ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ANTIVIRAL DRUGS ADVISORY COMMITTEE (AVAC) MEETING**
>
> Wednesday May 14, 2003
>
> 8:00 AM
>
> Holiday Inn
>
> Two Montgomery Village Avenue
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> Roy M. Gulick, M.D., M.P.H., Chair
>
> Tara P. Turner, Pharm.D., Executive Secretary
>
> MEMBERS:
>
> Courtney V. Fletcher, Pharm.D., Consumer Representative
>
> Princy N. Kumar, M.D.
>
> Wm. Christopher Mathews, M.D., M.S.P.H.
>
> Sharilyn K. Stanley, M.D. (by phone)
>
> Victor G. DeGruttola, Sc.D.
>
> Janet A. Englund, M.D.
>
> Kenneth E. Sherman, M.D., Ph.D.
>
> CONSULTANTS (VOTING):
>
> Douglas G. Fish, M.D.
>
> Mary E. Guinan, M.D., Ph.D.
>
> George J. Pazin, M.D., M.S.
>
> Linda S. Potter, Dr.P.H.
>
> Ronald G. Washburn, M.D.
>
> GUEST SPEAKER (NON-VOTING):
>
> H. Hunter Handsfield, M.D.
>
> HHS FEDERAL GUEST (NON-VOTING):
>
> Katherine M. Stone, M.D.
>
> PATIENT REPRESENTATIVE (NON-VOTING):
>
> Charles Ebel
>
> FDA STAFF:
>
> Debra Birnkrant, M.D.
>
> Mark Goldberger, M.D.
>
> Harry Haverkos, M.D.
>
> Fraser Smith, Ph.D.
>
> [C O N T E N T S]{.underline}
>
> Call to Order, Roy M. Gulick, M.D., M.P.H. 4
>
> Conflict of Interest Statement, Tara P. Turner, Pharm.D. 6
>
> Opening Remarks, Debra B. Birnkrant, M.D. 11
>
> Public Health Aspects of Genital Herpes,
>
> H. Hunter Handsfield, M.D. 14
>
> Sponsor Presentation, GlaxoSmithKline:
>
> Introduction, David M. Cocchetto, Ph.D. 58
>
> Study Design, Methods and Results,
>
> Stuart M. Harding, M.D. 63
>
> Concluding Remarks, Clarence L. Young, M.D. 88
>
> FDA Presentation:
>
> Study Design, Dr. Harry W. Haverkos, M.D. 92
>
> Efficacy Results, Fraser Smith, Ph.D. 99
>
> Viral Shedding Substudy, Safety and Behavioral
>
> Results and Conclusions,
>
> Harry W. Haverkos, M.D. 114
>
> Questions from the Committee 126
>
> Open Public Hearing:
>
> James Allen, M.D., MPH,
>
> American Social Health Association 168
>
> Gray Davis, M.D., HIV Prevention Trials Network,
>
> Family Health International 173
>
> H. Hunter Handsfield, M.D., University of Washington 181
>
> Mark Wasserman, Ph.D., HELP of Washington
>
> (read by Roy M. Gulick, M.D., M.P.H.) 181
>
> Curtis Phinney, HELP of Washington 183
>
> Charge to the Committee/Questions for Discussion,
>
> Debra B. Birnkrant, M.D. 189
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order and Introductions**
>
> DR. GULICK: Good morning. I am Roy Gulick, from Cornell University in
> New York, and I am pleased to call to order this meeting of the
> Antiviral Drugs Advisory Committee today. We will start with
> introductions of the committee, and we will start on this side with
> Mr. Ebel. So, please state your name and your affiliation.
>
> MR. EBEL: My name is Charles Ebel. I am employed by the American
> Social Health Association. I have worked in patient advocacy for
> genital herpes for about fifteen years.
>
> DR. STONE: I am Katherine Stone. I am a medical epidemiologist in the
> Division of STD Prevention at the CDC, the Centers for Disease Control
> and Prevention.
>
> DR. POTTER: Hi. Linda Potter, private consultant\--
>
> DR. GULICK: Sorry, turn the mike on.
