSTEIN: So when I see more than 100
-- put that back up. When I see more
than 182 days, does that mean the person was around the whole time and
reporting at all your visits or does that mean oh, that person only came in
twice before 182 days, but I saw him at 190 days?
DR.
SILBER: No. What happens is the primary analysis
truncated at 182 days. Those who had
ongoing pain due to PHN continued to be followed beyond the six months.
DR.
SCHARFSTEIN: When I look at the people,
the 287 people who had more than 182 days --
DR.
SILBER: It may have been 183, 184.
DR.
SCHARFSTEIN: I understand, but does that
mean that they reported at -- you have to measure the pain, right, a bunch of
times. I mean, is it reported every time
during that period? Probably not.
DR.
SILBER: It was about 80 or 90 percent of
the time points, I think, were covered.
DR.
SCHARFSTEIN: At each individual time
point, right?
DR.
FLEMING: That is a key point that Dan is
asking. It's not enough just to know
that 90 percent had at least an assessment.
It's important to know how many people, what fraction of all assessments
were, in fact, captured.
DR.
CHAN: During the course of the six month
follow-up, on the average around 80 to 85 percent of the subjects that have the
mandatory visits that they are supposed to come in for the pain measures. And at the last visit, as Jeff just showed
you, pretty much over 90 percent have the complete follow-up at the last visit
besides those who don't have pain follow-up, about two and four in each group.
DR.
FLEMING: 20 percent missing. This is pretty high.
DR.
SCHARFSTEIN: I don't think that answers
the question. I mean, he said that 80
percent of the people had complete data in every one of the monitored visits up
until 182 days?
DR.
FLEMING: Can he repeat? I thought you were saying 82 percent of all
visits that were to be performed were performed. What?
Could you repeat what you are saying?
DR.
CHAN: On average for a given visit,
around 80 to 85 percent of the zoster cases came back for their visits. Sometimes, some of these visits are on a
weekly schedule. So if they are off by
one day, they got slotted into the next schedule which is the next week.
DR.
FLEMING: So much less than 80 percent
had all visits.
PARTICIPANT: Much less.
DR.
FLEMING: Yes.
DR.
SCHARFSTEIN: At each visit, you said 85
percent of the people showed up, right?
Is that what you said?
DR.
CHAN: Right, of all --
DR.
SCHARFSTEIN: In order to calculate AUC,
you have to have information at all the visits, that for which they are --
DR.
CHAN: Say if somebody skip a visit and
have to visit on prior on the next --
DR.
SCHARFSTEIN: Then you just extrapolate
between the two.
DR.
CHAN: Exactly.
DR.
SCHARFSTEIN: Right.
DR.
CHAN: And that is sort of a --
DR.
SCHARFSTEIN: So some people you're just
extrapolating from one missed visit, some you're extrapolating for two missed
visits. Some you are extrapolating for
five missed visits. Right?
DR.
CHAN: That is the method of calculating
the AUC, is really just not all the subject have the pain scores from every day
of the visit. So by design, that is the
way that AUC was constructed, yes.
CHAIRMAN
OVERTURF: Dr. Royal?
MEMBER
ROYAL: I have a question about just pain
itself. And granted, to just look at
pain scores you're leaving out some parameters that are going to be important
to a quality of a person's life. But
when you compare just the pain scores themselves initially and at the end of
follow-up, what do you see when you look at the two groups?
How
do they compare? How does the
distribution compare? And, specifically,
those who are considered to have significant pain, what sort of comparative
distribution do you see?
DR.
ROHAN: I don't think that the study
specifically -- and, again, I think you had asked this before and probably I
didn't actually answer the question.
Hopefully, I can now. I don't
think that the study was designed to look at different gradations of pain. Anyone that had a score -- all scores up to
the first 30 days after rash onset were counted.
Scores
of 3 and above on the 10 point scale were counted at time points after 30 days,
but I don't think that there was any kind of analysis done on people with the
highest pain scores. There were many
instruments that were administered with quality of life, health care
utilization, etcetera, that were monitored during the study though.
So
it was fairly extensive as far as the impact of the disease not just in
pain. And although a lot of our
conversations have focused on the pain and the area under the curve, really the
sponsor looked at every imaginable impact in people's life, quality of life,
pain medication usage, etcetera.
MEMBER
ROYAL: My understanding is that pain
scores were collected for every patient at every reporting point during the
study. So one should be able to know
what the individual scores were, what the median, the range for the group --
DR.
ROHAN: We do have that.
MEMBER
ROYAL: And you should be able to make
those comparisons.
DR.
CHAN: Slide No. 39. Dr. Ahnn, could you?
DR.
AHNN: Yes, that --
DR.
ROHAN: And I presented this earlier, so
this gives you an idea of the mean.
DR.
AHNN: Yes.
DR.
ROHAN: Worst pain at these various time
points.
DR.
AHNN: We kind of omit the number of
subjects who actually take the questionnaire.
So, for example, the day 1 in placebo group, there are like 58 patients
who answered the IZIQ, the initial questionnaire out of 642. And the day 1, I mean, the day 2, the next
day of the rash onset, 158 patient out of 642 HZ cases actually answer either
IZIQ or ZDPI, mostly I think IZIQ. And
day 3, 242 placebo HZ cases had answered the questionnaire out of 642 HZ cases.
So,
you know, I don't think, you know, everybody who developed HZ has same number
of questionnaires answered. You know,
it's very variable.
DR.
SCHARFSTEIN: Some of that is structural,
right, because --
DR.
AHNN: Yes.
DR.
SCHARFSTEIN: Some of that is
structural. The question is what is the
unstructured level of missingness in the study?
DR.
AHNN: You know, the data like 642 HZ
cases in the placebo group and all other like, you know, all others are
structural zero. But even with those,
among those 642 cases, there are still, you know, the area under the curve zero
because they didn't develop any pain at all.
So,
also, that's the same for the ZOSTAVAX group, too. That's the real zero and mostly others are
structural zero like automatic zero in terms of the area under the curve.
CHAIRMAN
OVERTURF: Dr. Farley?
MEMBER
FARLEY: I wonder if you could clarify
again for us the definition that changed in the course of the study that I --
as I recall, it was for postherpetic neuralgia and the time frame, it was
earlier. It had been planned to be 30
days, I think, and it was changed to 90 days.
Can
you just help us understand why that change was made halfway through and if
that is something that we should be thinking harder about?
DR.
ROHAN: I guess I would let the sponsor
answer the question, but the change was made after the last HZ case was
accrued. The study was completed and
terminated about six months after the last case was accrued, but the change was
made after the last case.
DR.
SILBER: The question relates to it was a
protocol amendment to. This was actually
generated, I think, at the request of the DSMB quite a time before that and Merck
and the VA -- and this was based on emerging literature among pain experts and
in the medical field that the definition of PHN was, in fact, evolving and that
the concept of acute and chronic pain was changing.
