November 17, 2010: Vaccines and Related Biological Products Advisory Committee Meeting Transcript

FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
VACCINES AND RELATED BIOLOGICAL PRODUCTS
ADVISORY COMMITTEE MEETING

November 17, 2010

Hilton Silver Spring
8727 Colesville Road
Silver Spring, Maryland  20910

This transcript has not been edited or corrected, but appears as received from the commercial transcription service.  Accordingly, the Food and Drug Administration makes no representation as to its accuracy.

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PROCEEDINGS   (8:30 a.m.) 
Agenda Item:  Call to Order; Administrative Issues
DR. ROMERO:  Good morning.  I am going to call the meeting to order.  I am going to turn it over to Mr. Donald Jehn to make some comments.
MR. JEHN:  Good morning.  I am Don Jehn, the designated federal official for today’s meeting of the Vaccines and Related Biological Products Advisory Committee.
I would also like to welcome all of you to the meeting of the advisory committee.  Our acting chair for today’s session is Dr. Romero.
Today’s sessions will consist of presentations that are all completely open to the public.
I would like to request that everyone check your cell phones and pagers.  Make sure they’re off or in silent mode.
I would also like to request that any media inquiries be directed to Ms. Shelly Burgess from the FDA Office of Public Affairs.
Now I need to read a brief COI, 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 November 16 and will be part of the public record for the Vaccines and Related Biological Products Advisory Committee meeting on November 17, 2010.
“This announcement addresses conflicts of interest for topic two, for the review and discussion of the effectiveness of vaccinating males and females with Gardasil manufactured by Merck & Company for the prevention of anal dysplasia and anal cancer.  This is a particular matter involving specific parties.
“Based on the agenda and all financial interests reported by members and consultants related to topic two, no conflict-of-interest waivers were issued under 18 U.S. Code 208(b)(3) or 712 of the Food, Drug, and Cosmetic Act.
“Dr. Theodore Tsai is serving as the industry rep for topic two, acting on behalf of all related industry.  He is employed by Novartis Vaccines and Diagnostics in Cambridge, Massachusetts.  Industry representatives are not special government employees and do not vote.
“The conflict-of-interest statement will be available for review at the registration table.
“We would like to remind members and participants that if the discussions involve any of their 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 have with any of the firms, its products, and, if known, its direct competitors.”
Thank you.  I turn the meeting back over to Dr. Romero.
DR. ROMERO:  Good morning.  I am going to ask the members of the committee to please introduce themselves.  I will start with myself.  I am Jose Romero.  I am a professor of pediatrics from the University of Arkansas for Medical Sciences.
I will go to Vicky.
MS. DEBOLD:  My name is Vicky Debold and I am with the National Vaccine Information Center, and I am the consumer representative.
DR. MARKOWITZ:  I am Lauri Markowitz from the Centers for Disease Control and Prevention.
DR. MOULTON:  Larry Moulton, professor of international health and biostatistics at Johns Hopkins University.
DR. SANCHEZ:  Pablo Sanchez, Pediatric Infectious Disease Neonatology at University of Texas Southwestern Medical Center at Dallas.
DR. WHARTON:  Melinda Wharton, Centers for Disease Control and Prevention.
DR. DURBIN:  Anna Durbin.  I am associate professor at the Johns Hopkins Bloomberg School of Public Health, Center for Immunization Research.
DR. TACKET:  I am Carol Tacket from the Center for Vaccine Development at the University of Maryland School of Medicine.
DR. ROBERTS:  Jeff Roberts, FDA Office of Vaccines.
DR. SUN:  Wellington Sun, Office of Vaccines.
DR. BAYLOR:  Norman Baylor, Food and Drug Administration, Office of Vaccines.
            DR. SCHRAGER:  Lewis Schrager, FDA Office of Vaccines.
DR. ENG:  Cathy Eng, M.D. Anderson Cancer Center, Associate Medical Director of Colorectal Center.
DR. DESTEFANO:  Frank DeStefano, Centers for Disease Control and Prevention.
DR. TSAI:  Ted Tsai, Novartis Vaccines.
DR. UNGER:  Elizabeth Unger, Centers for Disease Control and Prevention.
DR. GELLIN:  Bruce Gellin, National Vaccine Program Office of HHS.
DR. ROMERO:  Thank you all and good morning.
Agenda Item:  Presentation of Retirement Plaques
DR. ROMERO:  Now I am going to ask Dr. Norman Baylor, director of the FDA, to please come to the podium and present the plaques of retirement for Dr. Jack Stapleton, Dr. Pablo Sanchez, and myself, please.
It is the first time I’ve ever been promoted and retired on the same day.
DR. BAYLOR:  Good morning, everyone.
Before I present the plaques, I just wanted to thank the three members who are retiring from the committee this term.  It takes a tremendous amount of work, a tremendous amount of preparation, and a lot of dedication to be a member of this committee.  We have three members who are retiring now who have been exceptional in carrying out their responsibilities and duties for the Vaccines and Related Biological Products Advisory Committee.
Dr. Stapleton is one.  He is from the University of Iowa hospital clinic.  He has been a member since 2005.  He has been the chair for the past year.  He has chaired three laboratory site visits and he has attended 16 meetings.
I will announce you all, and then we’ll do whatever we’re supposed to do next.
Then we have Dr. Romero, who is the acting chair today for today’s session, from the Arkansas Children’s Hospital.  He has been a member since 2007.  He has chaired one site visit and he has attended 12 meetings.
We have Dr. Pablo Sanchez from the University of Texas, Southwestern Medical Center, in Dallas.  He has been a member since 2007 and he has attended 14 meetings.
Again, thank you guys so much for everything that you’ve done and your contributions to this committee and to the Food and Drug Administration.
(Presentation of plaques and applause)
DR. ROMERO:  Very good.
Now we will ask Dr. Jeffrey Roberts from CBER to do the introduction and presentation of discussion.
Agenda Item:  CBER Introduction/Presentation of Discussion
DR. ROBERTS:  Good morning.  My name is Jeff Roberts, and I am the clinical reviewer and the chair of the committee responsible for evaluating this application which is the topic of the advisory committee meeting today.
First of all, I would like to thank the committee members for being here.  We are aware of the time and effort involved, and we appreciate your input as we evaluate these data.
In the application we are considering, the sponsors submitted efficacy data in support of an additional indication for Gardasil, so prevention of anal dysplasia and anal cancer.
As many of you are aware, Gardasil is a noninfectious recombinant vaccine.  It contains virus-like particles or VLPs from HPV types 6, 11, 16, and 18.  It was originally licensed in 2006.
The current indications are as follows:  females 9 through 26 years of age for the prevention of HPV 6-, 11- 16-, and 18-related cervical, vulvar, and vaginal cancer and the related precancerous lesions, and for the prevention of HPV 6- and 11-related genital warts; in males 9 through 26 years of age for prevention of HPV 6- and 11-related genital warts.
In this application Merck is proposing to add the following additional indication:  males and females 9 through 26 years of age for prevention of HPV 6-, 11-, 16-, and 18-related anal cancer and AIN grades 1, 2, and 3.
Just to orient you, the precancerous lesions that can lead to anal cancer are also known to pathologists as anal intraepithelial neoplasia or AIN.  So you will hear this referred to by a number of different terms, usually AIN but sometimes anal dysplasia, sometimes anal precancer.  This is not the only abbreviation we will use today.  I have in the back of my slide set some of the most common abbreviations you will hear.
The study submitted in support of this new indication was a randomized controlled trial in about 600 men who have sex with men, or MSMs.  The primary prespecified endpoint was AIN 1+.  So that is AIN of any grade or anal cancer; in other words, AIN or worse.
Let me direct you to this footnote because this is an important concept.  Approval of this application would extend the indication, but it would not change the population for whom Gardasil is indicated.  So in the broadest of terms, it is new indication, old population.  In other words, we are considering new efficacy data, but the immunogenicity and the safety data in this population have been evaluated both internally by us and by this committee in the past, and those data are described in the current Gardasil package insert.
So as you hear these presentations, we would like for you as the committee to keep in mind the following discussion topics:  In the discussion, we would like for you to comment on the strength of the data to support an indication for the prevention of AIN and anal cancer in males; and the scientific rationale for extrapolating efficacy in the prevention of AIN and anal cancer to females.
Here is the agenda for today.  First we will hear from Dr. Palefsky, who will present an overview of anal HPV infection and progression of anal dysplasia.  Dr. Brill-Edwards and Dr. Garner will talk about Merck’s clinical development program for studying the prevention of anal cancer, and they will present the clinical data from the pivotal study.
Then I will discuss the review team’s evaluation of that clinical data.  I will also briefly touch on our assessment of the literature and other available data that is relevant to these discussion topics.  Then we will move on to the public hearing, and finally I will put the discussion topics back up on the screen as we move into the committee discussion and recommendations.
I think we are ready to move on, but I guess we could entertain any clarifying questions at this point.  I am seeing none.
DR. ROMERO:  Dr. Palefsky will now present an overview of anal HPV infection.
Agenda Item:  Overview of Anal HPV Infection, Anal Intraepithelial Neoplasia, and Anal Cancer
DR. BRILL-EDWARDS:  Thanks, Dr. Romero.
I am Dr. Brill-Edwards from Merck.  I would just like to do a little orientation and then introduce Dr. Palefsky.
Good morning to everyone, and thanks for attending this meeting.
We are here today to present the data that supports the use of Gardasil in the prevention of anal cancer.  There will be three speakers during this portion of this morning’s presentations.  As Dr. Roberts mentioned, Dr. Palefsky will present an overview of anal HPV infections, anal intraepithelial neoplasias, or AIN, and anal cancer.  Then I will provide the current status of Gardasil, and finally, Dr. Elizabeth Garner will present a detailed summary of our results.
By way of introduction to this topic, anal cancer is an HPV-related cancer.  The incidence of anal cancer has been increasing at approximately 2 percent per year for the last three decades in both men and women.
Men who have sex with men, or MSM, are at particularly high risk for anal HPV-associated disease because of sexual risk behaviors.  Thus, not surprisingly, HPV-related anal disease has been most extensively studied in this population.  Also for this reason, MSM were evaluated in the efficacy studies that we will discuss later this morning.
However, it is important to note that anal cancer is a disease of men and women, and although research has focused on the MSM population, keep in mind that the majority of cancer occurs in populations other than MSM.  In fact, women account for 60 percent of the cases of anal cancer.
To provide the appropriate background information for the committee this morning, we are fortunate to have Dr. Joel Palefsky with us.  Dr. Palefsky is a consultant and clinical investigator for Merck.  He is recognized as an international expert in the detection and management of HPV-related anal disease.  In addition to his research accomplishments, he is also a very busy clinician.
To briefly summarize his credentials, he is a professor of medicine at the University of California at San Francisco; he obtained his medical degree and his internal medicine specialty training at McGill University in Montreal; he did his subspecialty certification in infectious disease at Stanford.
He is the founder and director of the UCSF Anal Neoplasia Clinic; he is the founder and chair of the NCI AIDS Malignancy Consortium HPV Working Group; he is a member of the board for the American Society of Colposcopy and Cervical Pathology and the International Papillomavirus Society.  He is also a member of the board of the Foundation for HPV and Anal Cancer.
Dr. Palefsky.
DR. PALEFSKY:  Thank you very much.
I would like to begin by expressing my appreciation to the FDA for the opportunity to talk to you this morning about HPV and anal cancer.  It is a subject, as you can guess, which is very near and dear to my heart.
What I would like to do is start by just reiterating some disclosures.  You’ve heard that I am a recipient of grant funding and a member of scientific advisory boards for Merck and I am an investigator on the protocol that you’re going to be hearing about a little bit later.  I am also a member of two other scientific advisory boards for Pharmjet Incorporated and Aura Biosciences.
What I would like to do this morning with you is discuss the biological similarity between anal and cervical cancer, talk specifically about anal HPV infection and how it plays into the demographics for anal cancer.
I would also like to describe to you our understanding of the role of high-grade anal intraepithelial neoplasia, or HGAIN, as a precursor to anal cancer and talk about how that influences our approach to screening and treatment of AIN to prevent anal cancer, and then make some concluding remarks.
Firstly, I want to show a slide which I think many of you already are familiar with which describes the way that HPV gets through epithelium.  This is true both for the cervical epithelium as well as the anal epithelium.  Much of the work was done here actually at NCI by some of the members in this audience.  But basically it is now believed that the virus, shown here, needs to get through a variety of different epithelial cell layers and keratin layers to get to the basal cell layer where it sets up initial infection.
It is thought that a microabrasion or tear is necessary to do that, because of all these barriers, but once the virus is established, a set of early protein production happens, including expression of E6 and E7, which are the two most important HPV genes for oncogenesis.
As the cells begin to move up through the epithelium, the number of viral copies per cell goes up, the amount of viral gene expression goes up, and ultimately expression of late region proteins occurs around here in which the virus DNA is encapsidated, fully infectious virions are formed, and the viruses are then shed from that epithelium, available to infect somewhere else in the epithelium of that person or potentially a sexual partner.
We believe that the same thing happens in the cervix and the anus, and thus anal and cervical cancer are essentially the same diseases.  This is based on several different kinds of considerations.  This is based on anatomic similarity in terms of where the virus actually prefers to infect at these sites; in terms of the morphologic similarity, that the lesions themselves, once they turn cancerous, look very similar historically, and their precursor lesions also are very similar histologically; and then from an etiologic point of view, they share a very close relationship with the same HPV types.
Firstly, with respect to the anatomic similarity, in the cervix the primary target area is the cervical transformation zone, where the columnar epithelium of the endocervix meets the squamous epithelium of the exocervix.
There is a very similar transformation zone in the anal canal where the columnar epithelium of the rectum meets the squamous epithelium of the anus.  So this anorectal junction area is a preferred target for HPV.  This is where most of the anal intraepithelial neoplasia lesions arise and where the majority of the anal cancer lesions arise.
We do get cancers occurring perianally, but the majority of them occur intra-anally.  This transformation zone is the preferred target area because, just like in the cervix, the skin is very thin, it is highly metabolically active, there is a lot of movement, squamous metaplasia, movement back and forth between squamous and columnar epithelium.
One of the consequences of this is that since it is internal, just like in the cervix, most of these lesions are asymptomatic.  People don’t know that they have anal HPV infection, they don’t know that they have AIN, and they usually don’t know that they have anal cancer until that tumor grows to the point where it begins to affect nerves, causing pain or potentially bleeding.
From a histologic standpoint, the consequences of that HPV infection are summarized on this slide.  Most of you have seen this before in the context of cervical disease, but we very carefully added anal here too, again because these are really the same lesions.  AIN is the same lesion as CIN.
We divide these into low-grade disease -- condyloma, CIN or AIN grade 1, which in the older terminology was very mild to mild dysplasia.  This is not considered to be a direct cancer precursor but has the potential to progress to the high-grade version, which is a direct cancer precursor.  These are divided into CIN or AIN grade 2 and 3, moderate dysplasia, severe dysplasia, and carcinoma in situ.
This is the lesion that in the cervix we are primarily looking for to detect and treat before progression to invasive cancer ultimately occurs.  This is the very same approach we take to preventing anal cancer.  We are doing anal cytology screening in high-risk populations, followed by high-resolution anoscopy, equivalent to culposcopy, to identify the high-grade lesions and then remove them in an attempt to reduce the incidence of anal cancer.
From a morphologic standpoint, this just shows you how similar these lesions really are in the anus and the cervix.  These are low-grade lesions here in the cervix and the anus and then high-grade lesions.  In the low-grade lesion, you see some of the signs of koilocytosis and not very much atypia.  You see the same things here in the anal canal.
Here in the high-grade lesion you see a lot more atypia, a lot less differentiation.  You will also notice that you’re at the transformation zone with the presence of these columnar cells.  You see the same thing here in the anal lesion, and you will also notice the gland here indicating that we’re at the transformation zone in the anal canal.
So if I were to ask a pathologist to look at these pictures, they would say that yes, indeed, these are very, very similar anatomically.
I thought I would show you what some of these actually look like in the specimens that we collect.  I mentioned that we start off with anal cytology as a screening tool.  This is an example of what one such low-grade anal cytology looks like, showing the characteristic koilocytes, which are cells with enlarged irregular nuclei surrounded by a halo.