>
> DR. POTTER: There, now it is okay. My area of expertise is primarily
> compliance and adherence with regimens.
>
> DR. GUINAN: I am Mary Guinan, from the Nevada Public Health Foundation
> in Carson City, Nevada.
>
> DR. PAZIN: George Pazin, formerly from University of Pittsburgh; now
> at the VA Hospital in Pittsburgh.
>
> DR. FISH: I am Douglas Fish. I am the Division Head of HIV Medicine at
> Albany Medical College, in Albany, New York.
>
> DR. WASHBURN: Ron Washburn, LSU and Shreveport VA.
>
> DR. MATHEWS: Chris Mathews, University of California, San Diego.
>
> DR. FLETCHER: Courtney Fletcher, University of Colorado Health
> Sciences Center.
>
> DR. TURNER: Tara Turner, Executive Secretary for the committee.
>
> DR. KUMAR: Princy Kumar, Georgetown University, Washington, D.C.
>
> DR. SHERMAN: Ken Sherman, University of Cincinnati and Director of
> Hepatology and Professor of Medicine.
>
> DR. DEGRUTTOLA: Victor DeGruttola, Harvard School of Public Health.
>
> DR. ENGLUND: I am Janet Englund, pediatric infectious diseases,
> University of Washington.
>
> DR. SMITH: Fraser Smith, Statistical Reviewer, FDA, CDER.
>
> DR. HAVERKOS: Harry Haverkos, Medical Officer, FDA.
>
> DR. BIRNKRANT: Debbie Birnkrant, Director of the Division of Antiviral
> Drug Products, FDA.
>
> DR. GULICK: One committee member is joining us by teleconference. Dr.
> Stanley, can you hear us?
>
> DR. STANLEY: I can hear you loud and clear. Dr. Stanley, from Texas
> Department of Health, not in Oklahoma.
>
> \[Laughter\]
>
> DR. GULICK: We did wonder about that, Sharilyn.
>
> DR. STANLEY: Unfortunately, there are ploys why I am here and not
> there, and I wish I were there.
>
> DR. GULICK: Well, thanks for joining us by teleconference. Tara Turner
> will now read the conflict of interest statement.
>
> **Conflict of Interest Statement**
>
> DR. TURNER: The following announcement addresses the issue of conflict
> of interest with respect to this meeting and is made a part of the
> record to preclude even the appearance of such at this meeting.
>
> Based on the submitted agenda and information provided by the
> participants, the agency has determined that all reported interests in
> firms regulated by the Center for Drug Evaluation and Research present
> no potential for a conflict of interest at this meeting with the
> following exceptions:
>
> Mr. Charles Ebel will be permitted to participate in the committee\'s
> discussion. He is, however, excluded from voting.
>
> Dr. Princy Kumar has been granted a waiver under 21 U.S.C. 344(n)(4)
> for owning stock in the sponsor and competitor. The stock is valued
> from \$5,001 to \$25,000.
>
> Dr. Roy Gulick has been granted a waiver under 18 U.S.C. 208(b)(3) for
> consulting to the sponsor on unrelated issues. He receives less than
> \$10,000 a year.
>
> A copy of these waiver statements may be obtained by submitting a
> written request to the agency\'s Freedom of Information Office, Room
> 12A-30 of the Parklawn Building. The signed disclosure statements are
> available for public review at this meeting.
>
> With respect to FDA\'s invited guest speakers. there are reported
> interests that we believe should be made public to allow the
> participants to objectively evaluate their comments:
>
> Dr. Hunter Handsfield would like to disclose the following interests
> in GlaxoSmithKline. His employer, the University of Washington, has
> received contract and/or grants from GlaxoSmithKline and he is an
> investigator on GlaxoSmithKline sponsored studies. He receives
> compensation for serving as a scientific advisor to Glaxo and speaking
> fees from agencies that received unrestricted educational grants from
> Glaxo.
>
> Dr. Katherine Stone is an employee of the Centers for Disease Control.
> Dr. Stone is the first author on a scientific manuscript, with
> GlaxoSmithKline co-authors, on the results of a Glaxo acyclovir and
> valacyclovir pregnancy registry and she served on their advisory
> committee for the registry during 1984-1999.