And,
in fact, there was much debate as to whether the change should be to 90 or 120
days. In fact, two members of the DSMB
are part of the literature that has emerged on this. And if we could go to slide 623, please.
So
this was something that was discussed amongst us and then in the end submitted
to the FDA about the time the last case was accruing, but prior to unblinding
of the data. And I had mentioned earlier
when I went through the primary PHN analysis that a sensitivity analysis using
different time points had, essentially, the same information.
What
we have here is that with each successively later time point, the point
estimate for efficacy goes incrementally up a little bit. At the same time, there are fewer subjects at
the time points and so the lower bound of the confidence interval remains the
same. But this is a change that, again
was driven by the DSMB and was driven by an evolution in the medical literature
and the understanding of pain in the community.
And
then if I could just turn to 625 for a moment, I would like to try to get back
to Dr. Royal's question. I'm not sure if
this quite gets there, but if we take sort of in the theme of levels of pain,
this slide shows the different time points.
And,
also, if we were to use a cutoff of 2 or a cutoff of 4, and again what we see,
as we have seen as a recurring theme, set the bar higher. Use a level of 4 and relative to what we saw
with the cutoff of 3 or now the cutoff of 2, the vaccine effect is just a
smidgen higher.
CHAIRMAN
OVERTURF: Dr. Scharfstein?
DR.
ROHAN: I just had one comment. In changing the definition of PHN, the
sponsor specified that the point estimate had to be at least 62 percent for
this endpoint. And you can see that from
the slides that were previously presented, at day 30 and day 60, that endpoint
would have failed based on the specified endpoint of at least 62 percent. So it was changed to 90 that if you look at
the time course, that's the first point at which it was above 62 percent.
CHAIRMAN
OVERTURF: Dr. Scharfstein?
DR.
SILBER: If I may clarify. The time point and the point estimate were
actually changed in concert and so if the 30 day time point had remained the
point estimate observed at 30 and 60, it would have met the original criterion
and so --
DR.
ROHAN: But the original criteria did not
include a point estimate, I believe. It
did? It was -- excuse me? 59 percent.
So I guess, obviously, what -- the minimum efficacy that is expected
depends on when you see it. But, again,
it was changed after the last case was accrued.
CHAIRMAN
OVERTURF: Dr. Scharfstein, you had a
comment.
DR.
SCHARFSTEIN: This is a naive
question. Is it possible that the effect
of this vaccine is not to prevent herpes zoster, but to just prolong its
occurrence?
PARTICIPANT: No, sir.
DR.
SCHARFSTEIN: Because it shifts the time
at which you would get herpes zoster, so we have only got three years of
follow-up on each patient.
CHAIRMAN
OVERTURF: Actually, that issue has been
raised already, I think, and I raised it.
DR.
SCHARFSTEIN: Yes.
CHAIRMAN
OVERTURF: All right. Thanks.
DR.
SCHARFSTEIN: Do you want another answer?
CHAIRMAN
OVERTURF: Yes, but I think the sponsor
might want to answer that.
DR.
SCHARFSTEIN: Well, are you satisfied
with the response?
DR.
SILBER: Well, although it's certainly
reasonable that the vaccine efficacy might wane over time, we have not seen
this and this again being a memory response, people are boosting due to
endogenous and exogenous exposure to the virus all the time. One would expect that this T-dependent
response would come back with a subsequent vaccination.
In
fact, booster vaccinations or a two- dose regimen in a short period have shown
that the response does, in fact, come back to the level seen after a first
dose. So we would anticipate that should
the data evolve to demonstrate that there is waning efficacy, that there would
be benefits from a subsequent dose.
CHAIRMAN
OVERTURF: Yes. I think actually that addresses actually a
couple of questions we have not addressed in the 3(c) and (d), which is that I
think post-licensure studies have got to include some component of active
surveillance or relatively active surveillance to look at this issue, because
we really have a four year period of duration right now in any age group.
And
it will require, I think, some continued look at this because I think the
question you asked is pertinent and relevant to what we are all
considering. So I think that we will
probably agree, unless somebody disagrees, that some active component or some active
subset needs to be continued to be looked at very actively. This may be done in a number of settings.
We
talked yesterday about using VSD data to look at this, which would be one
active component, and obviously there will be -- it might be actually included
in the vero subset, which is the occurrence of herpes zoster following -- it
should be reporting of herpes zoster following the receipt of the vaccine ought
to be part of the vero subset as well.
Yes, Dr. Gellin?
DR.
GELLIN: I want to go back in follow-up
to a question that Monica started about the medical care of the patients or the
subjects in this, and that we heard early on the medical need for this vaccine
was because there was -- available therapies had limitations, but built into this
was both pain management and antivirals.
Now,
I wonder what we have learned about modern day intervention of ready access to
these through this trial.
CHAIRMAN
OVERTURF: Clearly, it was a benefit of
the trial, I think. I think they have
made that point, was that enrollment in this trial actually enrolled you in
some very good pain management.
DR.
SILBER: Obviously, the trial is not
designed to look at the treatment of herpes zoster. But when we look at the fraction of
individuals who received antivirals, who received anticonvulsant medication
such as gabapentin, who received opiates, and when we compare that with large
databases that look across a general population, the frequency of use of all of
these medications was actually substantially higher than is seen in general
medical practice, so again speaks to the level of care across all of the
subjects, vaccine and placebo recipients who might have developed zoster.
CHAIRMAN
OVERTURF: Dr. Fleming?
DR.
FLEMING: I was actually going to wait to
make this comment until we were answering the question, but I think our
colleagues have raised this issue and it maybe is better to have it open in the
discussion.
And
I would like to just pursue a little bit further the idea of might we be
delaying? And to the credit of this
trial, it provides very good data in terms of durability of effects out to
three to four years, but this issue of whether we are allowing people to remain
at risk to a later point in time is certainly a very relevant one.
The
data that we see indicates that there is a substantial immune response that is
provided by the vaccine, but roughly in terms of geometric mean titer ratios,
twice that that comes from an actual case of herpes zoster. And so the question that I might wonder, is
herpes zoster the best approach to protect against a PHN case?
Well,
the issue is not if there is, in fact, a risk of a PHN case when you have
herpes zoster, but the data that are fascinating that the sponsor has put
forward is where you have high levels of risk of herpes zoster relative to risk
of PHN is in your 50s.
And
if you have 1,000 people and, based on the data, maybe if the sponsor said 300
of them over a 25 to 30 year period would, in fact, be at risk for a case of
herpes zoster, during that first decade of the 50s, if you start at age 50 for
example, you're accumulating five to six cases per year that you're
preventing. That adds up to 50 to 60
cases out of those 300.
Would
it have been better for those people to have, in fact, had cases of herpes
zoster where they are at, essentially, no risk for PHN, and this is a question
specific to starting in your 50s, rather than to allow those or are you better
to prevent those cases or allow them to occur when the PHN risk is going to be
low in your 50s?
DR.
WHARTON: I would point out that in
otherwise immunocompetent subjects, once you have a case of herpes zoster, your
risk for having a subsequent episode is 5 percent or less based on literature.