This is the lesion that was biopsied, again showing those koilocytes in the tissue.  This is what the lesion actually looked like when we put an anoscope in and looked with vinegar and magnification.  You can also see a bigger lesion behind it, but this is the warty lesion that was biopsied.  You can imagine this is not an easy lesion to treat.
In contrast, the high-grade lesions have Pap smears that have very large, irregular nuclei and a large nuclear cytoplasmic ratio -- you can readily appreciate the difference between these cells and the cells I showed you before -- and also a more normal squamous cell with a much smaller nucleus and a larger cytoplasm.  Here again you don’t see those koilocytes, but you see a lot more nuclear atypia through the more superficial layers of the epithelium.
Then looking at this lesion, I think you will also appreciate a very big difference from the last lesion I showed you.  This is flatter, it has a much more atypical vascular pattern.  This is what we call punctation, this is mosaicism.  This is an ugly lesion, and actually I would worry quite a bit that this might be a cancer, which as it happens was not.
This is a cancer.  We don’t often see the cancers on cytology, but we did on this one.  This is very ugly-looking squame.  Here you see the islands of invading squamous cells in the biopsy, and here is a cancer as we see it through the anoscope.  It is ulcerated and rather ugly looking.  You can also see foci of disease elsewhere.  I am going to come back to this one because this is actually a patient whom we saw who had high-grade disease who did not get treated and who progressed to cancer despite having been followed.
What this slide shows you is the relationship from an etiologic standpoint between anal and cervical cancer.  It makes really two points.  The first is that the relationship between cervical cancer and HPV 16 and 18 specifically is very similar to the relationship between anal cancer and HPV 16 and 18.  The other point that this makes is that anal cancer in men is the same as anal cancer in women.
If you look on the left part of the slide, you will see that a high proportion, not 100 percent but a high proportion, are associated in both men and women with HPV.  You will also notice that the great majority of those are HPV 16 and 18, with a smattering of a few other types, including the occasional one that has type 6 or 11 alone.
In fact if you look at the HPV-positive anal cancers, a higher proportion of those are 16 and 18 than are true for HPV-positive cervical cancers.
You may also wonder why we don’t get 100 percent of anal cancers being positive like we do in the cervix.  My own feeling is that this is a technical issue and that we have not been studying enough anal cancers using the best detection methods that are available to us, and that if we do that, then we will see a number more closely approaching 100 percent than what you’re seeing here.
Before I turn to a discussion of the data on precancers and HPV specifically, I just want to reiterate a point that Dr. Brill-Edwards made to you, and that is the data that you are about to hear are primarily from the MSM population.  That is primarily because we started there, since this is the group that has the highest incidence of any group, namely men who have sex with men.
This is also a population that was readily available to us in San Francisco, where most of these studies started, and so most of the data come from our group and from people whom we have trained around the country and the world.  But it is very important to remember that in terms of absolute numbers, most of the cases of anal cancer in the general population are women and a very substantial number of the cases in men are occurring in men who have sex with women and not only men who have sex with men.
Here is some of the data on anal HPV infection.  To those of us in the HPV world, I think we are a little bit used to them by now, but they never fail to amaze me personally.  Basically, what you find is that in HIV-positive men who have sex with men, nearly everybody is HPV-positive in the anal canal, as shown over here, regardless of CD4 levels as an indicator of immune suppression.
Even in the HIV-negative men who have sex with men in this particular cohort study, about 60 percent of them had anal HPV infection, which is very, very high, because most of these men were in their early thirties to late forties, well past an age when if you looked at a similarly aged group of healthy women, they would already have cleared or most of them would have become cervical HPV DNA-negative at this point in time.
We always wonder when we do a cohort study, is this representative or not?  Are we seeing something unusual or odd in San Francisco?  One of the ways that we deal with that question is by broadening our studies to other sites.
This is a study that we did in four different cities around the United States where we had healthy HIV-negative men who have sex with men and did anal swabbing on them both for anal cytology, as I will show you a little later, and anal HPV testing.  They showed us two things.  One is that the data that we found in San Francisco were basically the same as we found in these four cities, and they were very high, showing a prevalence of HPV between 50 and 60 percent.
The other very interesting thing was that the pattern of HPV as a function of age was very different from the typical female cervical pattern.  Women typically get their HPV infection within their first few sexual partners.  Their peak prevalence of HPV is in their late teens and early 20s, and then most of them become HPV DNA negative by the time they are 30.
We did not see this kind of drop.  Instead we see a flat curve at this very high rate throughout the age range that we studied between less than 25 and greater than 55.  We are not entirely sure what the reasons for this difference in the pattern are, but we could speculate in discussion afterwards if you would like.
The gold standard, if you will, of these kinds of studies is to do population-based analyses, because these were still all convenience cohorts.  One way to do that is a study that involves random-digit dialing, where you literally pick up the telephone and invite people to participate in studies randomly.  So we did that in San Francisco, and we got a group of people who self-identified as men who have sex with men and who agreed to come in for testing.
Again, what we found in this random sampling was that 57 percent of the HIV-negative men had anal HPV, about a third had a cancer-causing HPV type.  Again, these numbers are huge compared to the numbers you would see in the cervix of a general population of women.  In the HIV-positive participants, again we saw almost everybody being positive, 88 percent, with more than 70 percent having at least one cancer-causing HPV type.
What I’ve shown you so far is that there is an awful lot of anal HPV infection in both HIV-negative and HIV-positive men who have sex with men.  Now what about women?  Of course there have been many, many studies of cervical HPV infection.  We did the first studies of anal HPV infection in women.  This wasn’t the first one but it was one of the bigger ones.
What it showed was that in a high-risk population -- this is done in the Women’s Interagency HIV study which consists of HIV-positive women of different CD4 levels and a high-risk, risk-matched HIV-negative group women, women who have a history of commercial sex work or injection drug use.  The surprising thing was that in each of these groups, anal HPV infection, in purple, was more common than cervical HPV infection.  So again, we were left wondering, can this be extrapolated to more generalized populations or is there something unique about this group?
Others have done some really nice studies and have shown that in fact it is generalizable.  These are some data from Marc Goodman’s group in Hawaii from healthy Hawaiian women.  They did anal and cervical HPV testing, and what they showed here is that if you look in green, the proportion who were cervical HPV-positive was 13 and 14 percent, or 27 percent overall.  The proportion who had anal HPV infection, in yellow, was also 13 and 14 percent.  So the proportion who were positive in the anal canal was the same as in the cervix.
We then did a more intermediate population study in San Francisco where we had women come in who had no history of cervical abnormalities but were sexually active and coming to our clinics for advice on contraception.  In that study about 60 percent of them had anal HPV infection and about 50 percent had cervical HPV infection.  So even in healthy populations, it is very safe to say that anal HPV infection is as common as cervical infection and probably more common in many of them.
The last frontier, if you will, is heterosexual men, men who have sex with women.  This was the last group to really be approached with any vigor, I would say.  The data on this group are still relatively sparse -- they are emerging -- but I just thought I would show you one study from the HIM study, the HPV-in-men study, in which men had sampling taken from the penis but also from the anus.  In this population of men who had sex with women, overall 13 percent had any HPV type and 7 percent or so had type 16 or 18.
So although it is not as common as in the other groups, it is still present in a substantial proportion of men of this population.  So, basically, anal HPV infection is quite ubiquitous.
How do people get it?  The usual question I am asked is, is it anal intercourse?  Do you have to have receptive anal intercourse to get anal HPV infection?  To summarize our synthesis of many different studies, I would say that it helps but it is not the only way to get anal HPV infection.  It is probably the most efficient way to get anal HPV infection.
But we do know that many people who have never had a penis inserted into their anal canal have got detectable HPV infection, and it makes sense because the perianal area and that transformation zone that I told you about is really quite close up inside.  It is not hard to imagine inoculation with the presence of other potentially HPV-carrying or -infected objects, such as fingers or toys or just about any other skin-to-skin contact that occurs in the perianal area, could with not much difficulty infect the intra-anal area.
In addition, we know that immune suppression is an important risk factor because, in addition to HIV, people who have a history of iatrogenic immune suppression for graft transplant rejection to prevent that are also at increased risk of anal cancers.
So for both men and women, we think these are some of the key risk factors.  For men it could also spread from the anterior genitals, perianus, penis, and scrotum, and then for women, potentially from the cervix and the vulva.  We think of HPV infection as a field infection and not just an infection of any one single site.
In the next set of my comments, I would like to comment on the clinical implications of this phenomenon and what anal HPV infection actually does.
From a morbidity and mortality standpoint, obviously the most important is anal cancer, but I want to focus also on AIN 2/3 because we do believe that its treatment or its prevention might actually prevent the development of anal cancer.  I also want to say a word about anal warts, because although we tend not to focus on them since they don’t directly cause mortality, they are a very serious issue, particularly to people who have them.
As we mentioned before, anal cancer is a disease predominantly of women in the general population.  In 2010 the American Cancer Society estimated that there would be roughly 5,260 cases of anal cancer, 3,260 in women, 2,000 in men, and a proportional amount of deaths in men and women from this disease.
One of the key points, though, is that although this is a relatively rare cancer, it is increasing in the general population in both men and women, and has been since the 1970s, by about 2 percent per year.  This phenomenon has been shown very consistently in every developed country where they were able to keep track of these data.
In some countries the curves diverge a little bit, but for the most part that increase is seen equally in men and women.  Our best guess is that this reflects changes in sexual behavior that began perhaps in the late 1960s or early 1970s.  These are diseases that have long latency periods, and perhaps now is the time when we’re starting to see the consequences of those behavioral changes.
I would like to focus a little bit on the groups that are at the highest risk of disease.  That is MSM and HIV-positive MSM.  Again, since anal and cervical cancer are the same disease, I like to put them in context.
If you look at the incidence of cervical cancer before we were doing cervical screening, that was about 40 to 50 per 100,000.  Now it is down to about 8 to 10 per 100,000, we think largely due to the introduction of cervical cytology screening.
If you at the incidence of anal cancer in men who have sex with men before the HIV epidemic, it was estimated to be as high as 37 per 100,000.  So though that cancer is rare in the general population, in MSM it was more or less at the same level as it was in the United States in women before we were doing cervical cytology screening.  That kind of makes sense, since we don’t routinely do anal cytology screening at this point.
Now we throw immune suppression in on top of that in the form of HIV and we see that HIV-positive men are at nearly 38-fold higher risk of developing anal cancer than the general population of men.  And given the numbers I have shown you about anal HPV infection in women, it should not surprise you that HIV-positive women are also at increased risk of anal cancer compared with the general population of women at nearly sevenfold higher.
These were also data that were collected before the introduction of antiretroviral therapy when people would die quickly, unfortunately, of other HIV-related complications.  Now we have ART, which helps people to live longer.  I will remind you we have a lot of anal HPV infection.  I will show you we have a lot of AIN 2 and 3.  We are not routinely screening, but people are living longer, and so it is kind of a perfect storm for an increased risk of anal cancer, which is what we predicted would happen, and in fact that is what we are seeing.  Several papers are now out showing that not only has anal cancer not gone down since the introduction of ART but that it actually continues to go up.
Here are some publications showing unacceptably high rates of anal cancer, 75 per 100,000 in France, 78 per 100,000 from the SEER database here in the United States, 137 per 100,000 in the MAX cohort here in the United States.
In countries where cervical cancer is very common, such as India, those numbers rarely exceed 75 per 100,000 or so.  So these numbers actually show that in HIV-positive MSM, the incidence of anal cancer is higher than the highest incidence of cervical cancer practically anywhere in the world.
So what are the risk factors for anal cancer?  Well, HPV, I am saying -- we could discuss this, but I do believe HPV is necessary.  We definitely know it is not sufficient by itself, but I think that HPV probably is necessary, and if it isn’t necessary for all cancers, it is necessary for the great majority of them.
In independent analyses, the number of sexual partners, receptive anal intercourse, and current smoking are risk factors.  I think a very important one is history of fissures, fistulas, and hemorrhoids, because we think that chronic inflammation is a key risk factor and may help to explain why the incidence of anal cancer on a per-HPV infection basis is higher in MSM, say, than it is in women, because we think there is more chronic stimulation and other things going on in the anal canal of your average, if you can call it that, MSM compared with women, in the form of new sexual partners, other STIs, other things that may cause inflammation in response to various infections.
Of course, immune suppression, as I mentioned, is a key risk factor as well.  That can occur in the form of HIV infection, it can occur in the form of iatrogenic immune suppression, as I mentioned.  Other chronic diseases may also be associated with increased risk of anal cancer, including diabetes.  Not surprisingly, if you look in the literature -- this has been known for a number of years -- in women, other HPV-related cancers are clearly associated with an increased risk of anal cancer, as you might expect if it’s a field infection, and that includes cervical and vulvar cancer.
I want to emphasize that AIN 2 and 3 or the combination -- we combine them into high-grade AIN -- is the true anal cancer precursor.  This is important because we believe that identifying and treating high-grade disease will reduce the incidence of anal cancer, although that has not yet been directly proven.
Here is that case I told you about at the very beginning.  I showed you this picture of the cancer.  Here is the same fellow who came in about a year before but was lost to follow-up.  We biopsied this.  It looked nasty even then, but it was just high-grade disease.  Then this is what happened over the course of about a year.
This is what you very frequently see when you’re looking at invasive anal cancers.  You see the high-grade disease over here and you start to see these budding protrusions of invasive cancer just starting.
There is also a literature in which people who had high-grade disease and who were not treated were followed.  One of them shown here for perianal disease, classically known as Bowen’s disease, which is flat hyperpigmented lesions, shows a 5 to 10 percent progression rate to invasive cancer.
A group in Britain showed that in immunosuppressed people three out of six of them progressed to cancer over a 5-year period when they had AIN 2 to 3.  Another one from New Zealand showed 15 percent of both men and women progressed to cancer.  This was over a slightly shorter period of time.
Then in San Francisco we have been following a group of people, a bigger group of people, who for a variety of reasons could not or would not get treated.  We have now seen at least 21 of those individuals progress from high-grade disease to invasive cancer in the exact same place where we diagnosed the high-grade lesions.  That was typically over an average of 47 months.  So we have virtually no doubt that AIN 2/3 is a precursor lesion to anal cancer.
Consistent with that, when you look at the HPV types in those lesions, they are the same as what you see in anal cancer.  In yellow is the distribution of types in anal cancers, and then in green is what you see in AIN 2 and 3.  Not surprisingly, the great majority of those AIN 2/3s are HPV 16.  There is some 18 and a smattering of some of the other classic oncogenic HPV types.
What do we know about how common this cancer precursor lesion is?  Here is that study in the four cities that I showed you before where we did anal HPV testing.  In this case we did anal cytology testing.  I will remind you that, just like in the cervix, anal cytology has limited sensitivity.  It is only about 50 percent sensitive.  So the numbers that we’re seeing here probably underestimate the true prevalence of disease by about 50 percent.
We see a flat curve between 18 and 23 percent of cytologic abnormalities, just like we saw a flat curve for HPV.  Here is AIN 2/3 with that number starting to tick up in the older age group.  But our estimate based on these was that the true prevalence of AIN would be between 30 and 40 percent in a healthy HIV-negative population.
So we went back to that population-based study in San Francisco.  Here what you can see is that when we did not only cytology but high-resolution anoscopy and biopsy, the gold standard of diagnosis, in healthy HIV-negative participants, 35 percent had AIN of any grade and a quarter of them had a cancer precursor, AIN 2 or 3.  In our HIV-positive participants, 57 percent had AIN of any grade and 43 percent had a cancer precursor.
So again, these numbers are enormous.  If we put them in the context of the general population of cervical disease in a healthy population of women, the proportion who would have high-grade cervical disease would be 1 percent or less.
In the women where we found so much HPV infection, we also find AIN.  In the WIHS study we see relatively little high-grade cervical disease and we don’t see a whole lot of high-grade anal disease either, but we saw quite a bit of AIN and CIN 1, in fact at the same levels in both the HIV-positive people, at 16 percent, and in the HIV-negative women, not surprisingly the HIV-positive women have more disease both in the cervix and the anus than the HIV-negative women.  The fact is, though, those women do have AIN.