>
> Lastly, we would also like to note for the record that Dr. Eugene Sun
> is participating in this meeting as the acting industry
> representative, acting on behalf of regulated industry. Dr. Sun is an
> employee of Abbott Laboratories.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which FDA participants have a financial
> interest, the participants are aware of the need to exclude themselves
> from such involvement and their exclusion will be noted for the
> record.
>
> With respect to all other participants, we ask in the interest of
> fairness that they address any current or previous financial
> involvement with any firm whose product they may wish to comment upon.
> Thank you.
>
> DR. GULICK: One clarification on that, Dr. Sun was unable to be here,
> on the committee, today. Dr. Katherine McComus, from the University of
> Maryland is going to take a minute to tell us about a side project
> that is going on today.
>
> DR. MCCOMUS: Thank you and good morning. My name is Dr. Katherine
> McComus and I am at the University of Maryland. I am here today to ask
> your assistance in a survey that I am conducting with collaborators at
> the Food and Drug Administration to examine public attitudes and
> understanding of the conflict of interest procedures that the FDA uses
> to manage and monitor real or potential conflicts of interest of its
> advisory committee members. People in the audience are being asked to
> complete this questionnaire and members of the advisory committee are
> also distributed a questionnaire under a separate cover. If you have a
> chance to complete it today\--I realize it is a very busy day, but
> there is a box outside at the registration desk and you can drop it in
> there. Otherwise, there is a business reply envelope and you can mail
> it back to me later.
>
> Your responses are anonymous. Your participation is voluntary but your
> participation is very important to the reliability and validity of
> this study. This study is being conducted across several centers at
> the FDA and at multiple advisory committee meetings. We would like as
> a high a response rate as possible so that we can accurately represent
> your opinions, provide feedback to the Food and Drug Administration
> and perhaps improve overall satisfaction with the advisory committee
> process.
>
> I will be here today if you have any questions. Thank you again for
> your time. Thank you for the opportunity.
>
> DR. GULICK: We were advised yesterday that informed consent is not
> required for this but that it has been approved by local IRBs.
>
> We will now turn to Dr. Debra Birnkrant to make some opening remarks
> on behalf of the agency.
>
> **Opening Remarks**
>
> DR. BIRNKRANT: Good morning. I would like to welcome back our advisory
> committee members and extend a welcome to our guests and consultants
> this morning.
>
> \[Slide\]
>
> Today we will be discussing the supplemental new drug application
> 20550 for valacyclovir for the prevention of the transmission of
> genital herpes amongst monogamous heterosexual couples. We are
> bringing you this application today because we seek your input in this
> discussion, and this is the first time we are being requested to
> include wording in labeling \"for prevention of sexually transmitted
> viral infection.\" We will also be asking you to comment on public
> health implications as well.
>
> \[Slide\]
>
> Although Dr. Hunter Handsfield will be presenting an overview of
> genital herpes this morning, I wanted to start this morning off with a
> few comments related to management of herpes infections, and this is
> taken from the CDC STD treatment guidelines, published in the MMWR,
> May, 2002.
>
> There are three key principles of management of genital herpes,
> consistent and correct use of condoms; counseling and chemotherapy
> with three approved antiviral drugs, one of which, valacyclovir, we
> will be focusing on today.
>
> \[Slide\]
>
> Valacyclovir is approved for first, recurrent and suppressive episodes
> of genital herpes. These regimens are actually taken from the CDC
> guidelines and are slightly different from the labeling of the
> product. In addition, we recently approved valacyclovir for
> suppressive therapy in HIV-infected subjects with CD4 counts greater
> than 100.
>
> \[Slide\]
>
> In addition to these indications, GlaxoSmithKline studied valacyclovir
> for the prevention of transmission of genital herpes amongst
> monogamous heterosexual couples in study HS2AB3009. This was a study
> in more than 1,400 discordant couples for genital herpes. This sample
> size was achieved after screening more than 4,000 discordant couples.