DR.
FLEMING: Precisely. Therein lies the issue we're discussing.
CHAIRMAN
OVERTURF: Any further questions,
comments? Dr. Hetherington?
DR.
HETHERINGTON: I apologize if this was
covered previously, but did you look at the use of pain medications across
treatment arms as a potential confounding factor in the pain assessment?
DR.
CHAN: So your question is whether we
have looked at the pain medication uses as part of the assessment of vaccine
efficacy. We did. Obviously, when we look at the zoster
endpoint, the pain medication don't come into the picture because all those
come after the zoster surveys.
When
we look at the supportive analysis in terms of the severity-by-duration of
zoster pain among the cases, we did take that into account, and all we found is
in general the pain medication uses are very balanced between the two groups
and there is no effect on the vaccine effects because of use of the antiviral
or pain medications.
DR.
SILBER: I would like to get back to Dr.
Fleming's point again about the potential for delaying. The evidence that we have is that the vaccine
effect is durable and, although people in the 50 to 59 age group do not have
PHN at the rate that older individuals do, they have often very severe, acute
pain.
200,000
people a year have acute herpes zoster in this age group with severe pain. The rate of complications, other than PHN, is
about as high in people 50 to 59, including the ocular and other potentially
severe complications and so --
DR.
FLEMING: Then why weren't they included
in the trial? If it's so obvious that
these people are at such considerable risk and potential for benefit, why
weren't they in your trial?
DR.
SILBER: Well, again, to go back to the
original point, that the primary benefit that we would anticipate to see in the
younger individuals is from prevention of the episode outright. The scientific information available to Merck
and the VA in 1997 when this trial was initiated, in 1992 and 1994 when the
protocol was drafted was that the vaccination could not accomplish that.
Further
to the point, even if the vaccine at some point wanes and is not durable, that
doesn't mean there is no benefit to the individuals. And, again, what we have seen in three
different studies with second vaccinations and as we would anticipate since
this virus is kept quiescent for many years is that immunologic boosting that
could eventually be given with a second dose, if necessary, would biologically
plausibly prevent that episode from happening at a later time.
CHAIRMAN
OVERTURF: I would agree that it's
biologically plausible, but the issue really is why wasn't it studied? If it was part of the original hypothesis,
then it should have been studied. And,
obviously, you have explained a little bit why it was not and I'm sympathetic
with that, and I think the issue is almost more of a public health issue at
this point.
This
is going to be an issue about how best to control herpes zoster in this
population, and I think the question before the Committee to me is do we have
data to support this method of control for this public health problem? Dr. Royal?
MEMBER
ROYAL: Just going back a minute to
potential effects of treatment of individual patients on some of the parameters
that you measured.
Is
there any reason to think that patients who are treated with an antiviral might
have had some differential difference in the frequency with which you isolated
your vaccine strain virus versus non-vaccine strain from the lesions
themselves? So I believe you found your
vaccine strain in two patients, in lesions from two patients, but not in the
rest.
Do
you think that their being on an antiretroviral would affect that at all?
DR.
SILBER: The question refers to the
isolation of the VZV in the PCR. I think
we may be dealing with two separate issues.
In the Shingles Prevention Study, the Oka strain was not seen in any
individuals during the efficacy follow-up.
All of the cases of zoster that occurred were with wild type. All of the rashes that occurred that had
specimens within 42 days were wild type.
In
two other trials, one subject each developed -- among those with VZV-like
rashes, there was these two individuals who had rashes from whom the PCRs
disclosed Oka strain. In one case it was
a 92 year-old man who had just a few, some papular lesions 17 days postvaccination,
in the other study a 23 year-old female from the VARIVAX study who was
seropositive and had some lesions about a week after vaccination. So this was in the immediate postvaccination
period.
DR.
GUTSCH: One other point to this question
is that the samples for PCR were collected before acyclovir was being
administered.
CHAIRMAN
OVERTURF: Dr. Markovitz?
MEMBER
MARKOVITZ: I'm curious how the decision
was originally made to only give one dose of the vaccine. It seems like, you know, you obviously have
efficacy in certain populations. I'm
wondering why a booster given a month later or something wasn't pursued. I know you did that in some of your earlier
studies, but I'm curious why that strategy fell by the wayside.
DR.
SILBER: A question about the single dose
regimen. Again, the studies that had
been conducted previously and, in fact, the studies that have been done
subsequently have indicated that there was not further immunologic benefit from
a second dose, that it got back to where you were with dose one. Now, whether that could translate into some
qualitative difference was not studied.
CHAIRMAN
OVERTURF: Hearing no further questions
or comments from the Committee, I think we'll progress to the main questions
and we're instructed to answer these questions as they are asked.
If
there are portions of the question that any given Committee Member, when
polled, disagreed with, please, state your reasons and provide input to the FDA
on what you think needs to be done in order to fully support that particular
indication.
So
I'm going to start with Dr. Karron. And
the first question is "Are the available data adequate to support the
efficacy of ZOSTAVAX when administered to persons greater than 50 years of age
in preventing herpes zoster, preventing postherpetic neuralgia, preventing
postherpetic neuralgia beyond the effect on the prevention of herpes zoster,
decreasing the sponsor-defined burden of illness and decreasing the
sponsor-defined burden of illness beyond the effect on the prevention of herpes
zoster? If not, what additional
information should be provided?"
MEMBER
KARRON: Herpes zoster is an important
cause of morbidity in the elderly and a vaccine that effectively prevented
zoster and its complications would make an important contribution to public
health.
The
sponsor has shown that ZOSTAVAX is effective in decreasing the incidence of
zoster, preventing postherpetic neuralgia and decreasing the sponsor-defined
burden of illness in individuals who are 60 to 69 and over 70 years of age.
However,
as shown in the additional analysis, efficacy against the incidence of zoster
is substantially decreased in individuals over 80 on the order of about 18 to
20 percent, though there may be better efficacy against postherpetic neuralgia,
burden of illness or prevention of perhaps the most severe pain
complications. Though, obviously, the
numbers are small and here the confidence intervals overlap zero.
Although
the sponsor has asked for an indication for use in individuals over 50 years of
age, only 185 individuals in the 50 to 60 year-old age group have been studied
and those individuals have been studied for safety.
While
it's likely that a vaccine that is efficacious in individuals over 60 would
also be efficacious in individuals in that 50 to 60 year-old age group, the
question needs to be addressed more completely.
Perhaps additional assessments of immunogenicity with a bridging study
could be contemplated since the rate of zoster is quite low in the 50 to 60
year-old age group.
An
additional important issue that has been touched on by many of the people here
today is the issue of duration of protection against zoster. And this is not only a question regarding the
need for booster doses to prevent the breakthrough disease, but also
importantly the question of whether immunizing the young elderly, those say 50
to 70 years-old, will only delay the time to occurrence of zoster potentially
with worse complications in older individuals.