Then more recently a paper was published in healthy HIV-negative women asking the question, if they have high-grade cervical disease, how many of them have AIN?  What this study showed was that in women who had had high-grade cervical or vulvar disease, 12 percent or so have AIN, including 8 percent with AIN 2 or 3, again all consistent with the idea of HPV as a field infection.  If you’re at risk of high-grade disease at one site, you’re probably at risk of disease at the other site.
Lastly, as far as incident disease is concerned, we have relatively limited data on this, but I will show you that from the Merck 20 protocol that you’ll hear about more from Dr. Garner we showed that in people who were naïve to the vaccine types, there was incident high-grade disease despite the fact that this is a very young group, 21.1 years mean age, 3.1, and a higher proportion developed high-grade disease in the intent-to-treat analysis, because many of those individuals already had the infection of the types that were going to cause the high-grade lesion.  So that is not surprising.
But in our San Francisco cohort study where we called the people prospectively, these are now men who are 45 years old, and they still have a high rate of incident high-grade disease, not terribly dissimilar from the younger men.  Then here are the incident rates in the HIV-positive folks.  So it seems as though there is a steady and high rate of incident high-grade disease throughout a wide age range, not surprisingly increased in the setting of HIV infection.
Now just one more promised word about anal warts because again I do believe that these are very important lesions from a clinical standpoint.
When you work in an SDI clinic, when you work in clinics that deal with young people, this is one of the most common things that we see, and they are very, very troublesome to the individuals who have them.  They are quite common, they are very contagious.  About 4 percent of sexually active men 18 to 59 years of age will ever be diagnosed with one.  Most of their sexual partners will develop warts.  It is even more common in HIV-positive people, and they are harder to treat in HIV-positive people.  In everybody they are often associated with itching, burning, and bleeding, and they are associated with a lot of psychosocial stigma and distress.
So to the degree that anything that we’re talking about today has the potential to reduce the incidence of anal warts, I as a clinician who sees these patients view that as a major plus.
I’ve told you that we have a lot of anal HPV infection, we have a lot of high-grade disease, and the question is, What do we do about it?  So we founded the world’s first clinic devoted to prevention of anal cancer, called the Anal Neoplasia Clinic, at UCSF.
We basically use the same methods that have been used in the cervix.  We screen for AIN using cytology, we use high-resolution anoscopy, and then we treat high-grade AIN.  This is the protocol that we use.  I am not going to go into it in great detail.  It is quite similar to what is used in the cervix.  For anal cytology it serves as a screening tool.  If the person has high-grade disease, we treat it whenever possible.  With AIN 1, we will treat it if the patient wants it, but we definitely follow it because we want to make sure that it doesn’t persist and progress to high-grade disease, as we have shown it can.
The groups that we think need to be considered for screening follow from everything I told you before.  They include all HIV-positive men, regardless of sexual orientation.  They include HIV-negative men over the age of 40.  I chose that number fairly arbitrarily because cancer is not that common in HIV-negative people under that age.  But that is discussable.  Women with high-grade cervical or vulvar lesions or cancer; all HIV-positive women; people with perianal warts, because if you have warts on the outside, there is a very good chance you have stuff on the inside; and then solid organ transplant recipients.
The treatment, I have to emphasize, is not a walk in the park.  In this population the lesions are multifocal.  They are often rather large.  We often need multiple procedures.  There is a high recurrence rate, there is a high incidence rate of new lesions, and the therapy is typically ablative.  We cannot give the equivalent of acyclovir, so we typically have to burn the lesions off, and that is often done with a technique called infrared coagulation or an acid called 85 percent TCA, trichloroacetic acid.
The reason we are not doing this routinely is primarily for the following reasons:  One is that this is still a very new field and there is still a huge shortage of people trained to do the techniques that I have just described to you.  When people call me up and say, “I’d like to start a screening program, what do I do?” I say, “Don’t even think about it until you have the entire spectrum of expertise on your team that’s needed to fully take care of the patient.”  That means screeners, treaters, pathologists, surgeons, et cetera.
Also, and very importantly, is that since we are in the era of evidence-based medicine, the professional societies that review guidelines want to see proof that the treatment of the high-grade lesions reduces the incidence of anal cancer.  We think that is a very important study and we’re planning to do it, but it hasn’t been done yet, and so most guidelines are not in place yet.
I would like to conclude by emphasizing that anal cancer is the same disease as cervical cancer, as are the precursors of cancers AIN and CIN 2/3.  I also want to emphasize that these are same diseases in men and woman and that it is a problem that is growing in both men and women in the general population and in select risk groups.
Anal HPV infection is a fact of life for a very large proportion of us, more than I think any of us ever thought would be the case, frankly, until we did some of these studies.  So it is not surprising that AIN 2/3 is common in select risk groups as well.  It is very difficult to treat high-grade AIN, and screening is not standard of practice.  So any measure that we can do to reduce the burden of HPV infection, the causative agent, I think would be a major step forward in the prevention of anal cancer.
Thank you very much.
DR. ROMERO:  Thank you, Dr. Palefsky.
Are there any questions?  Go ahead.
DR. MCINNES:  Dr. Palefsky, just to round out the clinical management piece, could you just get some high-level earlier treatment of anal cancer itself?
DR. PALEFSKY:  Sure.  This is an evolving area too.  In the past when there was no proactive screening, people did not appear typically until they had symptoms, and typically those lesions were reasonably advanced.  So the standard of care for those patients is chemoradiation therapy.
The problem of chemoradiation therapy is that while it is successful most of the time, there is a lot of morbidity associated with the radiation, so that even if the treatment is successful, often the patient has a bad clinical outcome.
One of the things that is changing is that for those who are actually screening proactively, we are now seeing patients who have the equivalent of microinvasive cervical cancer because we are catching them, just like some of these folks, and we are doing a protocol now where we are doing a wide local excision which spares their sphincter -- no colostomy needed -- and spares them chemoradiation therapy.  Out of 22 patients, so far only two have required chemoradiation.  But we are still worried about them because they continue to have high-grade disease, and we are also concerned that they may be at increased risk of recurrences.  So they need to be followed very carefully.
DR. ROMERO:  I have a question.  Concerning this treatment of the condyloma, I would think that this also requires a direct in-clinic treatment rather than home treatment as would be for other genital warts.  Is that correct?
DR. PALEFSKY:  Yes.  Practically, the only kind of wart treatment that can be done at home is for perianal disease because that is where the patients know where to put the treatment.  Anything intra-anal almost by definition requires a clinician to do the treatment directly.
DR. MOULTON:  You haven’t shown us any longitudinal data, but indirectly it looks like the clearance of HPV might be much higher in the cervix than in the anus.  Is that the case?
DR. PALEFSKY:  It’s a really good question.  We don’t really have longitudinal data yet on anal HPV infection.  I will give you my own bias, which is that nobody clears HPV ever.  I think most of us control it to the point where it becomes DNA-test negative.  I think that may happen perhaps more quickly in the anus in women compared with the cervix.
But data from the WIHS study where we follow HIV-positive women prospectively, when we detect new HPV types in the cervix, for example, which is quite common, about half the time there has been no new sexual exposure to explain that.  So I think there is reactivation of old HPV that is occurring there, and perhaps for some biological reasons like hormones, that tends to happen more often in the cervix than in the anus.
DR. PALEFSKY:  Any other questions?  Thank you very much.  We will move on to Dr. Brill-Edwards, please.
DR. BRILL-EDWARDS:  Thank you for that comprehensive overview, Dr. Palefsky.
I will now present the current status of Gardasil.
As Dr. Roberts mentioned, Gardasil is a quadrivalent vaccine.  It contains virus-like particles or VLPs for HPV types 6, 11, 16, and 18.  It is given in three doses at zero, two, and six months.  It contains Merck’s adjuvant that has been in use for over 20 years.  The VLPs are manufactured in yeast, which is a well-accepted method.  The VLPs are not viruses, so they cannot cause infection or disease.
Gardasil was approved in 2006 on the basis of an extensive clinical development program in girls and women.  Some of the key studies listed here are ongoing to provide additional long-term data.  If you recall, last September we presented the results of the primary efficacy analysis of external genital lesions in males that led to the October 2009 approval of Gardasil for use in boys and men to prevent genital warts due to HPV types 6 and 11.
The focus of today’s presentation is the data from the AIN substudy of approximately 600 men who have sex with men, which was submitted in February of this year.
As you will see, the safety and efficacy results of the AIN study are consistent with previous studies of Gardasil.  Recall that at each step of the clinical development program, first in women for the endpoints of high-grade cervical, vulvar, and vaginal precancers, as well as genital warts, and then, in men, for genital warts, efficacy was high against all HPV-related genital diseases.  This high efficacy is reflected in the current Gardasil label, which I will discuss in a moment.
First, there is an unmet medical need to prevent anal cancer.  Up to 90 percent of anal cancer is caused by HPV.  Anal cancer is more common in women than men, but the incidence is rising in both groups.  Anal cancer treatment, as Dr. Palefsky mentioned, even when successful, is associated with substantial morbidity; for example, radiation-induced proctitis can result in chronic problems such as pain and bloody diarrhea.
Gardasil can help address this unmet medical need.  Currently there is no vaccine approved for the prevention of HPV-related anal precancers or cancer.  The AIN study builds upon the high efficacy previously demonstrated against all evaluated genital endpoints in men and women, and the results of the AIN study confirm the established favorable safety profile of Gardasil.  Given the totality of the data, the AIN study extends the potential benefit of Gardasil to anal cancer prevention in both men and women.
I will now highlight the proposed indication.  This is the current label for Gardasil, and in the yellow text you can see that for girls and women we propose adding prevention of anal cancer caused by HPV types 16 and 18 and prevention of AIN grades 1, 2, and 3.
Similarly, for boys and men, we propose adding prevention of anal cancer caused by HPV types 16 and 18 and prevention of AIN grades 1, 2, and 3.
The rationale for these additions to the indications section are that the proposed indication is based on disease endpoints, and although we studied an MSM population, anal cancer is the same disease in men and women, so an indication is being sought in both males and females.
Most anal cancer is caused by HPV.  AIN 2/3 is the precursor of anal cancer, and thus preventing AIN 2/3 will prevent anal cancer.  The benefit/risk profile continues to be favorable.
In addition to Dr. Palefsky, Merck has several consultants in attendance today, and I would like to acknowledge them now:  We have Dr. Catherine Dean from the Washington University School of Medicine; Dr. Anna Giuliano from the H. Lee Moffitt Cancer Center and Research Institute; Dr. Mark Stoler, University of Virginia; and Dr. Lee-Jen Wei of Harvard University.
Now I will ask Dr. Garner, the lead clinical monitor, to summarize the results of the AIN study.
DR. GARNER:  Thank you very much.
Good morning.  My name is Elizabeth Garner, and I am the lead clinical monitor for the male efficacy study.  As an obstetrician-gynecologist and subspecialist in gynecologic cancers, previously in practice treating many women affected with HPV-related genital and anal disease, I feel very privileged to talk to you today about the extension of Gardasil’s efficacy to include HPV-related anal disease and its potential role in addressing the unmet medical need of anal cancer prevention in men and women.
Today I will present the evidence for the role of HPV in anal cancer in men and women, review the burden of anal cancer in men and women, discuss the role of high-grade anal intraepithelial neoplasia as the precursor of anal cancer, present the AIN study design and results, and provide an update of postlicensure safety surveillance and plans for longer term effectiveness studies.
I will conclude with a summary of the rationale for proposing an indication for Gardasil in the prevention of anal cancer in boys and girls and men and women from 9 to 26 years of age.
First, the role of HPV in anal cancer in men and women.  By way of a brief review, human papillomaviruses are non-enveloped, double-stranded DNA viruses.  To date, over 100 types of HPV have been identified, approximately 30 to 40 of which are sexually transmitted.
HPV are classified as low- and high-risk types based on their level of association with benign and malignant anogenital tract disease, respectively.  Both low- and high-risk HPV types contribute to a high lifetime risk of HPV-related pathology in both men and women.
The four HPV types prevented by Gardasil, types 6, 11, 16, and 18, together cause the majority of benign and malignant HPV-related disease in the anogenital tracts of men and women.
The HPV-related anogenital tract cancers all develop through a similar pathogenetic process which has recapitulated in the various epithelial tissues of the anogenital tracts of men and women and starts with initial infection of the epithelial basal cell.
As Dr. Palefsky described to you in his talk, an incidence of HPV infection may become a persistent infection, and although it does not appear to be sufficient, this persistence of HPV infection is a necessary event in HPV carcinogenesis.  So without it, HPV-related cancers cannot develop.
In persistently infected epithelium, cell growth may be altered, leading to the development of clinically apparent precancers that can progress from the precursor lesion of intraepithelial neoplasia 2/3 or high-grade intraepithelial neoplasia to invasive cancer.  This HPV-related carcinogenetic process is similar for the HPV-related cancers and similar across the genders.  As a result, HPV causes multiple related cancers in the anogenital tracts of men and women.
Each year approximately 28,000 cases of HPV-related cancer occur in the United States.  The most well described of these is cervical cancer, the first cancer for which the causal link to HPV was made.  Presence of HPV in cancer lesions is now widely accepted as evidence for the etiologic fraction of HPV-related cancers.  On this basis, virtually 100 percent of cervical cancers are HPV-related.
The numbers provided in this table are 2010 estimates published by the National Cancer Institute and the Centers for Disease Control and show that substantial percentages of vulvar and vaginal cancers in women, penile cancers in men, and oral cavity and oropharyngeal cancers in men and women are caused by HPV.
With approximately 5,000 new patients diagnosed per year, more HPV-related cases of anal cancer occur annually than HPV-related vulvar, vaginal, and penile cancers combined.
Close to 90 percent of anal cancers are caused by HPV, and, as is the case with cervical cancer, the majority of anal cancers are HPV 16- or 18-related.
So overall, from an etiologic and pathogenetic standpoint, anal cancer is more similar to genital malignancies than to other cancers of the gastrointestinal tract.
In addition to the similar causal relationship of these cancers to HPV, there are other types of evidence that support that anal cancer is analogous to cervical cancer.  First, the risk factors for anal and cervical cancer, including lifetime number of sexual partners and prior history of HPV-related disease, are similar, and many are notably common in the general population.
Additionally, as you heard from Dr. Palefsky, similar to cervical cancer, anal cancers arise in the analogous transformation zone of the anal canal.  The histology and molecular characteristics of anal cancer are similar to cervical cancer.
The evidence also supports that anal cancer is the same disease in men and women.  This statement is supported by similar types of evidence as supports the similarities of anal cancer to cervical cancer:
First, the predominant causal HPV types for anal cancer are the same in men and women, and HPV-related anal cancers arise in the same anatomic location and cell type in men and women.  The molecular characteristics of anal cancers are the same between the genders.  And finally, just as cervical and anal cancers are identical, anal cancers in men and women are histologically indistinguishable.
All of this evidence is strongly supported by the epidemiologic data, which has reproducibly shown that the risk factors for anal cancer are the same in men and women regardless of sexual orientation.  As with cervical cancer, populations in which these risk factors are more prevalent have higher incidences of anal cancer.  Notably, the lifetime number of sexual partners is strongly positively correlated with risk of anal cancer.
Anal intercourse is also a known risk factor for anal cancer, but multiple studies have shown it is not required for anal HPV infection or cancer development in men or women.
This table of combined data from five epidemiologic studies of patients with anal cancer, totaling approximately 1,200 subjects, shows that the majority of women, all heterosexual men in these studies, and a substantial proportion of self-described men who have sex with men with anal cancer report no history of anal intercourse.
Having reviewed the evidence that HPV causes anal cancer and that it causes the same disease in men and women, I would like to focus briefly on the burden of anal cancer and remind you of what you heard earlier about the burden of anal cancer and the unmet need for prevention of this disease, which is increasing in incidence in both men and women.
As Dr. Palefsky described, 5,260 new cases of and 720 deaths due to anal cancer were predicted to occur in the year 2010 in the United States.  Approximately 60 percent of new cases of and deaths due to anal cancer occur among women, and there is evidence to support that among men a substantial proportion of cases occur in heterosexual men.
Dr. Palefsky also pointed out that the incidence of anal cancer has been steadily increasing at a rate of approximately 2 percent per year in both genders for the past several decades.  I would also point out that deaths from anal cancer have followed a similar pattern and have been increasing at approximately 1.7 percent per year.