> It studied the dose of valacyclovir 500 mg daily for eight months. In
> this study, which you will hear much more about later this morning,
> condom use was encouraged and the primary endpoint was clinical signs
> or symptoms of genital herpes plus laboratory confirmation.
>
> \[Slide\]
>
> The issues we will be asking you to address this afternoon include the
> following: The appropriateness of the endpoint in the clinical trial
> and for future clinical trials, as well as the trial design; the
> applicability of the results to other populations, given the
> restricted patient population that was studied in this clinical trial;
> screening issues related to the fact that more than 4,000 couples had
> to be screened in order to achieve more than 1,400 couples to enter
> the clinical trial; an issue related to the high dropout rate in
> relation to the event rate in the clinical study\--again, we will be
> asking you about the impact on public health guidelines and, as with
> all antiviral drugs, we will be asking a question about resistance
> issues with wider use of valacyclovir.
>
> \[Slide\]
>
> An overview of the day is on this slide. As I mentioned, Dr. Hunter
> Handsfield will be giving opening remarks with regard to geital
> herpes. This will be followed by the GlaxoSmithKline presentation.
> Actually, we may delay clarifying questions until after the FDA
> presentation, which will be done by Drs. Harry Haverkos and Fraser
> Smith. Then there will be a time for questions and discussion. The
> open public hearing will be held this morning, before lunch. Following
> lunch we will have a charge to the committee and questions. Thank you
> very much.
>
> DR. GULICK: Thanks, Dr. Birnkrant. We will turn now to our guest
> speaker, Dr. Hunter Handsfield, from the University of Washington.
>
> **Public Health Aspects of Genital Herpes**
>
> DR. HANDSFIELD: Good morning. Dr. Gulick and colleagues and interested
> persons, thank you very much for the invitation to participate in
> this. I have been looking forward to it with some enthusiasm. Thanks
> in particular, Harry Haverkos, an old friend from his days at the
> Division of STD Prevention at CDC, for those of you who are not aware
> of his background in that arena.
>
> In the further discussion of conflict of interest, it actually
> directly relates to why I am here today in a way. I spent my career in
> sexually transmitted diseases, more than a 20-year career in
> prevention, epidemiology and so on, predominantly in the bacterial
> section of transmitted diseases. I had the opportunity to take
> sabbatical leave at CDC in 1997 and 1998, and my sabbatical was
> largely supported financially by Glaxo Wellcome and SmithKline
> Beacham. My focus in that sabbatical was to really take the first
> steps with the Division of STD Prevention to look systematically at
> prevention aspects and public health issues concerning the viral STDs
> other than HIV and hepatitis, which is not directly the responsibility
> of the STD Division. That led me into essentially a year of delving
> into the public health aspects of genital herpes in particular.
>
> My sabbatical was followed, as it happens perhaps as an indirect
> indicator of CDC\'s growing interest in viral STDs, by Dr. John
> Douglas who spent a similar year working mostly on human papilloma
> virus infections and, perhaps not insignificantly, Dr. Douglas has
> recently agreed to assume the position of Director of the Division of
> STD Prevention, perhaps indirectly reflecting the level of interest of
> CDC in looking carefully at the public health aspects of viral STDs.
>
> My task this morning I see as sort of to set the context of some
> thoughts about the epidemiology of this disease from a public health
> perspective. It is really a review and I hope there is not very much
> new to most of you. In fact, those of you on the committee who had the
> time and energy on the airplane flying in to read GlaxoSmithKline\'s
> overview in their application, the epidemiology data and so on is
> actually quite excellent and I thought quite objective, and an
> excellent summary and so much of what I have to say will highlight
> some points that are made there. It also allows me to gloss over some
> things because they are clear in that fashion.
>
> \[Slide\]
>
> A simplistic review\--I hope everybody knows about the basic biology
> of these two viruses. With mucocutaneous infection, retrograde
> infection along sensory nerves, latent infection potential for
> recurrences\--some of the terminology is evolving whether there are
> true biological recurrences in terms of viral replication or some
> level of ongoing viral replication, things other than replication per
> se that influence transmission of virus down nerves, and recurrent
> mucocutaneous lesions is an issue that I think is still not totally
> settled and discussed by people who study this disease at a laboratory
> level.