So
my conclusions are that the data are not adequate to support efficacy in
persons over 50 years of age, though there may be data to support efficacy in a
subset of that group.
CHAIRMAN
OVERTURF: Dr. Fleming?
DR.
FLEMING: Well, I too think this answer
requires some specific consideration of groups or subgroups of patients. As the question relates to people in their
ages of 50 to 60, there are no data that have been presented to us. And I do believe in principle that labels
should reflect what the eligibility criteria and exclusion criteria are in
clinical trials. And if people have been
systematically excluded in their 50s, it seems logically inconsistent to then
judge we can use evidence from that trial to address whether or not efficacy has
been established and safety has been established in that group.
It
is the case that PHN risk is low below the age of 60. And I think that does, in fact, provide some
logic to why those participants weren't included in the trial. And as we were discussing in our open
discussion period, there is at least uncertainty about the issue of the
prudence of delaying herpes zoster cases in people in their 50s when they are
at very low PHN risk to then be at continued risk in ages later in time when
PHN risk is much greater.
As
it regards to efficacy for preventing herpes zoster in patients over the age of
60, I believe that there are positive efficacy data to establish effects on
herpes zoster. As an aside, I would
argue as always we should be doing an ITT analysis. The sponsor here did an MITT analysis
excluding those cases in the first 30 days, where, in fact, there was evidence
of benefit. So as an aside, again we see
an instance where start at time zero and count everything that happens, both
analyses would have shown essentially the same thing in this case.
The
issue though is one of generalizability, as has been pointed out, and we're
going to come back to those issues of generalizability. One of the aspects though of generalizability
is specifically age. And experience has
shown that it's treacherous to look at results by subgroups with the risk of
being misled that differences that are uniform may be interpreted or facts that
are uniform may be interpreted to be different by subgroups.
However,
I do think in this case the evidence for a waning effect or for a lessor effect
in older participants is very strong with estimates for herpes zoster on the
order of about 64 percent relative efficacy, if you are from 59 to 69, dropping
down to 44 in your early 70s, 36 in your late 70s, 20 in your early 80s and
about 12 above 85. A monotonic trend in
a study of this size that provides very strong indication of an effect that is,
in fact, age-specific.
And
we see a similar type of evidence for PHN and for BOI. So as we move forward to Part B for
preventing PHN, I do believe that there is evidence here in this study for
reducing PHN at targeted levels, protocol-specified targeted levels for people
who are in their 60s to 80s. But for
people who are above 80, the overall PHN efficacy is well below the targeted
level. And a similar situation arises
with BOI where there is evidence of benefit in those who are in their 60s to
80, but above 80 one again is below targeted levels for efficacy.
Now,
key questions are also asked in BNC about how much of the effect goes beyond
the prevention of herpes zoster. So
specifically, in B, how much of the PHN effect goes beyond prevention of herpes
zoster? My own sense about this is again
this is an age-specific answer. If you
are in your 60s, there is no difference at all.
So
the evidence, in fact, would considerably suggest that if you are in your 60s,
the effect on PHN is essentially reflecting the effect on herpes zoster. For participants who are in their 70s though
and even into their 80s, there is an indication that the effect is exceeding
that effect that is simply represented by herpes zoster.
For
the similar question as it relates to BOI, I struggle a bit more. Again, it's very clear. If you're in your 60s, there is no evidence
that the BOI measure of efficacy exceeds at all what was simply attributable to
herpes zoster. There is a suggestion
though as with PHN that when you are in your 70s and 80s, there may be some
added value, i.e., it's not just incidence, it's severity-by-duration.
But
I'm still struggling to understand the BOI.
I think the definition is somewhat problematic. The ascertainment of the outcome is not as
consistent as one would hope. I do think
there is a suggestion in the right hand tail, which would explain why the FDA and
sponsor's analyses are so different. So
at least, at this point, I'm willing to say like with PHN, there is a
suggestion that there might be more than just the herpes zoster effect when you
are in your 70s and when you are in your 80s.
I'm
going to stop at that point, because you are talking about what additional
information. I don't know if you want
that answer later, but one thing I have skipped over, because it comes in
Question 3, that I think is critical, at least in my answers to A, B and C, is
not only does this approval or does this conclusion have to depend on the age,
but it certainly is problematic that we have an absence of or very limited
information in critical cohorts.
Obviously,
nothing in the 50s to 60. In patients
with co-morbidities or chronic immunosuppression, we have also no
evidence. We have minimal evidence in
blacks and Hispanics. And the evidence
that we do have in those above age 80 and certainly above age 85 is very
concerning in terms of lack of persuasiveness.
So
the answers here, I believe, as has already been stated are very dependent on
the nature of the baseline characteristics and risk groups of the participants.
CHAIRMAN
OVERTURF: Dr. Word?
MEMBER
WORD: I don't think I'll be as long as
Dr. Fleming. I think he summed it up
very nicely. But anyway, I think what
the sponsor actually -- the indication that the sponsor is seeking is really in
individuals greater than 50. However, they
really only provide us with data that examines those and provides evidence for
those that are greater than 60 years of age.
And that's where I struggle with this.
I
mean, we're really based or asked to make a judgment call based on some
immunologic data or, you know, as you would say a leap of faith, well, if it
works better. We know they are younger,
so that they should have a better immunologic response. However, what we are missing are the hard and
fast data. So if I stick to what you
say, then, you know, some of the questions that I had, it still goes back to
the duration of the effect of the vaccine, giving it in this 50 year-old age
group.
I
don't know about the need for the booster or the effect administering the
vaccine that has been brought up by others if you give it earlier to people,
what long-term effect will that have. So
I guess if I took away the year 50 years and I took it to 60, then the answer
would have been yes. But because it
stayed at greater than 50, I would have to say my answer would have to be no to
all three.
CHAIRMAN
OVERTURF: Dr. Scharfstein?
DR.
SCHARFSTEIN: I think the sponsor showed
that there is a short-term effect of the vaccine on preventing herpes zoster in
the 60s and 70s. I'm concerned about the
50 to 59 year-old category as well as the over 80 category. I have serious concerns about the quality of
the pain data. It may be fine. I just haven't seen it. And so the endpoints, postherpetic neuralgia
and BOI depend critically upon that.
So
I would say that I am uncomfortable concluding that the sponsors have shown an
effect on preventing postherpetic neuralgia or on BOI. I also have concerns about the analyses that
are conditional on the presence of herpes zoster as those populations may or
may not be comparable. We saw some data
suggest that there were a couple on basepoint characteristics. However, there could be unmeasured
confounders that can explain some of these differences.
So
again, I'm not comfortable concluding that the sponsor has shown an effect of
preventing PHN above and beyond its effect on herpes zoster or its effect on
BOI above and beyond its effects on herpes zoster.
CHAIRMAN
OVERTURF: Dr. Rowbotham?
DR.
ROWBOTHAM: For the great majority of
persons who develop and episode of herpes zoster, it's a very severe, but
fortunately, relatively short illness.