In addition to the burden of anal cancer related to disease incidence and deaths are other factors that demonstrate that prevention of anal cancer is an unmet medical need.  First, anal HPV infection that can lead to cancer is common in men and women and is not easily prevented.  You heard many of the detailed numbers on anal HPV prevalence in various populations from Dr. Palefsky.
Given current overall rates of anal cancer, screening of the general population is not practical.  Related to this lack of screening, approximately 40 percent of anal cancer patients are diagnosed with regional or distant spread for which treatment is more extensive and survival is lower.
The unmet need for anal cancer prevention is also demonstrated when one considers the burden to patients related to treatment of the disease, which for most individuals consists primarily of combination radiation and chemotherapy.
Although current anal cancer treatment is often successful, radiation therapy in particular is associated with acute and chronic morbidity and negatively impacts many aspects of quality of life in patients who survive the disease.  Late effects of radiation, such as anal ulcers, stenosis, and necrosis or local disease recurrence in the anal area may necessitate colostomy in up to 6 to 12 percent of patients.
Some of the more common and particularly morbid of the side effects of radiation therapy are shown here and include radiation proctitis, radiation-related skin infection, and post-radiation anal stenosis, which may be accompanied by anal incontinence.
With all of this as background, and before presenting the clinical data, I would like to highlight the key types of evidence that support than AIN 2/3 or high-grade AIN is the precursor of anal cancer.
First are the epidemiologic data.  Prospective studies have consistently shown that compared to the general population, individuals with AIN 2/3 have a substantially elevated risk of invasive anal cancer.
The natural history studies also provide direct evidence of progression to anal cancer in screened patients with AIN and point to the limitations of AIN treatment, such as inability to remove the transformation zone of the anal canal, which can be done for treatment of CIN.
Molecular and histologic evidence support the epidemiologic data.  As you recall from the histologic image Dr. Palefsky showed you, histologic progression is frequently observed in tumor lesions, and when identified together, pre-malignant and invasive anal lesions share molecular changes.
It is notable that expert groups such as the National Cancer Institute, the American Cancer Society, and the American Society of Colon and Rectal Surgeons consider the evidence sufficient to recognize high-grade AIN as a precursor of invasive anal cancer.
In light of the evidence that HPV-related high-grade AIN is the precursor of anal cancer, it follows that prevention of high-grade AIN by prevention of HPV infection will prevent anal cancer.  In this context, I will now move on to the clinical study and the results.
Before I present the AIN study, I will briefly overview the overall rationale for the Gardasil clinical development program and provide a summary of the results from the overall male efficacy study, of which the AIN study was a part.
Several considerations were taken into account when the clinical program for Gardasil was designed.  First, Gardasil is a prophylactic vaccine designed to prevent and not treat HPV infection.  The efficacy of Gardasil is thus highest when it is administered prior to sexual debut, and therefore pre-adolescent boys and girls are the optimal age group for routine immunization with Gardasil.
However, given the nature of the trials required, efficacy studies among preadolescents are not feasible, and therefore efficacy was studied in adults and bridged through immunogenicity to preadolescents.
The first efficacy studies were performed in women and were the basis for initial licensure of Gardasil against cervical cancer based on prevention of CIN.  Similar methodologies were used in the male efficacy study, Protocol 20, which was a multinational, randomized, double-blind, placebo-controlled study of 3,463 heterosexual men, or HM, aged 16 to 23 years, and 602 men who have sex with men, or MSM, aged 16 to 26 years.
The overall study evaluated the efficacy of Gardasil against external genital lesions, or EGLs, persistent infection and DNA detection, immune responses, and safety.  Results from the overall study led to the approval of Gardasil in 2009 for HPV 6- and 11-related genital warts in boys and men 9 to 26 years of age and were presented in detail to this committee last year.
Following the primary analysis, subjects continued to be followed through to the end of the overall study, at which time end-of-study analyses were performed.  Overall, findings were consistent with the primary analysis.  The data were submitted in a supplemental license application and were reviewed in the background document you received.
To summarize them briefly, high efficacy against the primary endpoint of 6-, 11-, 16-, or 18-related external genital lesions was confirmed, the primary analysis having shown 90 percent efficacy.  End-of-study results showed efficacy of 91 percent.  Immune responses were robust, and a continued favorable safety profile was observed in both heterosexual men and MSM subjects.
The final study results are also consistent with other pivotal clinical trials of Gardasil and thus have contributed to the totality of the data on efficacy and safety in men and women.
The main reason we are here today is to present and discuss the data from the AIN substudy in MSM, which was a predefined study within Protocol 20 aimed at evaluation of the efficacy of Gardasil against anal disease in the 602 Protocol 20 MSM subjects aged 16 to 26 years.
I would also remind you that the MSM subjects contributed to the overall study endpoints as well as to the AIN efficacy evaluation.  However, data on anal disease efficacy were not presented last year because at the time of the overall study primary analysis, the prespecified number of anal disease endpoints required for the analysis had not yet accrued.  Thus, from an efficacy standpoint, last year’s advisory committee meeting was entirely focused on external genital lesions.
With respect to the rationale for this study population, men who have sex with men were selected for the evaluation of anal disease efficacy due to the high incidence rates of anal HPV infection and disease in this population.  This approach allows for an efficacy demonstration within reasonable study time lines.
In order to maximize the proportion of HPV-negative individuals for the prophylactic efficacy analysis, key inclusion criteria for MSM subjects included no history of HPV infection or disease, fewer than or equal to five lifetime sexual partners, and HIV-negative status.  Subjects were to be followed for up to 36 months.  For the AIN per-protocol analysis, the medium follow-up time for subjects was 32.2 months after dose one of Gardasil.
The objective of the study was, among MSM, to assess the efficacy of Gardasil against the combined incidence of HPV 6-, 11-, 16-, or 18-related AIN or anal cancer.  The analysis was to be conducted when at least 17 cases of HPV 6-, 11-, 16-, or 18-related AIN or anal cancer were observed.  As I just mentioned, this number had not yet accrued at the time of the primary analysis of the overall study.
For the evaluation of anal infection and disease endpoints, in addition to the procedures for the EGL efficacy analyses, MSM subjects underwent rigorous assessments for the complete ascertainment of anal disease.  Anal swab sampling was done for HPV DNA detection by PCR using the same PCR assays as in the female protocol.  A subject was considered HPV positive at a visit if the anal swab from that visit was PCR positive for the relevant HPV type.
In the same way as Pap smears were utilized to assess for disease in the pivotal female trials, anal cytology was used to assess for disease, and results were managed using a cervical cytology-based, protocol-specified anal cytology management algorithm.
High-resolution anoscopy with intra-anal biopsy was performed for evaluation of abnormal cytology results.  For complete disease ascertainment, a mandatory high-resolution anoscopy was also performed on all subjects at the final study visit.
With respect to disease endpoint identification and case definition, consistent methods have been used throughout the Gardasil clinical program.  For disease endpoint assessment, all anal biopsy specimens were processed in a standard manner at the central laboratory.  After fixation and paraffin embedding, consecutive thin sections were prepared.  While the first and the last thin sections were H&E stained and sent to the blinded pathology panel members for consensus diagnosis, thin sections adjacent to these were sent to the PCR laboratory for DNA extraction and testing by multiplex PCR, and a case of 6-, 11-, 16-, or 18-related AIN cancer was confirmed when any one of HPV types 6, 11, 16, or 18 was detected in a sample that received an endpoint diagnosis of AIN from the pathology panel.
The primary analysis of AIN efficacy was performed in a per-protocol population which comprised all subjects who received three doses of vaccine or placebo, were seronegative at day one and PCR-negative at day one and month 7 to the relevant HPV type.
MSM subjects were tested for HIV yearly during the study and had to be HIV negative to be included in the per-protocol analysis population.  Endpoints for this analysis were counted starting after month 7.
Supportive intention-to-treat analyses were performed in the full-analysis-set population, which comprised all subjects who received at least one dose of vaccine or placebo and had followed after day one.  Endpoints for this analysis were counted starting after day one.
It is important to note that efficacy in the FAS population was expected to be lower than in the PPE population because negativity to the relevant HPV type was not a requirement for inclusion and because cases were counted prior to completion of the vaccination regimen before full protection is anticipated.
By way of subject accounting for the per-protocol efficacy analysis, of the 602 randomized subjects, an equal number were in each treatment group.  Of the 299 subjects in each arm who received at least one dose of vaccine or placebo, approximately two-thirds were eligible for the per-protocol AIN 6, 11, 16, or 18 analysis.
The most common reasons for general exclusions from the per-protocol analysis were incomplete vaccination, missing PCR swab results from day one or month seven, and general protocol violations.
As shown in this table, the median ages of the MSN subjects were 22.2 and 21.1 in the vaccine and placebo groups respectively.
As the racial and ethnic distribution data show, subjects in the MSN population were a diverse group from multiple racial and ethnic backgrounds.
Overall, all evaluated baseline characteristics were similar in the vaccine and the placebo groups.
I will now move on to the efficacy results for the anal disease and infection analyses.  The tables shown in the next several slides have the same format.  The number of cases in the vaccine and the placebo groups are presented, followed by the efficacy estimate and related 95 confidence interval, along with statistical significance when applicable.
First are the efficacy results showing reductions due to Gardasil of HPV 6-, 11-, 16-, or 18-related AIN in the per-protocol population.  I would briefly remind you here that predefined study endpoint was 6-, ll-, 16-, or 18-related AIN or anal cancer; hence the use of the term “anal cancer” in these tables.
With five cases of HPV 6-, 11-, 16-, or 18-related AIN in the Gardasil group and 24 cases in the placebo group, the observed vaccine efficacy was 78 percent.  For the vaccine group subjects, HPV PCR results prior to and in the case biopsy tissue suggested the potential role of non-HPV 6, 11, 16, or 18 HPV types in development of these cases.  However, according to the case definitions, each of these was counted as a case in the treatment arm.
Despite this conservative approach, success was achieved in the test of the AIN efficacy hypothesis, showing strong and significant vaccine efficacy against the predefined study endpoint.
Having achieved success on the pre-specified endpoint, we also evaluated efficacy by an AIN grade.  While there were no hypothesis tests for these endpoints, these analyses provided important information to show that vaccine efficacy was equally high when evaluated by disease severity.  Efficacy against AIN 1 was 73 percent and against AIN 2 or higher, or high-grade AIN related to HPV 6, 11, 16, or 18, was 75 percent, showing consistent efficacy across lesion severity.
There were no cases of invasive anal cancer observed during the study.
The associated time-to-event curve shows in the Y-axis the cumulative percentage of subjects becoming cases and on the X-axis time since day one or the first dose of vaccine or placebo presented in months.  The numbers in these rows are the numbers of subjects in each treatment group at risk at each time point.  The yellow line represents Gardasil recipients and the white line represents the placebo group.
Early in the study, the incidence of disease was low in this per-protocol population.  Over time, as subjects were exposed to HPV, the curve separates as incident AIN cases begin to be observed in the placebo group, while the vaccinated subjects were protected.
In order to further evaluate consistency of the effect and better understand the potential of the vaccine to prevent anal cancer, vaccine efficacy against high-grade AIN related to HPV types 16 and 18 was assessed.  I already presented the efficacy for high-grade AIN related to types 6, 11, 16, and 18.  For 16 and 18 efficacy, one case was observed in the vaccine group and eight cases were observed in the placebo group, for an efficacy estimate of 87 percent.
Again, although there was no a priori hypothesis test of efficacy for this endpoint, the consistency of the effect provides important evidence of efficacy against high-grade AIN and, therefore, against anal cancer caused by these important HPV types.
Given the necessary role of HPV infection in HPV-related anal disease development, vaccine efficacy against persistent anal infection was evaluated.  To briefly review, the persistent infection endpoint was met if a subject was positive by PCR to a given HPV type in two or more consecutive anal samples collected 6 months apart.
The observed efficacy against types 6, 11, 16, or 18 persistent infection in the per-protocol population was 95 percent.  Given that HVP-related precancers and cancer do not develop in the absence of preceding HPV infection, these results provide important supportive evidence that complements and strengthens the disease efficacy findings.
Type-specific efficacy estimates against types 16 and 18 were each over 90 percent.  This high degree of type-specific prevention of persistent anal HPV infection, particularly against types 16 and 18 infection, further strengthens the type 16- and 18-related high-grade AIN findings and provides support for the potential of Gardasil to prevent high-grade anal intraepithelial neoplasia and anal cancer.
I will now shift from the per-protocol analysis to the intention-to-treat efficacy analysis in the full-analysis set.
The FAS analysis is a sensitivity analysis designed to provide supportive data to the per-protocol analyses.  As I described earlier, because these subjects may be HPV positive at base line and cases were counted prior to completion of the vaccine regimen, efficacy in the FAS population is expected to be lower than that observed in the PPE population.  In this population, efficacy of 50 percent was observed, supporting the results of the per-protocol analysis.
The consistency of efficacy across lesion severity was again seen in this population.  Similar efficacy results were observed for AIN 1 and high-grade AIN related to the four types and the vaccine supporting the efficacy findings in the per-protocol analysis.
The associated time-to-event curve in the FAS population showed similar rates of disease in the vaccine and placebo groups early in the study, reflecting the dominance of cases caused by prevalent infection.  As time progresses, the curves separate, showing continued accrual of cases in the placebo group and prevention of incident cases in the vaccine group.
To summarize the anal infection indices efficacy results, Gardasil is efficacious against the pre-specified endpoint of 6-, 11-, 16-, or 18-related AIN.  Relevant to the anal cancer indication we are seeking today, Gardasil is efficacious against high-grade AIN related to HPV types 6, 11, 16, or 18, and high-grade AIN related to the high-risk types 16 and 18, which cause the vast majority of anal cancers.
Gardasil is efficacious against persistent anal HPV 6, 11, 16, or 18 infection, which is strongly supportive of the disease efficacy findings including high-grade AIN.
The consistency of these findings from persistent infections across the levels of anal disease severity, when taken in the context of the previous efficacy results in men and women, contributes to the totality of the data on the efficacy of Gardasil across the genders and across multiple anogenital sites.
I will now move on to provide a brief update on the postlicensure longer term assessments of the safety and effectiveness of Gardasil.
Merck has implemented a comprehensive risk-assessment plan for Gardasil.  As key elements of this plan, Merck is conducting ongoing, longer term safety and effectiveness studies in both males and females.  These include extensions of the adolescent study in males and females and of the efficacy studies in men and women, as well as postlicensure safety studies in males and females.
In addition, safety surveillance for possible safety signals is carried out through continuous monitoring of spontaneous safety reports.  To date, findings continue to support the favorable safety profile of Gardasil.
With regard to Protocol 20 specifically, the long-term extension comprises regular follow-up of eligible subjects for up to 10 years from enrollment into the base study.  All subjects who agree to participate will be followed for safety and immunogenicity and for development of external genital lesions.  Participating MSM subjects will be evaluated for the development of anal disease with annual anal cytology and biennial HRA.
To conclude, the new data presented today show that Gardasil is efficacious in the prevention of AIN.  Taken together, the totality of the evidence supports an indication for Gardasil in the prevention of anal cancer in males and females.
To summarize the key elements of the rationale for proposing this broad indication, I presented earlier than MSM were studied due to their high rates of anal HPV infection and disease.  However, anal HPV infection and disease are not limited to MSM.  The same predominant HPV types cause anal cancer in heterosexual men and women as in MSM.
As both Dr. Palefsky and I have discussed today, there are no gender or population-specific characteristics of HPV-related cancer.  Anal cancer is the same disease in MSM, heterosexual men, and women.
Furthermore, the clinical studies have shown that Gardasil is efficacious in all studied populations.  AIN efficacy in MSM should thus reflect efficacy in heterosexual men and in women.
The proposed indications should therefore be broadly applicable to prevention of anal cancer in boys and girls and in men and women 9 to 26 years of age.
We have also shown you evidence today that prevention of anal cancer is an unmet medical need in men and women.  Anal HPV infection is common in both genders and is difficult to prevent.  Many of the risk factors for anal cancer, such as previous HPV-related disease, are common in the general population.
In addition, the burden of anal cancer with respect to both incidence and mortality is increasing in men and women.  At current rates of anal cancer, however, screening of the general population is not practical.
Taken together, all of these factors point to the conclusion that an alternative method is needed to prevent anal cancer.  The evidence we have today supports that this unmet need can be addressed by vaccination with Gardasil.
The HPV types prevented by Gardasil, types 16 and 18, cause most anal cancers in men and women.  And because AIN 2/3 does not develop without HPV infection, it follows that preventing this infection through primary prevention of anal HPV infection will prevent HPV-related anal cancer.
The new results from the AIN study have shown us that Gardasil is efficacious against anal HPV infection, AIN, and AIN 2/3.  Although this demonstration of efficacy was performed in an adult population for feasibility reasons, we do know that vaccination of individuals prior to sexual debut will provide the greatest public health benefit from Gardasil.
The AIN efficacy data, when considered in the context of all of the previous demonstrations of its consistent high efficacy against HPV-related diseases in both genders, extend the benefits of Gardasil to include the prevention of anal cancer in men and women.
Thank you for your attention.
DR. ROMERO:  Thank you, Dr. Garner.
Are there any questions for Dr. Garner?
DR. DURBIN:  There were no cases of anal cancer in your study.  Is that due to treatment of subjects who had grade 2/3 lesions or not a long enough duration of follow-up?  Are they continuing to be followed for that?
DR. GARNER:  It’s possible that it’s a combination of both things, but it is probably more likely it is related to the relatively short duration of the study.
DR. MARKOWITZ:  I know in some of your other analyses for other studies you have looked at efficacy against any HPV-related outcomes in your FAS population.  Do you have that for this study?
DR. GARNER:  Yes, we do.
Could you display slide 1041, please.
This is the analysis in the full-analysis set for any AIN.  As you can see, even in this population of individuals who came in with potentially prevalent infection and disease, efficacy -- we were able to show a benefit of 26 percent efficacy.
Could you also provide the summary table.
What this table shows you is that initial, that first line here, this is a table with the same format as you’ve seen previously, and these are the numbers that I just provided to you.  The efficacy is 26 percent.
But I mentioned the fact that in the FAS population you have quite a bit of prevalent HPV infection which leads to disease.
There are a couple of reasons why this number is lower than the HPV 6, 11, and 16 efficacy.  That has to do with the fact that, as you see here, there is a contribution of disease related to other HPV types.  And yet we were still able to demonstrate efficacy.
Of course, from an anal cancer standpoint, disease that is related to these HPV types is less likely to progress to anal cancer and has really -- it’s this efficacy against the types that are more related to cause anal cancer that is relevant for this population.  But despite the amount of prevalent disease here, infection, we were able to show benefit.
DR. MCINNES:  Dr. Garner, could we look at slide 96 again, please.
DR. GARNER:  Could you display 96?
DR. MCINNES:  With reference to the five cases in the Gardasil group, I believe you made some mention about their being non-6-, 11-, 16-, 18-related AIN.  That went by very quickly.  Could you elaborate, please?
DR. GARNER:  Certainly.  What I was describing was the approach, of course, that we take to defining our cases.  In this particular population, there was quite a bit of co-infection.  Patients commonly, in both treatment groups, came into the study with prevalent infection with HPV types, both the types that are in Gardasil but also quite a bit of non-6-, 11-, 16-, 18-type disease.
Could you display slide 1978, please.
This is a detailed presentation of the five cases in the Gardasil group.  Basically, what this shows you is that these are the baseline infections that were detected in two of the patients.  Not only did patients present with baseline infection but, as you can see, four of these patients had presence of non-6, 11, 16, 18 high-risk HPV types in their lesions.  As you can see, in a couple of these those types actually were present at base line.  So this suggests, of course, some possible contribution of those types to disease development in the vaccine group.
What is also very striking when we look at these data is that in fact the type to which we ended up attributing the lesion was actually not detected in the majority of these cases at base line.  So those two pieces of evidence together support the potential role of non-6, 11, 16, 18 types in disease development.
Nonetheless, of course, we have to stand by our predefined endpoint, and all of these cases were attributed to types 6 and 16.  Nonetheless, despite this heavy co‑infection and possible contribution of other types, we were still able to demonstrate excellent efficacy.
DR. SANCHEZ:  What is the immunogenicity of the vaccine in the HIV-positive population?
DR. GARNER:  HIV-positive patients, as I said, were actually excluded from the study.  That said, we did have a number, unfortunately, of people who converted to HIV during the course of the trial.  We did look at immunogenicity in this population and found that the vaccine was immunogenic in HIV-positive individuals as well.
DR. ROMERO:  Any other questions?  Go ahead, Dr. Moulton.
DR. MOULTON:  I have a few.  Shall I ask them one at a time?
DR. ROMERO:  That may be fairer to the presenter.
DR. MOULTON:  All right.  First of all, on the design on slide 88 --
DR. GARNER:  Could you display slide 88, please.
DR. MOULTON:  -- I wasn’t sure about the 17 cases here.  Was that for an interim analysis or was it to be the final analysis?  You ended up with I think 29 or something.  Was that just from momentum, or what is the relationship of 17 here to the design of the study?
DR. GARNER:  Sure.  So 17 cases was the target number of cases that we needed to identify in order to perform the analysis.  The 29 cases is the total number of cases that were observed at the end of the study.  So 17 was the target number in order to perform an analysis.
DR. MOULTON:  Okay.  There was no interim analysis for efficacy?
DR. GARNER:  As was described in the background document, at the time that the analysis for external genital lesions was presented, we had not reached that target number of 17 cases.  In order to be fully transparent, though, to the agency, we provided the information on the cases that had been identified.  But there was no inference made at that point on efficacy.
The agency did consider this, however -- despite not making any inferences on efficacy, the agency did consider this to be an interim look at the data.  In discussions with them, we agreed that an adjustment of the alpha was appropriate, and that is what is reflected in the 95.1 percent confidence intervals that you see.
With respect to continued conduct of the study, of course, all of the procedures related to disease ascertainment in terms of blinding of the pathology panel, the laboratory, anyone who was responsible for case ascertainment was completely blinded, so that did not change.
DR. MOULTON:  Okay.  On slide 93 --
DR. GARNER:  You can display that.
DR. MOULTON:  Do you have a more in-depth description of the difference between the last two lines there?  There is a lot there for the per-protocol analysis, and I was wondering how many of those are due to those who were seropositive at 7 months.
DR. GARNER:  Sure.
Could you display slide 982, please.
This is a breakdown of the main reasons for ineligibility for the per-protocol analysis.  Just one thing to point out on this particular slide is that subjects may have had more than one reason for exclusion, so you’re not going to be able to add up the numbers here.  But these were the main reasons the subjects were excluded from the population on a general basis.
The main reasons included not receiving three doses, having missing PCR results either at day one or month seven, and then a number of general protocol violations, which included such things as not being able to come in for a visit, a few of those the HIV diagnoses that I mentioned.  But these are the general exclusions.
Then, of course, for each population, there were exclusions based on PCR positivity that were the type-specific exclusions.
DR. MOULTON:  Yes, those were the numbers I was especially interested in.
DR. GARNER:  If you could display slide 1709.
This is a display of the baseline positivity for the subjects in the study.  You see the overall efficacy numbers here, the five and 24 cases.  Sorry, it wasn’t an efficacy slide we were looking for.  I’m sorry, just one minute.  I will find the correct slide.
Could you display slide 1111.
This gives you a general sense.  Of course, I am not necessarily showing data for each particular HPV type because every type is separately analyzed.  But this gives you the results of the baseline HPV 6, 11, 16, and 18 positivity by serology and/or PCR in the MSM subjects.
What is displayed on the side is the patients by treatment group, Gardasil and placebo, and the various categories of positivity, whether by serology, by PCR, or by serology and/or PCR.  Of course, this is for all the types combined.  As you can see, 22 percent and 24 percent, respectively, in the Gardasil and placebo group are positive by serology to at least one of these HPV types.  By PCR, 29 percent and 32 percent were positive, and by serology or PCR, 37 and 42 percent.
So it was balanced between the treatment groups, but you do see that there was quite a bit of baseline HPV 6, 11, 16, and 18 PCR and serology positivity.
DR. MASSEY:  And what about the PCR-related exclusions for 7 months?
DR. GARNER:  We do have that.  We have a breakdown of all of the -- (pause).  Please display slide 262.
This is actually the original slide we were trying to identify.  This gives you, going from the FAS population for whom PCR and serology positivity were not considered, all the way to the PPE population.  These are the reasons for exclusions from the PPE population that led to the FAS population.  I already mentioned the protocol violators and the missing PCR results.
These are the relevant data, I think, that you’re looking for, which is subjects who were PCR positive after day one up to month seven.  Then these are the initial ones that I was mentioning, the subjects who were sero- or PCR-positive at day one.
DR. MOULTON:  That’s good.  Thank you.
DR. ROMERO:  Any other questions?  Dr. Eng?
DR. ENG:  I just have one question.  For the MSM patient population in the medium of 32 months, can you just comment very briefly about any significant toxicities other than localized skin reaction of Gardasil?
DR. GARNER:  Sure.  For the overall safety profile in the MSM population, it was very similar to that which we’ve seen in both men and women in the overall population of the study.
I am just going to provide a summary for you.
Could you display 1313, please.
This is the safety summary for MSM subjects for the entire duration of the study.  What is displayed on this slide is the breakdown of Gardasil and placebo subjects and then in each row the number of subjects with each specific AE.  What this shows here is that the number of subjects in each group with one or more AE was about 70 percent in each group and was balanced.  Injection site adverse experiences were the most common, and that has been true throughout the Gardasil program.
The rate of systemic adverse experiences was pretty much consistent with what we’ve also seen before.  There were very few serious adverse experiences in the MSM population; in fact there were only two.  Neither of these was considered vaccine-related by the study investigators.  There were no deaths in the MSM population and very, very few discontinuations due to an adverse event.  So overall the safety profile was very favorable.
DR. MARKOWITZ:  I noted that you didn’t present any immunogenicity data, but I see that Dr. Roberts will be presenting that this afternoon.
But I did have one question about the nine subjects in the placebo group that were DNA positive between day one and day seven.  Was there any evidence of boosting of antibody due to natural infection in those individuals?
DR. GARNER:  Yes.  I don’t have for you the specific results for each individual patient.  We can provide that if you would like.  There was evidence of boosting in fact even in the PPE population.  In the vaccine group, for instance, there was a patient who had a response, it seemed, although he was of course negative coming into the study.  But it appeared very much to be an atomistic(?) response.
DR. ROMERO:  Any other questions from the committee?  Dr. Tsai?
DR. TSAI:  Earlier in the epidemiological presentation, it seemed that the contribution of 16 and 18 was very important for anal cancer and AIN, and the relative contribution of 6 and 11 was considerably lower.
I was just wondering, in slide 101 and also among the five breakthrough cases that were highlighted earlier, it seems like in this population at least HPV 6 accounted for a fairly large proportion of cases.  I was just wondering why that might be.
DR. GARNER:  Sure.  Well, 6 and 11, as you know, are clearly very important causes of anal infection or of anal disease.  This is why, of course, we looked at them for the overall endpoint.
With respect to anal cancer, it does appear that overall the literature is somewhat inconsistent on the specific role of 6 and 11 in anal cancer, and so for that reason I think we cannot really necessarily say that these data are inconsistent with what has been observed previously, because I would say the literature really is variable around 6 and 11.
Certainly our study supports that they can cause high-grade AIN.  However, specifically, I think overall one would conclude that probably from a cancer standpoint they are less oncogenic, they have less oncogenic potential.
That said, the high-grade lesions that we saw all, regardless of whether they are 6-, 11-, 16-, or 18-positive, are considered pre-malignant.  It is just that the lesions related to 6 and 11 are likely to progress probably at a slower rate overall and perhaps at a lower percentage overall, but they are still considered pre-malignant.
But it is specifically for these reasons that once we saw efficacy against the overall endpoint that we did look specifically at 16 and 18 efficacy because those are the most important for anal cancer.
DR. ROMERO:  Any other questions for the committee?  All right, thank you very much.
We are scheduled for a break here.  We’re running a little bit ahead of time, so why don’t we go ahead and do that?  We will take a 20-minute break, come back at 10:45 and continue then.  Thank you.
(Brief recess)
DR. ROMERO:  I just want to use this thing one more time so I am just going to call us to order (striking gavel).
Not to put anybody on the spot, but a number of the committee members were delayed this morning because of weather and travel issues, so if you didn’t have a chance to introduce yourself this morning, would you please do so as we get into the final session of the morning.
DR. MCINNES:  Good morning.  I am Pamela McInnes from the National Institutes of Health.
DR. GREENE:  I am Mike Greene from Massachusetts General Hospital in Boston.
DR. CHEUNG:  I am Ambrose Cheug, Department of Microbiology, Dartmouth Medical School.
DR. ROMERO:  Very good.  Thank you very much for being here.
We are going to now proceed with Dr. Roberts’ presentation on the clinical review of data supporting the efficacy of Gardasil in the prevention of anal dysplasia and anal cancer.
Agenda Item:  Clinical Review of Data Supporting the Efficacy of Gardasil in the Prevention of Anal Dysplasia and Anal Cancer
DR. ROBERTS:  Just briefly, to give you an outline of what I will talk about, the presentation will be divided into three basic sections:  First, I will briefly go through some background information, highlighting these two issues in particular, the use of AIN as a surrogate clinical endpoint, and in bridging efficacy to females.  Then I will review the efficacy data from the pivotal study.  Finally, I will present the discussion topics for the committee.
I thought Dr. Palefsky did a wonderful job reviewing the scientific background about anal HPV infection and pathology.
After looking at the slides a couple of days ago, we decided that it would not be productive to essentially repeat much of that information.  So, instead, we thought that another useful way to think about these issues is to go back to the comparable discussions we had at a previous VRBPAC.  So I will take you briefly back to 2001 when we convened the VRBPAC to discuss clinical endpoints for evaluating HPV vaccine efficacy in general, particularly for cervical disease.
You are now familiar with this spectrum.  In a minute I will put up kind of -- I agree where AIN 1, 2, and 3 go.  That will be up there in a minute.  But for the time being, we will go back to cervical disease.
At the time, the committee was asked to identify an appropriate surrogate clinical endpoint for cervical cancer.  They recognized that as you move to the right on this spectrum to endpoints to have increasingly severe dysplasia, you increase validity, you increase reproducibility, particularly for these histopathologic outcomes.  You increase overall relevance to health outcomes, and ultimately you increase the certainty that the prevention of the surrogate will accurately predict the outcome of interest, which is cancer.
On the other hand, as you move to the right on this spectrum, you also increase the expense, the size, the complexity of a trial, and ultimately you have to consider ethical issues.
So I will take on each end of the spectrum some of the potential endpoints that were discussed at that VRBPAC.
This is not going to do it.  I was going to point to the far right in here of invasive cancer.  Some consideration was given at the time to conducting a trial in which invasive cervical cancer was the clinical endpoint.  That would certainly be the most definitive and the most relevant endpoint.
However, in order to do such a trial well, you would have to enroll subjects into a placebo arm and follow them and withhold treatment until a certain number of them developed cervical cancer.  So the problems there are obvious.
So then on the far left end of the spectrum, let’s take, for example, incident infection.  Incident infection is the detection at any time point of HPV DNA by PCR.  We know that the vast majority of incident HPV infections resolve without producing any clinically relevant disease, much less cervical cancer.  In addition, some portion of incident infections are not in fact true infections, but they may be the result of contamination of viral particles that are shed from an infected partner.  This could obscure the assessment of vaccine efficacy because the vaccine would not be expected to prevent detection of previral particles.
I review all this background because much in those long-ago VRBPAC discussions I think is directly relevant to assessing AIN as the surrogate endpoint.
In that discussion, many panel members argued that because HPV infection is a necessary requirement for dysplastic progression, a virological endpoint such as persistent infection would be a reasonable clinical surrogate.  In other words, why do we need to demonstrate prevention of histopathologically proven disease when in theory none of that disease will occur if you prevent all virologically proven infection?
Ultimately, the committee decided on an endpoint of CIN 2+.  I think, looking back at that transcript, what was prominent in those discussions was a lot of uncertainty about theoretical efficacy concerns.
For example, if the vaccine turned out to be highly efficacious in the prevention of 16 and 18, would you see a more favorable niche for infection with the other oncogenic types?  There were several other potential efficacy issues that were discussed.