But for those whose pain lingers beyond a month, and even more so for
those who still have pain at six months or a year, there is no way to really
underestimate the burden of suffering.
This
brings up the importance of the right hand tail in the data, in that those
patients who have the very high burden of illness scores over the six months
after an episode of zoster, those people are very likely to continue to have
pain a year or even longer and be really quite severely disabled as a result.
However,
it's difficult to answer the three questions here, because of the lack of
direct data in the group between the age of 50 and 59. So I can's answer any of the three questions
on that. It would be speculative for me
to provide a direct answer. For the first
question of preventing herpes zoster, the answer is quite clear. That if you are year 60 or greater, there is
a very definite effect and that seems to carry on with some reasonable
confidence on up into the 70s or perhaps even into the 80s.
With
regard to the question of preventing postherpetic neuralgia, there is a
semantic difficulty which is that if you don't have herpes zoster, you can't
possibly get postherpetic neuralgia, as we usually define it. So to put out an indication for preventing
postherpetic neuralgia would encourage patients to try and get vaccinated as
soon as they get an episode of zoster in the hopes of preventing postherpetic
neuralgia.
And
I'm already getting calls from patients asking to be vaccinated even though
they have had postherpetic neuralgia for the past 5 or 10 years. So there needs to be clarity as to what
exactly the vaccine can do. And what is
most clear is that in this age group between 60 and 70, that the vaccine is
very effective in preventing herpes zoster.
Now,
in the older age group, there is evidence that there is a preventive effect on
postherpetic neuralgia beyond the effect of preventing zoster. And there, the labeling language would need
to be very careful to try and avoid confusing both patients and
clinicians. With regard to the third
question of decreasing the sponsor defined burden of illness, the problem there
is that the way it was defined also included the preventive effect on herpes
zoster.
And
so it's difficult to answer that question, because it's really something that
should be split out into looking at the burden of illness in those who have
developed zoster. And again, the data
suggests that especially in the older patients that in the pivotal study that
the patients over the age of 70 did have less severe pain, even when their pain
persisted. And so there, I think the
burden of illness question is very important and it does support that there is
an effect on burden of illness in those who are unfortunate enough to develop
zoster despite being vaccinated.
The
most difficult problem that will come up in the other questions is what to do
in the group between 50 and 59. And
there we are really hampered by the lack of information on the durability of
the vaccination and whether or not patients who are vaccinated at 50 should be
revaccinated at some additional time point before they turn 60, when the
likelihood of developing postherpetic neuralgia after zoster starts to greatly
rise.
CHAIRMAN
OVERTURF: Dr. Gellin?
DR.
GELLIN: I'll avoid summarizing a lot of
the data we heard, but given the question as framed, are there data available
to support efficacy of ZOSTAVAX when administered to persons greater than
50? We simply don't have sufficient data
in the 50 and above. So for me that
makes the answer to all the subparts easy, that there is not the data to
support that.
CHAIRMAN
OVERTURF: Okay. Dr. Wharton?
DR.
WHARTON: I would echo Dr. Gellin's
comments regarding the adequacy of available data to support the efficacy in
persons 50 years of age and older for herpes zoster, postherpetic neuralgia and
burden of illness.
That
said, there is good data in the pivotal efficacy trial to support efficacy for
prevention of herpes zoster in persons in their 60s and 70s, yet into their 80s,
as others have commented, postherpetic neuralgia and burden of illness
evaluations in those age groups are very strongly driven in the younger part of
that population by reduction of herpes zoster.
It does appear on the higher end that there may be independent effect,
but it was less definite than one might like.
CHAIRMAN
OVERTURF: Dr. Royal?
MEMBER
ROYAL: Thank you. I would also like to stick to the question as
posed to us. Looking at the data for
patients 50 years and over, there is non-uniformity in response and inadequate
data for the 50 and 60 year age groups.
So for that reason, I feel that the studies do not support efficacy for
patients greater than 50 years.
CHAIRMAN
OVERTURF: Your industry opinion, Dr.
Hetherington?
DR.
HETHERINGTON: Well, my comments will
parallel pretty much what you've already heard.
Just to put it in different words, durability is a relative term and for
the older age group, three to four years may put you in the ballpark of
something reasonable. But as you get to
somebody in the 50 and 60 year-old group, who has 30 to 40 years of life left,
then durability of three to four years really doesn't mean much.
And
until the question of durability or strategy to deal with any waning immunity
in those who might be immunized at a younger older age group is answered, I
don't think you could make a recommendation in that 50 to 59 year-old
group. The standard of approving
therapeutics is still based on data and data for the population that has been
studied. And that again is still
lacking.
That
said, for the subparts, there certainly is data showing this vaccine could be
effective in certain age groups for preventing morbidities associated with
zoster. Most of the improvements or
benefits seem to be in reducing the frequency of actual cases. I confess some indecision about whether the
things such as burden of illness or preventing PHN is beyond the effect of
prevention of herpes zoster. Nevertheless,
I think the bottom line is that there is an overall effect and a potential for
this therapeutic.
CHAIRMAN
OVERTURF: Dr. Farley?
MEMBER
FARLEY: I agree that as posed my answer
to Question 1 would be no, that we haven't been presented with adequate data in
the 50 and older category. I do think
that it's important to acknowledge that they have shown what I think is quite
impressive reduction in the incidence of herpes zoster in those 60 and
over. And I do believe that that's
something that needs to be visited with the idea of whether it has a role
currently in terms of the approval process for those for which it was tested.
I
believe that the additional data that we all want and would emphasize is in the
50 to 59 age group. Perhaps also in the
immunocompromised older elderly, but in the 50 to 59, the emphasis not only on
some sort of consistent bridging information, but with a mandate to really look
at the issue of the waning immunity and the idea of boosters and data on the
boosting effect over time.
So
I would vote or answer no to the question as posed, but would prefer to also
keep the idea of some consideration for the 60 and older category for
consideration of approval.
CHAIRMAN
OVERTURF: Yes, Dr. Markovitz?
MEMBER
MARKOVITZ: Yes, I would like to echo a
few things that were stated, but a few additional things. First of all, I think that, obviously, we
cannot say there are any data to support licensing this between age 50 and 60
or 50 and 59. It is unfortunate in the
sense that my guess is it will work once the company actually does the studies,
but until we have the studies, we can't really comment.
And
I'm a little reluctant to endorse, at least without a lot of thought, a
bridging study. I suspect an efficacy
study would really be substantially better.
That being said, I like the data for people over 60. I think they are pretty strong data. And I believe that it shows efficacy
certainly in preventing herpes zoster.
Now,
the issue that people have raised about postherpetic neuralgia and burden of
illness, I think that's important in terms of the labeling. But it's my impression that at least
clinically if you can actually improve on those parameters by simply preventing
zoster, that's still a very important improvement.
So
while I think there may be some discussion about how to label this if it does
get approved, I think in terms of real life clinical efficacy, I think that
preventing zoster and then impacting on those other measures would be fine with
me. So I vote, I guess I'm voting no for
50 to 59 and yes for 60 and above, if that's allowed.