I think it is fair to say that in the ensuing decade of studies with HPV vaccines generally, those studies have been fairly definitive in rejecting many of these theoretical efficacy concerns.
In terms of perspective, what we are referring to as AIN 1+ or AIN or worse is the endpoint, the prespecified primary endpoint, in the MSM substudy.  What this represents on this spectrum, then, is a slight shift to the left.  So that is just for perspective.
Again, instead of reviewing all of the relevant literature, what we decided to do is just give some summary observations as it relates to these issues.  In terms of the use of AIN as a surrogate endpoint, we did feel that the histopathology provides sound theoretical support, and there is a strong association between anal HPV infection and AIN and cancer.
On the other hand, compared with the epidemiology of cervical disease, the data on HPV and anal disease is slightly less well established, particularly when it comes to progression of AIN.
In addition, unlike cervical cancers, not all anal cancers are associated with HPV.  So HPV cannot be said to be, quote/unquote, necessary and sufficient for the development of anal cancer.  I guess this is the one area where I think we may diverge ever so slightly.
If I had to guess, my feeling about it is that the subsequent studies are going to be very much the way Dr. Palefsky characterized it, that as we get better at the techniques, it will turn out that a decreasing percentage of anal cancers do not have HPV.  I think it is fair to say that early in the investigation of HPV’s association with cervical cancer, there was a similar paradigm.  Early on, it appeared that a substantial percentage of cervical cancers were not associated with HPV, but as it was more rigorously studied, it became more clear that it was essentially 100 percent.
But what we know now is that at least 10 percent and probably more, depending on the population, do not indeed have detectable HPV.  I would point particularly to I think it was the cohort that Frisch followed, the Danish cohort, in which the heterosexual men had a rate of HPV positivity in their anal cancers of around 58 percent.  So I would characterize this as there being quite a bit more uncertainty than I think was conveyed before.
Perhaps most importantly is that for the most part these hypothetical efficacy concerns, like type replacement, have been shown to be very unlikely for a very similar disease process.
In terms of just general observations regarding extrapolating efficacy to females, we have not found any evidence that there are fundamental gender differences in terms of anatomy, histology, physiology of the anal canal.  So one would not predict a priori that there would be any fundamental differences in the pathophysiology of HPV infection or HPV-related disease, and there are these strong behavioral and immune risk factors like receptive anal intercourse and immune status, but these don’t appear to be different across gender.
Efficacy is well established at another site in females; in other words, the cervix.  Also, immune responses in Gardasil in males and females are very similar.  But again, anal HPV-related disease in women, and again particularly this issue of progression of AIN, is very much less well characterized in females than in males.
I think the design of the study was explained very well, and I hope not to belabor this too much but just to go over it briefly.  About 4,000 subjects, about 3,500 of whom were heterosexual males, or HMs, and 602 MSMs, 16 to 26 years of years, randomized one to one to Gardasil or placebo.  You saw again the results of the primary efficacy objective for the entire study, which was prevention of vaccine-type related external genital lesions, or EGL.
But everything I will talk about here is the primary efficacy objective for the MSM substudy, which is prevention of 6-, 11-, 16-, and 18-related AIN and anal cancer in MSM subjects.
The key exclusion criteria were that no subjects could have any history of or current clinical evidence of genital warts, no gross genital lesions suggestive of sexually transmitted disease.  Any subjects with autoimmune disorders or other conditions leading to immunocompromise were excluded, and the lifetime number of sexual partners had to be greater than zero, less than or equal to five.
These exclusions probably list for a relatively HPV-naïve population, at least compared to a broader MSM population, because we know that history of genital warts and obviously immunocompromise are strong risk factors for HPV disease.
I won’t belabor this.  I think you are familiar with what the surveillance was for the efficacy endpoints.  Again about the per-protocol efficacy, these were subjects who were PCR negative and seronegative at day one through month seven for the type being analyzed, and cases were not started counting until month seven.
I also will quote some data from this GHN population, or generally HPV naïve.  So it is worth putting on the table what that population was exactly.  These were subjects who were seronegative to the vaccine types and PCR negative to all 14 types tested.  I have listed them here, the two, quote/unquote, low-risk types of 6 and 11 and then 12 high-risk types which include 16 and 18 from the vaccine.  These subjects were negative at day one.  They received at least one dose of vaccine and cases were counted starting at day one.
Obviously, the full-analysis set is simply all the subjects who were vaccinated once and cases were counted starting at day one.
These are the demographics for the MSM substudy.  I haven’t split these out by vaccinees or placebo recipients because they are well balanced.
This is some more about the subject characteristics at enrollment.  Even though, as mentioned, this probably represents a relatively HPV-naïve population compared to MSMs generally, the rates of preexisting anal disease and anal HPV infection at screening are relatively high.  For example, you can see that approximately 40 percent of subjects were positive either by serology or by PCR to a vaccine type.  So in other words, all of those subjects either had antibodies indicating that they had previously been exposed and cleared the disease or they had active infection.  And that is just for the vaccine types 6, 11, 16, and 18.
It was noted that there were slight imbalances in the rates of preexisting disease, with slightly more disease in the placebo group at base line.  For example, you can see that nearly 8 percent in the placebo arm versus about 5 percent in the Gardasil arm had a low-grade lesion on anal Pap at screening.
Just to orient you again, this is very similar conceptually to the way these data were presented before, but on this side you’ve got endpoint.  This is the Gardasil recipients and the controls and the point estimates of efficacy, followed by the 95 percent confidence intervals.
So this is the primary analysis.  Remember that the PPE population is subjects who were negative for the type being analyzed at base line, and then they developed disease associated with that type at some point after 7 months.
The composite endpoint prespecified for the study was AIN and anal cancer, and as has been noted, there were no cases of anal cancer, so essentially we’re talking about anal precancer.
I just highlighted, because it’s the primary endpoint, the AIN and anal cancer, which I refer to as AIN 1+, and the AIN 2+ endpoint, because that was comparable to the one we discussed before at a previous VRBPAC.
Also, just of note, among the AIN 1’s that occurred, we placed more emphasis on the estimate for the non-acuminate lesions.  You can see that split out right here.  The reason for that is although the condylomatous lesions have the pathologic hallmarks consistent with AIN 1, they are essentially warts, and the vast majority of them eventually would be expected to regress, I would think, whereas it is thought that a larger majority of these non-acuminate lesions may progress.
This is disease due to one of the vaccine types, and in this case it is in this full-analysis set, or FAS, population.  This can be thought of as an ITT or intent-to-treat analysis.  Our thinking is it might better reflect what can be expected in a broader population who is not subjected to the intense screening at the beginning of the study.
As expected, the point estimates of efficacy are somewhat lower and, as has been pointed out, probably largely due to the burden of preexisting disease.
Here at the bottom, it is worth taking a minute with this.  I have started to quote, just for the sake of comparison, the analyses that I think are the most comparable from the studies in females.  This is the young-adult women and the mid-adult women.  The distinction is 16 to 26 years old compared to 27 to 45 years old, and they go by these unfortunate abbreviations of YAW and MAW sometimes.
So these are the FAS analyses of these populations for CIN 2+ due to vaccine-type disease.  I have the asterisk here to show you what it is comparable to.  In the young adult women population, you can see that it is very much comparable to point estimate of efficacy.  In these mid-adult women, who would obviously be expected to have been exposed to a lot more HPV, you can see that the point estimate of efficacy is substantially lower.
This analysis is identical to the previous slide, except this is disease regardless of HPV type, not just HPV types 6, 11, 16, and 18 that are in the vaccine.  Now, this is something that I personally have been scratching my head about for essentially the entire time I’ve been reviewing these vaccines.  Many times the heading of such a table will say, “Efficacy Against AIN and Anal Cancer Due to Any HPV Type.”  But from what I can tell, and we can maybe talk about this more later, it isn’t due to any HPV type; it is regardless of HPV type, because as far as I can tell there are cases that aren’t due to any HPV type.
We can figure out exactly what was meant by that nomenclature later, but this is my understanding of it, and if so, this is perhaps the most rigorous ITT-type analysis of the potential population impact in the prevention of any disease at all, which I think is a very important analysis.
So, as you can see, among the generally HPV naïve, the point estimates of efficacy are relatively high, even though it is regardless of any HPV type.  Again, from the analyses that I could find that I thought were comparable among the young adult women, the efficacy on this outcome in the generally HPV-naïve populations for prevention of CIN 2+ is around 43 percent compared to 53.
In terms of the full analysis set, I have again quoted here the comparable analyses.  This is an ITT, regardless of type, prevention of disease.  Again, you can see that the numbers are basically comparable in the young adult women who are in the same age range as the MSM population.  However, in the mid-adult women, obviously efficacy drops again substantially.
For completeness’ sake, I have included the main efficacy endpoint here, stratified by baseline characteristics.  I am not sure how useful this kind of post-hoc analysis is in such a small study.  The confidence intervals are very wide, obviously, in the overlap.  The one exception, I think, that is worth pointing out is the clear result that reinforces the concept that the vaccine has no therapeutic efficacy among subjects who were infected with a vaccine type at the time of vaccination, certainly no prevention of disease against that type.
Again, just for completeness’ sake, I have included this comparative analysis of immunogenicity across age and gender.  For those of you who were present at the previous VRBPAC, you may recognize this because I just took this slide from my previous VRBPAC presentation.  We don’t have any new immunogenicity data.  Our assessment continues to be the same.  There is not a meaningful difference, I don’t think, in immunogenicity from male to female.
I put this slide up again to point out that the approach to bridging efficacy in the younger population will be the same as it has been for previous indications.  Again, in general, the younger population has a more robust immune response, on the order of two or three times better.
I would just like to briefly acknowledge the hard work of the review team, particularly Laura Montague, who has done a wonderful job of keeping things on course.  Many other people contributed a lot of time and effort to reviewing this application.  Particularly, I would like to acknowledge a lot of help from a few of those folks:  Nancy Miller, Douglas Pratt, Lew Schrager, and Christine Walsh.
That concludes my presentation, so I think we can go on to the discussion topics.  I guess we will do them one a time, so I will just read the first one again.
DR. ROMERO:  Open public hearing is next.
DR. ROBERTS:  Oh, yes, open public hearing.  All right, I will leave this up and we can go into that afterwards.
DR. ROMERO:  Thank you, Dr. Roberts, for that presentation, in particular for slides, at least on my part, 20 and 21, because I think it summarizes some data that are very important for us regarding previous studies of this vaccine in women.
Are there any questions for Dr. Roberts, by the way, before he leaves?  Dr. Roberts, I think there are some questions for you.  Don’t leave the stand yet.  Dr. Eng will begin.
DR. ENG:  Actually, it is specifically regarding slides 20 and 21.  Regarding the mid-adult women, you mentioned that the reduction actually decreases in this older age group but it is present.  And then can you just comment, do we know how many of those individuals actually were exposed to HPV in the past?  You said because they were older, they were likely exposed earlier.
DR. ROBERTS:  Yes.  We have data on that in the form of serology and PCR at screening, and I don’t have those data available because I don’t have slide 1852.
(Laughter)
It’s very impressive.  I have to admit it’s very impressive, but I don’t have that at my fingertips, but it is pretty clear that there is a lot of previous HPV exposure, and you cannot capture it all because many of these women have been exposed, have cleared their disease, and may not be seropositive.  So that is an element of uncertainty in that population.
DR. ENG:  And then regarding slide 21, it actually looks like there were more cases?
DR. ROBERTS:  Yes, it does appear to be so.  I’ve looked at these data very carefully, and it seems pretty clear to me that there was a slight imbalance at the beginning of the trial in terms of disease both by Pap screening, by preexisting HPV by PCR, and so on and so forth.  I think that explains this slight negative case split.  So I think it just demonstrates that it is hovering around zero in terms of the point estimate of efficacy.
DR. ROMERO:  Dr. Moulton?
DR. MOULTON:  Yes.  I was looking for slide 20.5.  It’s an efficacy analysis in the GHN population for the vaccine serotypes.
DR. ROBERTS:  Yes.
DR. MOULTON:  Did you do it for the vaccine serotypes in the GHN population?
DR. ROBERTS:  Yes, that analysis has been done, and I am sure we can pull those slides up.  Obviously -- well, I guess it not obvious, but I can just tell you that the point estimates of efficacy are higher because it’s vaccine type-related disease.  It is going to be quite a bit higher.  I don’t remember the numbers.  I am guessing mid-70s.
PARTICIPANT:  Ninety.
DR. ROMERO:  Would somebody from the Merck team like to comment on that?  I see some activity over there.
DR. GARNER:  We have the slide up for you.  Could you display 1021, please.
(Laughter)
This is the analysis in the GHN population for HPV types 6, 11, 16, and 18.  I think, as you can see here, the type-specific efficacy estimates are actually very high.  This has to do with the fact that these are generally HPV-naïve individuals, in fact more so even than the PPE population, because the PPE subjects have to only be negative for one specific type.  So really this shows -- this is meant to reflect really the target population for vaccination, so very high efficacy.
DR. ROMERO:  Any other questions or comments?  Dr. Tacket?
DR. TACKET:  You present some data on geometric mean titers.  Do you have data on seroconversion rates?
DR. ROBERTS:  Yes, those data exist.  Again, I can tell you that the seroconversion rates are very high.  I mean they are on the order of 99 or 100 percent at month seven.  I think I’m getting that right.
For type 18, when you get many years out, the seroconversion rate particularly falls a little bit.  But I cannot see that there is any decrease in efficacy associated with that so far in the clinical development program.
DR. ROMERO:  Anybody else from the committee?  Yes, please, Dr. Greene.
DR. GREENE:  Just one comment.  The problem with trying to define a seroconversion rate is that you have to define what the minimum titer is that would be efficacious at preventing disease, and it is not at all clear exactly what that is.
DR. ROMERO:  Excellent point.
Any other comments or questions?  Very good.  Thank you very much.
Agenda Item:  Open Public Hearing
DR. ROMERO:  The next item on the agenda is the open public hearing, and I will need to read a -- oh, I’m sorry, go ahead, Don, take it over.
MR. JEHN:  As part of the FDA advisory committee meetings 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.
Dr. Romero, would you please read the open public hearing statement.
DR. ROMERO:  Thank you.  “This is an open public hearing announcement for particular matters involving specific parties meeting, for example, in this case a specific product:
“Both the Food and Drug Administration (FDA) and the public believe in a transparent process for information gathering and decision making.  To ensure such transparency, at the open public hearing session of the advisory committee meeting, FDA believes it is important to understand the context of an individual’s presentation.  For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement, to advise the committee of any financial relationship that you may have with the sponsor, its product, and, if known, its direct competitors.  For example, this financial information may include the sponsor’s payment of your travel, lodging, or other expenses in connection with your attendance at the meeting.
“Likewise, FDA encourages you, at the beginning of your statement, to advise the committee if you do not have any such financial relationships.  If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.”
MR. JEHN:  Thank you, Dr. Romero.
I have received seven written statements, and a copy of these statements have been placed in the committee’s folders, along with the viewing notebook outside at the registration desk, and they will be made part of the meeting record.
I have received four requests to speak during the open public hearing session.  Speakers that have asked to speak thus far are Justine and Camille Almada from The Foundation of HPV and Anal Cancer; Janet Trenet; Dr. Diane Zuckerman, National Research Center for Women and Families, Cancer Prevention and Treatment Fund; and Roberta Boyce from truthaboutgardasil.org.  Each will be given approximately 5 minutes to speak, and then we will ask if there are any other people that would like to speak.
Justine and Camille, do you want to go first?
MS. ALMADA:  Sure.  Where?
MR. JEHN:  Over there in the middle would be best.  Thank you.
MS. ALMADA:  Good morning.  Thank you for the opportunity to testify today.
My name is Justine Almada, and I am a member of the board of The Foundation for HPV and Anal Cancer, a non-profit, nonpartisan organization that I co-founded with my two siblings.  I am here with my sister, Camille Almada, also a member of the board.
Our organization aims to educate the public about anal cancer, to address the stigma associated with the disease, to advocate for prevention and improved early screening methods, to provide resources for patients, caregivers and members of the scientific and medical communities, and to invest in research for therapeutic treatments.
No entity, including Merck, has influenced our comments or paid for our travel to be here today.
We hope our efforts will lead to improved patient knowledge, choices, quality of life, and survival.  The approval of the anal cancer indication for the HPV vaccine for both mean and women is one of many tools to advance these efforts.
We lost our mother 7 months ago to stage IV anal cancer.  She was asymptomatic, exercised regularly, and ate well when she was diagnosed.  She had raised three children and was about to embark upon a career change that focused on her passion.  Instead, at the age of 51, she began a two-year marathon that ended in her tragic death.
Our mom was a vivacious, beautiful, and dedicated woman -- the type of mom who would support you when you made a mistake, work hard to make sure her kids were clothed, fed, housed, and educated, and was always the life of the party.
She faced her diagnosis with emotional and physical strength.  She continued to work, and pursued a master’s degree program at night, while enduring chemotherapy, until the last 3 months of her life.
Over 5,000 people a year are diagnosed with anal cancer -- some like my mom, and some different -- yet the vast majority of these cases are caused by the human papillomavirus.  We commend the steps the FDA has already taken to aid in the reduction of HPV-associated cancers in girls by approving the HPV vaccines, Gardasil and Cervarix, for the prevention of cervical, vulvar, and vaginal cancers.  We strongly urge you today to approve expanding the Gardasil indication to include prevention of anal dysplasia and anal cancer in both females and males.
While those suffering with anal cancer endure a physical battle with toxic chemotherapy and radiation, it is hard to think of a cancer with a more oppressive social stigma.  People are afraid to say the very words “anal cancer,” to openly discuss it, and to share the experience of this illness with the ones they love.  Our mother felt this way, hiding her cancer from others because she was afraid of being judged.
The data presented today shows that the majority of anal precancer could be prevented with the HPV vaccine, but the FDA has not yet had occasion to take this step to protect men and women.  You have that opportunity today.
Everyone deserves protection from cancer.  In the men-who-have-sex-with-men population, the need for this vaccine is great.  HIV-negative MSM are 17 times more likely to develop anal cancer.  For men and women with compromised immune systems, including people living with HIV and AIDS, the rates of anal cancer development are higher and the need for the vaccine is even more pronounced.
Promisingly, the study discussed today shows that Gardasil decreases the chance that HIV-negative MSM obtain an HPV infection by 78 percent.  But this vaccine should be recommended for approval in all boys, as MSMs may not self-identify until sexual activity has already commenced.  Furthermore, if all boys are similarly vaccinated (regardless of sexual orientation), the number of women who encounter these cancers through sexual activity will decrease.
The study also illustrates that the similar natural histories of HPV infection in men and women indicate the vaccine will also be effective in preventing anal precancer and cancer in women.
According to the American Social Health Association, 75 percent of U.S. citizens between the ages of 15 and 49 have been infected with a genital HPV in their lifetime.  HPV causes cervical, anal, vulvar, vaginal, penile, and head and neck cancers and recurrent respiratory papillomatosis.
The approval of the anal cancer indication for the HPV vaccine will offer a new method to prevent a painful diagnosis and death from a disease in which significant progress in treatment has stagnated for decades.  It will protect a vulnerable population made more so by the stigma associated with anal cancer.  And it will logically extend the commendable work the FDA has undertaken in vaccinating women from HPV and the diseases associated with it.
The incidence of anal cancer in the United States is currently growing, and therapeutic measures to treat patients are not improving.  That is why we are here today.  We urge you to approve the indication for all boys and girls in the effort to prevent anal precancer and cancer and its consequences.
Thank you.
MR. JEHN:  Thank you.
Next, Janet Trenet.
MS. TRENET:  Thank you.
A year and a half ago, I was diagnosed with perianal cancer by HPV.  This came as a complete surprise to me.  For the last 25 years, I haven’t missed an annual Pap smear and never had signs of HPV.
For at least the last 10 years, I have asked several gynecologists about a growth on the outside of my anus.  Each doctor told me not to worry, that this was just a hemorrhoid.  Several of my girlfriends complained how painful their hemorrhoids were when they were pregnant.  I had two children, and each time I was pregnant, this “hemorrhoid” never bothered me.  I thought this was very bizarre, so I decided to have it removed last spring of 2009.
My doctor told me he could do it right now just with a local.  The next day I looked.  It was still there.  Two weeks later, I received a phone call from my gynecologist that I had what Farrah Fawcett had left untreated and that I should see a rectal surgeon and an oncologist right away.  He told me I should never miss a cervical Pap smear again in my life and that it was very important that I follow up with this.  I was very confused, because I thought he had just removed a simple hemorrhoid, and I didn’t realize he had only taken a biopsy.
I had the rest of the cancer surgically removed and random biopsies taken from the inside of my anus.  I was told that I had high-grade level 2 and 3 dysplasia, and I was given a cream to take care of this.  The follow-up would be to go back to the hospital every 6 months for random biopsies to see if this was removed.
The word “random” never sat well with me.  At the time I was 39 years old and had a 2- and 4-year-old.  My youngest is autistic, and he needs me to be well so I can be there for him physically and mentally every day.
I had asked the doctor if he would follow the same course of treatment for his wife or daughter.  He looked up at me and told me no, and he gave me another doctor’s name.
After getting my second opinion, I was sent to Dr. Goldstone(?) in New York City.  I was told by the second doctor that there were no doctors in the state of New Jersey that even had the equipment to treat me.  Again, “random” was not a word I would accept.  Dr. Goldstone was extremely knowledgeable with this virus and location of HPV.  He eased my mind and he performed an anal Pap and proceeded with ablation.
I had to go through this again in August.  Each time I get an ablation, it is painful and extremely time-consuming.
It is very scary having this virus.  Many doctors, including my gynecological oncologist, have given me misinformation and incorrect treatment options. 
I am fortunate to be where I am today.  However, I always have to worry, not for me but for my family.  I want to make sure that I am around for a long time to take care of everyone.
I am bringing this to your attention today because there is not a lot of awareness that Gardasil can prevent anal cancer.  The focus seems to be always on the cervix.  My perianal cancer was caused by HPV, something that could be prevented with a simple vaccine.
Thank you.
MR. JEHN:  Thank you.
Is Dr. Zuckerman in the room?  If not, Roberta Boyce.
MS. BOYCE:  I just want to start by saying I have no conflict of interest.  In fact I sold all my Merck stock when I found out what it had done to my daughter.
I am here today because my daughter was harmed by the Gardasil vaccine.  My daughter was actually sterilized by the vaccine.
I don’t have a medical degree but consider myself pretty well educated.  I’ve spent the past 2 years researching medical papers so I could understand why my daughter had such debilitating side effects post-Gardasil, and I read hundreds of medical papers from various sources.  There is a lot of misinformation out there about what causes HPV, in my opinion.
I presented information last September against the vaccine at a similar FDA meeting when you were considering extending the vaccine to boys and older women.  At that time I told the advisory panel that many of the Gardasil girls were showing symptoms of severe vitamin deficiencies, specifically niacin.  That in turn causes pyruvate kinase deficiency, something critical to the Krebs cycle.  For those of you in the audience here that don’t know, the Krebs cycle is a vital function in the body that provides nutrients for new red blood cells, energy, and glucose, and repairs cell damage during periods of stress.
If the person has severe pyruvate kinase deficiencies, the person exhibits a myriad of symptoms and can never recover unless they take supplements.  If they don’t get supplements, they continue to deteriorate.  That is what is happening with many of the Gardasil girls.  The symptoms are slightly different because of individual genetic makeup; however, all the side effects exhibited are caused by the same PK deficiency.
Unfortunately, since PK deficiency is a relatively new finding, only discovered in 1996, the majority of doctors have never heard of it.  I am certain they don’t understand that the Gardasil vaccine would have catastrophic implications for these individuals.
Since PK deficiency or hemochromatosis is the most prevalent genetic trait in the United States, any individual having it would have a difficult time recovering from a vaccine.  But my daughter was never tested for this prior to vaccination, even though your charts show that you do not include people with those autoimmune disorders in your studies.
Does this mean that each person getting the Gardasil vaccine will actually get cancer from the vaccine if they have PK deficiency?  I don’t know, but certainly there are those with genetic deficiencies that will have issues with it.
Already the May 2006 FDA VRBPAC reports that if a woman has HPV and receives Gardasil, her chances of getting cervical cancer increase by 44.6 percent after inoculation.  Is it just possible that HPV is caused by PK deficiencies?  I believe so.  Shouldn’t patients be tested for the most prevalent genetic trait prior to vaccination if this vaccine would be so dangerous to them?  And what about the test studies?  Were individuals with PK studied, a predominantly Northern European trait included in the test studies?  Right now today you showed they were not.
In my opinion there were not parallel populations put in these studies, unless the study that was included from Costa Rica, they were expecting to market this vaccine to Hispanics, which I doubt, since it’s the most expensive vaccine ever produced.
The Merck Manual clearly cites several types of PK deficiencies and even suggests that individuals with these inherited disorders would not be candidates for vaccines.  A few types of PK deficiencies I would specifically point out are G6PD, a traditionally Jewish trait, sickle cell anemia, and thalassemia.  There are many other names for the same deficiency, such as Celtic Curse, HH, HFE, mel(?) or iron overload, but they are all the same PK deficiency.
In fact most if not all of us have a slight form of PK deficiency because of several issues, including toxins in our environment, in our homes, excess minerals in our drinking water and foods, alcohol consumption, and a gamut of other factors, including stress and exercise.
I don’t believe scientists developing this vaccine had access to all the information they should have.  I want to believe that they did not understand that PK deficiency is also environmentally caused.  Everyone here needs to understand that PK deficiency is no longer just a genetic trait.  The effect of a live vaccine like Gardasil has tremendous implications for all of us because we all have some form of this deficiency.  We will not be able to recover from this vaccine and, perhaps slowly, will continue to exhibit debilitating side effects post-vaccine.
In April 2008 the FDA sent a warning letter to Merck citing two lot numbers, X and U, that had extra yeast.  I believe these lots exacerbated the problems of the vaccine, and the side effects that normally would have taken years to show up became obvious almost immediately.  Some side effects that normally might have been mild have now exploded.  Today there have been 84 deaths and over 20,000 severe side effects documented in our government VAERS system, and now Gardasil makes up more than 65 percent of the entire VAERS database.  The vast number of side effects that have been reported are from lots X and U that have the extra yeast.
India has already outlawed this vaccine because of what they have seen post-vaccination.
Many of you are aware that there is currently a lawsuit in the Supreme Court that will decide on certain vaccines having design flaws.  Gardasil, in my opinion, should be considered one of those vaccines.
First, the test trials never had a true placebo but instead used an aluminum adjuvant as the placebo.  Second, the vaccine was marketed as a vaccine to prevent cervical cancer, and yet the HPV virus has never proven to positively cause cervical cancer.  I would strongly argue that it is caused by genetic and environmentally caused PK deficiency.  Third, the long-term side effects of polysorbates, which can also cross the blood-brain barrier, were never thoroughly explored.
There are many medical papers documenting fertility issues in mice that have been administered polysorbates, and yet the long-term implications of these were never tested.  Merck has come right out and said they do not know if fertility will be an issue for these vaccinated children in the future.  This is a critical issue.  Could Merck have known that this vaccine would cause fertility issues in women wanting to conceive in the future?
Last year I stumbled upon a World Intellectual Property Organization paper which discussed pyruvate kinase deficiency in animals.  This was many of the “God moments” that I’ve had in the past 2 years since I found out my daughter was injured.  I know that’s not a popular stance to take in a government meeting, that I’ve had all these “God moments,” but let me tell you, it happens when you know your daughter is dying after a vaccine.
The paper I read talks about fertility impairment of cats and dogs.  The vaccine was administered in three doses over a 6-month period, and one of the main ingredients was polysorbates, also in Gardasil.  What was interesting about the paper was the animals with PK deficiencies did not sustain any sensation of menses post-vaccination -- very interesting and very scary, because it was exactly what I was seeing in my daughter post-Gardasil.
My daughter recently tested sterile at age 21, although she is still getting a relatively normal period.  Could it be that Merck intentionally developed this vaccine thinking it would affect a small number of individuals with PK deficiencies?  Is this what their intent was when they developed their recently approved fertility drug Aleva, which was just passed for European use?  I wonder if Merck and other big pharmas have intentionally taken advantage of genetic deficiencies.  I believe they have, and I believe this is what has happened many, many times over.  In fact today’s presentation by Dr. Garner clearly stated that DNA extractions were performed in their tests.
Imagine how a mother who wanted her daughter to have a vaccine would feel after learning all this information.  I was distraught knowing my daughter would likely be sterilized from the vaccine and it was my fault.  In my eyes, it seemed certain that my daughter had either a genetic or environmentally caused PK deficiency, since she had been exhibiting menopausal symptoms for several months and erratic periods, sometimes very heavy, usually coming every 2 weeks.  She complained of hair loss, experienced severe PMS symptoms and mood swings, and those were the more mild symptoms.
After recent tests my daughter had done, I can now positively confirm that my daughter tested post-menopausal as it relates to her hormone levels, with no family history of early menopause.  She is no longer ovulating and she has hormone levels of a 50-plus-year-old woman.  My worst nightmares have come true.
Because I am privy to information about the health of other girls through support groups that I am involved with -- two of them are truthaboutgardasil.org and sanevax.org -- I know there are many other girls who are also experiencing similar testing and their results are comparable to my daughter’s.
I am grateful to God for guiding me to the Gardasil groups I belong to.  There are many Christians among this group.  Both are very large and have hundreds of members like me, desperately trying to stop the HPV vaccine and find answers to help their daughters.  The sanevax.org group, which is a spinoff of truthaboutgardasil Web site, now has 69 countries spanning the globe using their resources.
God made us all slightly different, and we all have subtle genetic imperfections.  That is what makes us unique.  Unfortunately, I believe unethical people in big pharma have figured out how to take advantage of these imperfections.  That’s how they’ve made money in the past, and that’s how they intend to continue making money in the future, because they are beholden to their stockholders to bring in profits no matter what the cost, even if it means harming children to get their money. 
I must reiterate that I honestly doubt they took into account PK deficiencies were environmentally caused.  In my opinion, they didn’t know the damage done would be so astronomical.  But so far they have taken no action to help those harmed.  When families call Merck trying to get help, they will not even return phone calls.  Doctors don’t know how to correct the damage done and throw up their arms, saying the CDC and FDA say it’s safe.  These cases seem so complex, but clearly this vaccine is not safe.
I am pretty certain doctors aren’t even aware of the myriad of side effects they are saying are caused by PK deficiency.  Remember, it’s relatively new, only discovered in 1996.  It is horrifying to see previously perfectly healthy children now having seizures, migraines, pneumonias, personality disorders, fatigue, menstrual issues, vomiting, diarrhea, and the list goes on, post-Gardasil.  This vaccine needs to be pulled immediately.  Over 20,000 families are now begging for help, and no one is answering their desperate pleas.
I am begging you, do not expand this vaccine until there are answers to the problems that have already arisen.  How many children will have to die because this vaccine was a mistake of crazy proportion?  How many will be sterilized?
It’s my duty to leave you with one last thought, another God moment I had.  St. Augustine prophesied that Christians will make their own demise because they do not spread the word of God.  He called it the Celtic Curse.  Go look it up on the Internet.  It’s the same as hemochromatosis or PK deficiency.  Another coincidence?  I don’t think so.  Imagine if our entire world were vaccinated with Gardasil.  Will we all be sterilized?  The truth needs to be told.
Thank you.
DR. ROMERO:  Thank you, Ms. Boyce.
Are there any other public comments?
If not, then I would like to thank the speakers for their comments, and we will move on.
Agenda Item:  Committee Discussion and Recommendations
DR. ROMERO:  Next is the committee discussion and recommendations, and if we could flip up the slide for comments.  It should be 24.
Just to remind the committee, the discussion comments are as follows:
First, please comment on the following:  the strength of the data to support an indication for the prevention of AIN and anal cancer in males; and, second, the scientific rationale for extrapolating efficacy in the prevention of AIN and anal cancer to females.
Why don’t we start by going around the room and seeing if there are any comments.  Does anybody want to start, or should I just rotate to my right?