CHAIRMAN
OVERTURF: Yes, I'm actually splitting
the vote on this. I would like to really
congratulate the sponsors on what I think was an excellent and a difficult
trial. It's a trial because it's one of
those -- it's similar to many vaccines that we now are beginning to develop,
which really have to deal with long-term consequences that occur long after the
vaccine is given.
I
suppose that was always true, but with childhood vaccines, we are often dealing
with issues like rubella that would occur very shortly after immunization or
would have occurred very shortly after immunization and we're somewhat
universal and didn't also carry some of the chronic and difficult consequences
like zoster does.
That
said, actually I think I could move into the hypothetical realm and use what I
know about the immunological data in the 50 year-old age group and would have
been willing to. I think the biggest
concern here is that you're really talking about giving this to a universal
large population with what I don't think are adequate safety data yet.
That's
perhaps the biggest limiting factor and perhaps probably needs to be the most
important prerequisite for post-licensure, if that's going to come. It does also -- and I think another issue is
the long-term public health consequences of that vaccine given in that age
group and whether that's the best strategy.
And I don't think we have enough information.
Plus,
we don't have enough -- this sounds to me like it echos an awful lot on what we
used to say about when the varicella vaccine was first licensed. We were all -- there was so much concern and
still is some concern that we were going to be delaying the problem until a
later point in which the severity might be greater. And I think that still is an issue here. Although, obviously, with the varicella
vaccine, which the sponsors have also provided, we have eliminated perhaps an
awful lot of the wild disease that would have contributed to part of this
problem.
So
I think to me the data do support the use of the vaccine very clearly in
individuals over 60. I think there were
strong suggestions that it probably does lower not only the incidence, but
probably also somewhat the severity of the disease in individuals over 70. And I think even though at times the data
suggests a minimal effect, I think that could have major public health
consequences, even with the minimal effect.
So I would support the use of the vaccine in individuals over 60, at
this point.
We
need to proceed to the second question and I think, at this time, what I would
suggest we do is at the time I polled the Committee at this point, I would --
if you have additional questions that you want to address under Question 3, I
would make that point at this time. If
there is any further or last minute clarifications that you think should be
brought out by either the FDA or the sponsors, we'll take that at this time as
well.
And
we ended with Dr. Markovitz and we'll start with him on this one. The second question being "Are the
available data adequate to support the safety of ZOSTAVAX when administered to
persons greater than 50 years of age? If
not, what additional information should be provided?"
MEMBER
MARKOVITZ: Well, the simple answer for
me would be yes, again, talking about really over 60. Although, there are some pretty decent safety
data for over 50. So I guess here we
could even say over 50. I am a little
concerned about various follow-up issues that have been raised and the
statistical issues that have been raised.
Although, I think I would probably defer to my more statistically
sophisticated colleagues to talk about that more.
So
my overall answer is yes, I think the safety data are okay. The second question you raised, Gary, in
terms of Question No. 3, "What else do we need?" I think it's obvious we need 50 to 59. We need more data on the more elderly. As I mentioned before, I wonder if really one
dose is really the optimal way to proceed with this vaccine or one might be
better off with two in the long run.
And
then the obvious thing is the people who suffer the most clinically with zoster
are obviously people who are immunosuppressed, people on steroids, people with
HIV. For these people, this problem is a
disaster. Not to downplay the problems
with an otherwise healthy person, zoster is an awful disease in those people,
too. But I think we clearly need data on
the immunocompromised and I don't mean just minor impairments, but truly
immunocompromised people.
CHAIRMAN
OVERTURF: Dr. Farley?
MEMBER
FARLEY: In terms of No. 2, I'm satisfied
with the safety data as presented for those 60 and older, of course, not for --
and I'm not for those under 60. Just a
couple of comments on No. 3. I'm
actually -- I have much less concern about the Subgroup A in that I think these
people may get a benefit. It's possible
it may be a little less beneficial.
These patients may be -- because of their co-morbidities might respond a
little less, but they also because of who they are and where they are living,
their life span may be shorter than those who were in this study.
So
I'm not all that concerned about expanding or generalizing or at least making
it available to those in the Subgroup A.
I think Subgroup B will need some very careful attention in terms of
post-licensure studies that would assure the safety of the use in that
group. I think that it would be to our
collective benefit for us to really be establishing good monitoring systems for
and in an active way and this isn't necessarily all driven by the sponsor, but
also by CDC and elsewhere, active surveillance for herpes zoster.
I
think it is important from the standpoint that we have now, you know,
generation coming along without wild type disease, without native disease, that
are vaccine protected, never had chicken pox, where will they go with zoster,
and those who would have been boosted by that, the elderly and then introducing
this vaccine, all of these things are going to be a complex mixture to be
studied and that we need to have a system that accurately assesses it in the
best way possible with the best tools.
And
let's see, I think I'll close at that.
CHAIRMAN
OVERTURF: Dr. Hetherington?
DR.
HETHERINGTON: I think I would put a
qualified yes on the adequacy of the safety data. There are a couple of issues that I'm still
wrestling with and I hope that the FDA will drill down on these as they
complete their review. What is the
dependence upon recall, patient diaries for the collective safety data? And the second is the use of the subset. While we were told it was comparable to the
general population in the study, we weren't shown the data. It wasn't shared. And there may be some subtle differences that
may need to be explored a little bit more.
And again, I hope that the FDA will take that into account during their
review.
The
presentation of the safety data, I think, was somewhat limited, but on the top
line looked fairly reasonable. For
Question No. 3, I'm just going to pick on two issues. One is interaction studies with other
vaccines and I believe the sponsor showed that they were planning on doing a
study to look at the interaction between flu vaccine and this vaccine. And I think that will be critically
important.
The
second, I think, would be Part A under 3 and that is the use of vaccines in
persons, particularly those who are residing in assisted living situations or
nursing homes. While in this population
you didn't see any of the vaccine strain appearing, any herpes zoster, perhaps
that would not be the case in somebody in more of a debilitated state, somebody
who was on some sort of chronic immunosuppressive therapy and in a nursing home
setting. There may be the potential that
the vaccine strain could be spread cutaneously.
So these are the things that I think that the postmarketing
pharmacovigilance study would need to address.
CHAIRMAN
OVERTURF: Okay. Dr. Royal?
MEMBER
ROYAL: I would also say that the data as
presented does to a limited extent support the safety of the vaccine and
individuals greater than age 50 years. Although the data in the younger age group
could be a bit stronger, I do feel that it's good enough, at this point. I would also like to recommend that the
sponsor consider looking at a group of patients that can provide information
that's more generalizable to the general population by looking at individuals
with chronic conditions, not necessarily chronic, immunosuppressive conditions.
I
also feel that it would take a more special look at that group. And also to keep in mind the fact that even
within the VA population that there is a fair amount of variability in the care
that's given, given the fact that many veterans don't use the VA as their only
point of care.