I certainly feel comfortable starting, and then we’ll just go around.  I think the current data that has been presented does support this indication for the vaccine for AIN and anal cancer in males.  I think that the data is sufficiently strong, and I think that the scientific rationale for extrapolating this efficacy is there.  The diseases do not appear to be different in males and females.  The pathophysiology seems to be quite similar, so I think that these are all logical extensions and certainly do support the data.
Dr. DeBold?
DR. DEBOLD:  Well, I don’t think this is so straightforward.  Looking at the FDA slides, like 19, 20, 21, we’re looking at efficacy values that range from a low of 24 percent up to highs in the 90 percents.  We’re dealing with a lot of extremely wide confidence intervals.  It’s hard to know what the true point estimate is here.  I am much less comfortable with this than Dr. Romero is.  I do think we need to make sure that we’re looking at the figures that are dealing with AIN 2+ and not AIN 1.
As far as generalizing the findings from this particular study population to other groups, I am not comfortable with that either.  I am not comfortable with assuming that the results that have been observed in a 16-to-26-year-old population will be what we see in a 9-to-15-year-old population for males; that there are important, I think, biological differences between prepubescent boys and young adults that need to be considered.  I am not at all comfortable with extrapolating to girls who have not been studied at all.
One of the reasons that I’m not comfortable is due to some of the data that’s on slide 23 that the FDA presented where we see much higher levels of immunogenicity in the younger age groups, and I can’t help but to wonder if some of this reactivity that we’re seeing here might also have a relationship to some of the safety issues that have been raised not only by the last public speaker but the enormous number of reports that are coming in to not only the National Vaccine Information Center but VAERS.
I am not reassured by the safety data that have been presented, partly because they’re using a reactive placebo, an aluminum-based placebo, rather than something that is nonreactive.  I think that it makes it very difficult, if not totally impossible, to understand what is truly going on.
DR. MARKOWITZ:  In terms of the first issue here, which is the strength of the data to support an indication for prevention of AIN, anal cancer in males, I think that the data are very strong to support that, and I am in favor of extending that indication.
I think that the difference between the efficacy in the per-protocol population, FAS population, as with women, indicates the importance of vaccinating prior to exposure to HPV.  But I do think the data are very strong.
In terms of extrapolating efficacy for prevention of AIN and anal cancer to women, I am also in support of that.  I think we have a fair amount of data now accumulated since 2006 when FDA first reviewed the data in females to look at cancer endpoints in females, immunogenicity in females, and now we have the cancer endpoints in males.  Based on the information we heard today about the similarity of the natural history of anal cancer in males and females, I’m in support of that extension.
DR. ROMERO:  Thank you, Dr. Markowitz.
Dr. Moulton?
DR. MOULTON:  Thank you.  With respect to the first, I do believe there is sufficient strength of the data to support the extension of the indication.  The strength of the data lies in the data presented in the FAS and the GHN populations.  I have much less confidence in the analyses on the PPE population.  I’m not sure I’ve ever seen a study with such a big difference between the FAS and PPE populations.  For some of those serotypes, only about half of the individuals were evaluable.  Usually in vaccine studies, these populations are much closer.  But I think the GHN population, I think the slide 1021 results are the most appropriate for extension of the indication.  They looked very strong.
I would also support extrapolating to females.  I think the data are definitely sufficient.  We see no biological reasons, either in response to the vaccine or in the disease.  This vaccine is a twofer.  I think it’s a good one.
DR. ROMERO:  Thank you, Dr. Moulton.
Dr. Sanchez?
DR. SANCHEZ:  For the first, with regard to the strength of the data for males, I agree that the strength of the data is there, and I would be in favor of that, even extrapolation to the younger age group.
I have some less -- I am a bit torn with the females.  I see the biologic plausibility, I see the similarities, but at the same time, we are granting an indication for a process or disease that we really don’t have that data to say that it is preventive.
At the same time, we’re extrapolating also to the younger boys based on the same immunogenicity data.
So I’m a little bit torn with respect to the females, although I understand that the similarity in the males and females -- I am still a little bit hesitant, but at the same time, these women would be receiving it for cervical cancer prevention.  I think I would just like to see some data among those women that it did something to the anal pathology.  But I guess that’s still not there.
DR. ROMERO:  Thank you.
Dr. Wharton?
DR. WHARTON:  The disease is complicated and the endpoints that have been looked at are many, and with looking at multiple different types, there’s very complex study designs that are needed to evaluate them, and the exposures in a certain subset of the population were used to look at these endpoints because of the frequency at which those endpoints occur and the level of exposures.
I’m left wondering to what degree the natural history is the same in the study population compared to the more general population.  But in spite of that, I am persuaded that fundamentally we’re dealing with a disease that is caused by oncogenic types of human papillomavirus.  I am convinced that the data support that the vaccine prevents those persistent infections, and therefore the clinical endpoints of interest should be prevented.
Regarding the disease in women, again, I think that the data are persuasive, and the reasoning by analogy that we’re being asked to accept, I am willing to accept.  I think that the majority of women who end up with anal cancer wouldn’t get it if they weren’t infected with HPV and that by preventing that infection we will be preventing that clinical outcome.
DR. ROMERO:  Thank you.
Dr. McGinnes?
DR. McGINNES:  I think that there is a very robust set of data that were shown here and analyzed at length in high-risk HPV infection with AIN and subsequently anal cancer.  I think the discussion and the reiteration of almost 10 years ago of AIN 2+ in particular being a reasonable endpoint, correlate endpoint, I think still holds.  So I would consider there to be a robust data set.
With regard to extrapolating for efficacy from these data in males to females, I think that it’s a beautiful presentation on the epidemiology of the disease, the histological features of the disease, what we know about the pathogenesis of this infection and disease, and I think that it’s a very reasonable scientific rationale for this extrapolation, and I do support it.
DR. ROMERO:  Thank you.
Dr. Greene?
DR. GREENE:  Thank you.  I’ve actually been involved in deliberations about the HPV vaccine since the original meeting in November of 2001 when the agency was trying to develop guidelines for outcome measures for the HPV vaccine in women.  The precedent was established at that time that it was inappropriate to actually look for the final true outcome measure, which is cancer.  It’s a relatively uncommon outcome and, under the circumstances, would require basically withholding of normal appropriate care to result in cancer, which is obviously unacceptable.
So the surrogate measures of intermediate levels of abnormality in the epithelium for true cancer I think is an acceptable proxy for the true disease that we’re interested in.
As far as the limitations to this current data set, it seems that there are several.  One is preexisting incidence of HPV infection in the population being vaccinated, and in none of the data that has come forward in testing either vaccine, this vaccine or the GSK vaccine, in women has there been any evidence of any efficacy in women, in persons who are already infected.  So that’s not a surprise and is what’s seen in this data set.
The other limitation to the apparent efficacy here is just the small numbers of events.  The numbers of patients who have been enrolled and the numbers of outcomes are considerably smaller than in the prior presentations in women.  So that’s why we have such obviously wide confidence intervals for estimates of the effect size.
Another issue that is very obvious to everyone is the induction interval from the exposure to the infection until the outcome, which can be relatively lengthy for both cervical and anal disease, and it will never be possible to prove, quote/unquote, the relationship between HPV and cancer if you want a rigorous demonstration of Koch’s postulates.  So that is just not going to happen.
Finally, the last question that frequently comes up is, What is the etiologic fraction of all anal cancer or high-grade anal intraepithelial neoplasia that comes from 16 and 18, the only two highly oncogenic types that are included in this vaccine, as opposed to all of the other oncogenic types?  That’s obviously a judgment decision in terms of which types to include in the vaccine.  It seems to have been an acceptable -- reduce the disease acceptably in women, so I think it’s reasonable to anticipate that it will prevent a substantial fraction of disease in men as well.
So I think that the strength of the data to support the indication is there.  I think that the apparent discrepancies between this data and that for the prior presentations for indications in women are explicable on the basis of the numbers of patients enrolled and the numbers of outcomes observed, and I think that there is no reasonable reason to think that there will be significant immunologic differences between men and women.
DR. ROMERO:  Thank you.
Dr. Cheung?
DR. CHEUNG:  I think I’m trying to decide on basically several aspects.  It seems like, first of all, I believe the rationale for such a vaccine in there.
In looking at the data, I believe the data are very robust, very strong, to support the prevention of using this vaccine in AIN and anal cancer in both male and female by extension.
The thing I have a lot of hesitancy is about safety.  There are only like, in that last set of data presented, there was like several hundred cases with a couple of cases with some systemic AE which subsequently did not go through the trial.  If the recommendation were to give this vaccine to males between 16 to 20 years of age, you’re looking at a very large number of individuals who will receive this vaccine.
And so given that if possible the side effects are very low, but given a very large population base, I’m not so sure that we have very clear-cut data to show the long-term efficacy, and I know Merck is trying to at least follow up on that.  But I have some hesitancy about the long-term safety for administering this vaccine to so many people.
DR. ROMERO:  Thank you.
Dr. Durbin?
DR. DURBIN:  I think the data are very strong to support the extension of the indication for the prevention of AIN and anal cancer in males, as Dr. Greene said, even though there were no cases of anal cancer in the studies for the reasons Dr. Greene explained; it would be unethical to let a study go until we can prove that particular endpoint, and that the surrogate endpoints were certainly supported by the data that were presented today.
I also believe, based on what we know about the anatomy, the histology, and the epidemiology of anal cancer, that the data also support this indication for women as well.
DR. ROMERO:  Thank you.
Dr. Tacket?
DR. TACKET:  I found the data with regard to safety to be reasonably persuasive in terms of prospectively collected data among the participants in these trials, which is very reassuring.
With regard to bullet number 2, like many of my colleagues, we were convincingly -- it was well discussed that the differences between males and females in terms of the biology and histology and so forth are not observed.  So I feel comfortable with extending it to females.
DR. ROMERO:  Thank you.
Dr. Eng?  Oh, I’m sorry, do I start -- Dr. Roberts, Dr. Sun, comments?  They don’t -- 
DR. ROBERTS:  We’re listening.
DR. ENG:  Sorry, I didn’t realize that.
I did feel compelled that the strength of the data is robust for the endpoints that were presented here, and I also did feel that the rationale can be extrapolated to females.
As I said earlier, I did have some concerns about the short-term follow-up regarding toxicities.  The vaccine is approved in females, and I guess the original meeting was in 2001.  But regarding males, I don’t think we have enough long-term follow-up right now.  I would be very interested to see obviously the data -- I know they’re including a long-term follow-up for these individuals who are participating in the study, and I would like to eventually see that.
The other question I guess I still have is we know that there is an association with reactivation of HPV, and that is what is commonly associated with the development of this cancer in older females.  I guess I still in my mind wonder if the efficacy, when provided so young, still lingers when individuals -- because the average aged patient is a 60-year-old female and not an immunocompromised individual.
But I do obviously have a personal interest because I’m an oncologist.  This patient population represents about a third of my practice.  There was a lot of discussion regarding toxicities of therapy.  The reality is that you need to go to the right center.  The reality is that this is a rare malignancy and most oncologists won't treat this cancer on a regular basis.  So a lot of the toxicities associated with treatment are really attributed to lack of experience.  It is a very treatable cancer but obviously with the ideal to prevent the cancer from developing.
I think it is important to point out that this will continue to increase in incidence, especially in the HIV-positive patient population, because despite the use of antiretroviral therapy, which was pointed out, it is not reducing the incidence.
So I do have a personal interest, I have to admit, in that.  But I do have some concerns about the long-term toxicities at least in the male population because we just don’t have a lot of data right now.
DR. ROMERO:  Thank you.
Dr. DeStefano?
DR. DESTEFANO:  In terms of the first point, I think the data are strong to support an indication for prevention of AIN, I think for the various reasons that have been stated.  It has not been possible to really nail down the progression to anal cancer, so that that link is not as strong, but I think what has been presented on pathogenesis, et cetera, I think it’s reasonable to conclude and support the indication for prevention of anal cancer in males as well.
I think the case has been made that the disease has similar epidemiology and biology in males and females, so I would support the second indication as well.
I guess a few comments on safety.  What I’ve seen from the pre-licensure data and such didn’t raise any signals of severe safety problems.
I could speak to our experience with Gardasil in women in the postmarketing data that we have.  The vaccine appears to have an acceptable safety profile both from the spontaneous reporting data that we have as well as the monitoring we’ve done in population-based managed care organizations.
But obviously, as with any new vaccine or any change in indication for a vaccine, you don’t even as large enough population or long enough follow-up in the pre-licensure setting to firmly establish the safety for very rare adverse events or long-term events.  So it will be important to continue to monitor safety should this indication or these indications be approved.
DR. ROMERO:  Thank you.
Dr. Tsai?
DR. TSAI:  I apologize for this.  It is probably a question that should have been asked earlier in the morning.  I don’t have any comment on the voting points, but I just wondered, because analogies were drawn between CIN and AIN, what is known about the cellular receptors for HPV and their distribution in the genital tract and the anus and, for that matter, the oropharynx, especially the larynx?
DR. ROMERO:  Does anybody want to offer a comment on that question?  It’s a good one, it’s an excellent one.  Please?  Dr. Palefsky?
DR. PALEFSKY:  It’s a really good question I think.  What you’re getting at is does HPV get into the epithelium in the same ways in the different mucosa.  I don’t think we really have a good answer to that, except that we know that the virus does get in, and they have the same kind of epithelial structure, which suggests that they could have the same receptors.  The virus still needs to sit on the base of that membrane.
Dr. Schiller, who is actually here in the audience, has done some very elegant work showing what happens.  There is no data to suggest that that process would vary from site to site.
DR. ROMERO:  Thank you.
Dr. Unger?
DR. UNGER:  Just to start out, I found it very helpful to remember that this indication really does not change the population that is being vaccinated, the target population, so it’s just an additional indication.  So the safety and immunogenicity aspects have been considered before in this population, and I don’t think there is any additional data to change the conclusions that were reached before.
I do find the strength of the data on the prevention of AIN and anal cancer in males to be very convincing and very clear.
I had a little bit more thought that I had to do in making the extrapolation to females, but I was able to transition to that.  Again, I realize that we do not have actual demonstration of any change, even HPV detection, in females, but if anything, females raise better antibodies, so there is no reason to expect that the response would be different.
DR. ROMERO:  Thank you.
Dr. Gellin?
DR. GELLIN:  I want to start by reinforcing what Beth just said, because while Dr. Roberts didn’t have slide 1827, he did have slide 3 with a tiny footnote.  The footnote is really very important, the one that Beth just highlighted, that what we’ve seen here today is the building on top of the existing database for this vaccine.  So in the same population we’ve learned that this vaccine has even more power to prevent serious disease, and it’s really just an extension of the logic that got it licensed in the first place, that when you have the opportunity to prevent an infection by an oncogenic virus, you then can prevent all the downstream impacts.  I think it is important to keep that in mind. 
We didn’t have a discussion about the safety profile because that’s not what this meeting was about.  It’s building on others.  So I just think we have to put that in the context of our discussions today, because it was really about this indication on top of the full data package for this vaccine that’s presented.
So given that, I think that we got a good lesson in pathophysiology, and I think that based on the discussions of oncogenic viruses and the pathophysiology, I think that the data we’ve seen I think supports both the indication for the prevention of AIN and, therefore, the progression of anal cancer in males.
Similarly, we didn’t hear anything about any genetic differences in the pathophysiology or the immune response that would predict that this vaccine wouldn’t have the same impact on cancer in females.
DR. ROMERO:  Are there any other comments from the committee?
Dr. Baylor, have we addressed the areas of comments sufficiently?
DR. BAYLOR:  I think you have.  I mean we wanted to make sure that the approach that was taken as far as supporting an indication, we wanted to get your opinion on that as well as whether the data, the rationale can be extracted to women, and I think you’ve all commented on that.
If there are any additional comments on follow-up, phase 4 recommendations, that might be useful, but I leave that to the committee.
DR. ROMERO:  Any other comments?  Go ahead, Dr. Gellin.
DR. GELLIN:  To just reinforce what many have said and we probably hear in every advisory committee meeting is just to ensure that there’s a continued look for duration of protection for a vaccine that’s given at a younger age when the diseases will potentially occur later, particularly a latent disease like this.
DR. ROMERO:  Anyone else?
Then I think we’re adjourned.  Thank you all for your participation and for coming.  Safe trip home.
(Whereupon, at 12:12 p.m., the meeting was adjourned.)