CHAIRMAN
OVERTURF: Dr. Wharton?
DR.
WHARTON: As written, as the question is
written, I don't believe you have all the data adequate to support the safety
in persons 50 years of age and older.
Although, I would give a qualified yes for persons 60 years of age and
older. I'm still troubled by the fact
that there were information on 7 percent of vaccine recipients were obtained
more than 60 days out and I'm concerned about the ability to adequately
ascertain safety information with information apparently obtained late.
That
said, the information such as it was didn't suggest any safety-related
problems. However, as the vaccine is --
assuming the vaccine is licensed and is introduced into general use in the
elderly, there will be, I suspect, large numbers of frail elderly people with
many co-morbid conditions who will be vaccinated. And it's clear that information is needed on
the vaccine used in the more general population of the elderly.
And
I remain concerned that safety issues will arise which may have nothing at all
to do with the vaccine and maybe have to do with the underlying health status
of those persons, that there will need to be a population laboratory so that
those questions can be answered in a way that is efficient and can rapidly
resolve the issues. And clearly,
duration of immunity will need to be addressed as well.
CHAIRMAN OVERTURF: Dr. Gellin?
DR.
GELLIN: Again, as written, I don't think
there is sufficient data in that 50 to 59 year-old group to answer the question
overall and I won't get into the subgroup analysis. Although, I want to comment that I felt that
the safety data was otherwise sufficient.
On a tangential note, I had by serendipity over the past several years
have met many people who have been involved in this study and I would encourage
the sponsors to in some way capture the information that happened here today
and report back to the volunteers who may read about what happened here today
in a different light.
And
I think that also speaks to these incredibly large studies and more and more
people are involved in these studies. We
want to make sure that people continue to want to participate in such studies.
CHAIRMAN
OVERTURF: Dr. Rowbotham?
DR.
ROWBOTHAM: With regard to this question,
I think I would like to just point out that the 009 study had only 185 subjects
between the age of 50 and 59. And I
don't think that's enough to say that's adequate safety data when the target
population in the overall U.S. population is many, many millions.
For
patients over the age of 60 though, I think the Shingles Prevention Study,
which is really a landmark for those of us who work primarily in the pain area,
is adequate to suggest that the safety is quite good, especially given the
potential benefits in that age group.
Through post-licensure studies, I do have a couple of comments.
I
think a very good postmarketing study would be to examine patients who are
living in assisted living or nursing homes.
And that's a particularly difficult group to manage. If they do develop shingles, their
communication abilities may be quite impaired.
They may be cognitively impaired.
They can't tolerate any of the more aggressive invasive injection
procedures, like epidural injections that can be used in younger patients or
healthier patients.
They
tend to do spectacularly bad on sedating drugs like some of the anticonvulsants
and the opiates, so this is a group that's really tailor made for a preventive
type treatment like the vaccine. It's
important to get this information on patients with chronic immunosuppressive
therapies, probably in a progressive approach with those -- starting with those
who are the least immunologically impaired and then going on steadily into more
and more impaired groups.
The
persons with HIV infection actually offer a ready model there, because you can
look at the T-cell counts and state the severity of immune system damage in
that disorder. So there was an interest
in looking in that particular population.
You could start with HIV-positive patients who have the least damage to
their immune system with a treatment like this before going on to the more
severely impaired ones and that certain group that's very high risk for zoster
and also has quite a high incidence of postherpetic neuralgia.
The
duration of immunity as has been mentioned quite a bit, I think, is the major
factor limiting discussion of the utility of this in patients between 50 and
59.
CHAIRMAN
OVERTURF: Dr. Scharfstein?
DR.
SCHARFSTEIN: For Question 2, I feel that
there is data for subjects over 60 years of age to support the safety of the
vaccine, although I have some concerns about seeing the data with regard to the
comparability of the set of people who were followed in the AE Monitoring Study
and the rest of the study population, as well as the uniformity of follow-up
for safety information in the study.
In
terms of Question No. 3, it seems to me that A, B and D, we didn't have a lot
of data on those, so it's hard to comment.
In terms of C, in terms of the vaccine greater or equal to 80 years,
there wasn't a tremendous amount of data to support. There was some data, but not a tremendous
amount of data for over 80. And we
haven't seen the pharmacovigilance plan, but I would support active
surveillance if the vaccine was approved.
And I also have some concerns about generalizability as this was a
predominantly white population that was studied.
CHAIRMAN
OVERTURF: Dr. Word?
MEMBER
WORD: In terms of the available safety
data, I think if you were looking at over 60, I think I would be in agreement
with everyone else. I think when it
comes to the 50 to 60 year-old age group, as has been pointed out, while the
study seemed like it was reasonable, you have a very small number in that
population.
In
terms of additional studies, I think Dr. Hetherington mentioned one already
when he talked about co-administration.
He mentioned the -- the sponsor mentioned influenza. One of the other things that has been
suggested during the age range, that they should have gotten pneumococcal and
you may also look at DTaP, even though it's not been formally recommended, I
think ultimately it will be for that age group for adults as opposed to just
plain TD.
I
guess the other question I wasn't sure of was in the pharmacovigilance plan, it
talked about identification, some identification program, I'm not quite sure
what that is, in terms of being able to identify, I guess, the vaccine versus
wild type virus, but I don't know how you are going to disseminate that. And the other thing that just struck me as
odd is that you're looking at targeting a group that is over 50 and you have a
Pregnancy Registry. So I don't know if
that was just a carryover from the other vaccine, but it just seemed a little
odd that that was in there.
CHAIRMAN
OVERTURF: Dr. Fleming?
DR.
FLEMING: Whenever I answer the safety
issue, I always view this as an answer in the context of benefit to risk. So I always think of what is acceptable
safety based on what is the level of efficacy.
With that in mind, just very quickly again, my view is efficacy
essentially is established in the 60 to 80 range. We don't have data in the 50 year-olds and in
those above 80, HZ incidence was only minimally effected and BOI and PHN levels
didn't meet target.
So
the efficacy, as I see it, is in 60 to 80 year-olds where in that range
throughout there is HZ incidence data that is persuasive. Although, only in the 70s is there evidence
of added severity-by- duration beyond the incidence. So with that as background, I'll just very
briefly say that the safety data in the 50s, like the efficacy data, is
lacking. Although it was interesting to
me to look at the sponsor's slide 74 where there was more safety events that
were occurring in the 50s than above 50.
That was an interesting observation.
So
drilling down on the safety in 60 to 80 year-olds, one thing that I noted was
the SAE rate is relatively 60 percent higher in this cohort. And, in fact, in the 70s it's relatively 80
percent higher. That translates by my
calculation into something on the order of about six SAE events per thousand
people. And I put that in contrast with
six HZ events prevented and one PHN event prevented, although that is an
extension. That will extend over each
year in the future.
So
my sense about this is that based on what is known in the safety domain, the
overall benefit to risk does appear to be favorable in the 60 to 80
year-olds. I remain somewhat uncertain
and specifically again refer to the FDA's summary slide 83 saying
"Completeness of safety ATRS and study termination follow-up is
unclear." I, obviously, believe
that it's going to be important for the FDA to be as confident about the
completeness of this evidence as possible.
I
am suspecting that when that assessment is final, that the overall sense in the
60 to 80 year-olds would be that benefit to risk is favorable. As it relates to Question -- as far as
Question No. 3 is concerned and Parts A, B and C, I'll reiterate what I had
mentioned before. I don't look at this
just as postmarketing. I look at this as
premarketing. There are categories of
patients here that I would be concerned if they were included in the label.
Those
that are 50 to 60, those with co-morbidities on chronic immunosuppressives and,
in fact, because of the lack of benefit, those that are above age 80. Therefore, I would hope to see studies done
even before marketing that would enlighten us much more clearly about benefit
to risk in those categories.
In
blacks and Hispanics it is disappointing how limited the evidence is. I would urge the FDA to carefully consider
that evidence. I'm stopping short of
saying those categories shouldn't be included in the label, but I'm
disappointed at the limited amount of information we have there and would want
the FDA to look carefully at what information exists.
Regarding
duration of immunity, let me just step back and first as an aside make the
point that the nature of evidence that has been presented to us, for example,
that was on the sponsor slide 62, indicates that ELISA titers and ELISPOT
counts are correlated with the level of risk.
That is what we, in fact, know.
The
sponsor used orally the terminology "they are correlates of
protection," and on their slides said it's correlated with efficacy. Those latter two terms convey knowledge of
causality. The kind of data that is
available doesn't establish causality.
It simply establishes a statistical association or a correlation and I
have been arguing since 1990 on this Committee.
I
would prefer that we state what we know with data such as this, and that is
that this evidence is correlated with level of risk rather than calling it
correlates of protection or correlations with efficacy, the latter of which
suggests causality has been established.
Let
me though finish on a positive note. I
would like to congratulate the sponsor for conducting a clinical endpoint trial
not just an immunogenicity study.
Therefore, as it relates to question 3(d), duration of immunity, I think
we can trump the answer to the question "Is there evidence of duration of
immunity?" by saying the sponsor has established over three to four years
of follow-up that there is durable efficacy, and that to me is more impressive
than the answer "Is there durability of immunity?"
CHAIRMAN
OVERTURF: Dr. Karron?
MEMBER
KARRON: So I would say that in terms of
data to support the safety of ZOSTAVAX in 50 to 60 year-olds, I don't think
there is adequate data. I do think there
is adequate data for those over 60.
I
do share some of Dr. Wharton's concerns about that missing 7 percent and that
number is a bit flexible, but whatever that is, and I would at least encourage
the sponsor to get to the FDA some of those demographic data to assure us that
those missing individuals are not different from those for whom they were able
to get data.
In
regard to question 3, I don't think I will make any additional comments, except
that I did want to focus on that group over 80 and a comment that Dr. Overturf
made at the end of the last question, which is that I think we should not
under-estimate the morbidity in that age group, in the very elderly, and that
we might want to use a vaccine in that age group that has less efficacy.
I
mean, ideally, there would be a vaccine that had sustained efficacy over all
age ranges, but that a vaccine even with lower efficacy in that age group might
still provide a substantial public health benefit.
CHAIRMAN
OVERTURF: I don't think I have anything
to add. I think all the questions have
been added. I also, based on what I have
said previously, don't feel there is enough data to support. Although it suggests and I actually would
like to believe that there is safety for the 59 year-old age group, I don't
think there is sufficient data to support that.
I
have been asked by the FDA to poll the Committee one more time and I don't want
a lot of discussion, and I'm going to ask the same question and all I want you
to answer is yes or no as to the answer about 60 versus 50 to 59. So I would first ask you again.
I
think I have this recorded, but I think they want it on tape. So I would like to ask you first. You can actually ask both questions. I will ask you both questions. The first one is about safety and the second
one is about efficacy for the -- specifically, if we rephrased all these
questions for the 60, greater than 60 year-old age group. I think I heard one person in support of
adequate data for safety for 60, maybe two.
So
if I could have you -- I will poll this one more time. Let's go with Dr. Markovitz first. Safety and efficacy for those over 60
years-old?
MEMBER
MARKOVITZ: Right. I vote yes, there is efficacy and yes, there
are safety data to support licensing this in those 60 and above.
CHAIRMAN
OVERTURF: Okay. Dr. Farley?
MEMBER
FARLEY: Let me just clarify. Is it efficacy against herpes zoster? Are we keeping it simple?
CHAIRMAN
OVERTURF: We're keeping it simple.
DR.
FLEMING: But how can we keep it
simple? I mean, we have just gone
through two hours of clarifying that these aren't yes/no answers.
CHAIRMAN
OVERTURF: No, I agree.
MEMBER
FARLEY: But it would be if it's herpes
zoster for me at least, and my answer for 60 and older for efficacy against
herpes zoster, yes, and for safety, yes, given the caveat of making sure the
data is fully shared and nothing new comes up.
CHAIRMAN
OVERTURF: Dr. Hetherington?
DR.
HETHERINGTON: Yes. I would vote yes on both safety and efficacy
in the greater than 60 year-old group.
CHAIRMAN
OVERTURF: Dr. Royal?
MEMBER
ROYAL: I would vote yes to efficacy and
safety in the 60 year and above age group.
CHAIRMAN
OVERTURF: Dr. Wharton?
DR.
WHARTON: Yes on efficacy for prevention
of herpes zoster, a qualified yes on safety with the reservations I expressed
earlier.
CHAIRMAN
OVERTURF: Dr. Gellin?
DR.
GELLIN: For zoster, yes, for both
efficacy and safety.
CHAIRMAN
OVERTURF: Yes?
DR.
ROWBOTHAM: Yes on both safety and
efficacy.
DR.
SCHARFSTEIN: Yes on efficacy for
preventing herpes zoster and yes on safety provided -- with the additional
caveat.
CHAIRMAN
OVERTURF: Okay. Dr. Word?
MEMBER
WORD: Yes on both safety and efficacy.
CHAIRMAN
OVERTURF: Let's try you, Dr. Fleming.
DR.
FLEMING: I think I have nothing to add,
i.e., a qualified yes on efficacy and safety with in-depth discussion of the
qualifications already being on record.
MEMBER
KARRON: Yes on safety, yes on efficacy
with the qualifications on safety expressed previously.
CHAIRMAN
OVERTURF: Now, I think that was -- and I
also would vote yes on safety and efficacy for those over 60. I don't know if I dare ask this, but are
there any further comments or discussion that the Committee would like to put
forth at this point, any Members? Yes,
Dr. Wharton?
DR.
WHARTON: Thank you to the FDA staff for
all their work, as well as that of the sponsor for putting this on today.
CHAIRMAN
OVERTURF: I think with that, we will
adjourn the meeting. Thank you very
much.
(Whereupon,
the meeting was concluded at 4:01 p.m.)