>
> We have two viruses, cleverly called types 1 and 2. Type 1, as you
> well know, mostly causes oral labial disease but does cause high
> proportions, depending on where you are in the world and what
> population, of initial genital herpes. HSV-2, by contrast, is really
> rare in the oral area. It is a very rare person walking around with
> oral so-called fever blisters that has HSV-2 infection. When oral
> HSV-2 occurs it is almost exclusively in either overtly
> immunodeficient persons, such as persons with overt AIDS as has
> recently been published in studies, or in the context of initial
> infection when infection was simultaneously acquired in the oral
> cavity and the genital area.
>
> The corollary to that is that of recurrent genital herpes the vast
> majority is type 2 virus. If you are unlucky enough to get herpes but
> lucky enough for it to be HSV-1, and I will show you data on this, you
> are far less likely to have recurrent outbreaks of disease and also
> less likely to have subclinical shedding of the virus with the
> potential for sexual transmission, at least by vaginal intercourse.
>
> \[Slide\]
>
> It is not a formally reportable disease. Indirect methods and sentinel
> surveillance is required to understand the frequency of this disease.
> This data set is from the National Disease and Therapeutic Index, over
> three decades, and it is initial visits to clinicians\' offices
> because of genital herpes. The up and down is a sample size study
> design artifact. The upward trend is clear although, of course, these
> data don\'t let you distinguish between increasing incidence,
> increasing patient concern and increasing clinician acumen and
> diagnosis.
>
> \[Slide\]
>
> These data are in the information provided by the sponsor. They simply
> make the point that genital herpes is in the middle ground of the
> annual guesstimated\--and I have to say guesstimated incidence of
> sexually transmitted diseases. They suggest at the low end half a
> million; at the high end, in a recent analysis, 1.6 million new cases
> occurring per year in the U.S.
>
> \[Slide\]
>
> The prevalence of genital herpes, however, is highest of all STDs.
> That is because, as the cute saying in the STD world goes, \"what is
> the difference between herpes and true love? Herpes is forever.\" Once
> you get herpes, it stays. So, the seropositivity is an accurate
> indication of people who are infected, are believed to remain infected
> and so as long as infection is occurring at a rate higher than the
> rate with which people with herpes are dying in the population, the
> disease accumulates. So, we are dealing with something like a quarter
> of the U.S. population infected with genital HSV-1 or 2.
>
> \[Slide\]
>
> I think everybody in the room is aware of the National Health and
> Nutrition Examination Surveys, previously done in discrete cycles
> called one, two and three. What is now sometimes being called cycle
> four is really what is hoped to be, by the Center, an ongoing
> population-based sample. NHANES is a population-based access to
> Americans that includes extensive health questionnaires and also serum
> banking. The banked sera from these studies have been looked at for
> HSV-2 serology and they provide the core information now available on
> prevalence of this disease in the U.S.
>
> What it shows is that from the cycle that had a mid point in 1978 to
> the cycle that had a mid point in 1991 there was a 25-30 percent
> increase in overall prevalence that occurred in both men and women.
> The other point to draw from this slide is that in every survey ever
> done, for practical purposes, the prevalence of infection is higher in
> women than in men and the incidence of infection when people are
> followed at risk is higher in women than in men, probably reflecting
> differences in anatomy in terms of the nature of the exposure or the
> nature of the surfaces exposed to the virus during intercourse.
>
> \[Slide\]
>
> Here is where we come with that number that I showed you on the
> pyramid. The NHANES II data were around 16 percent after adjustment
> for various issues in study design, believed to have increased to
> about 22 percent prevalence in 1991, which translated to 45 million
> people. The number of persons infected since 1991 is a little bit
> conjectural but the estimate supports something in the range of 5-15
> million, depending on which rates of new infection you focus on.
>
> Some unknown number of the roughly 50 percent of the U.S. population
> as adults that are HSV-1 seropositive have genital as opposed to oral
> labial infection. It is impossible on a population basis to know that
> number very well so I put a double question mark here. I don\'t know
> whether it is two million, 10 million or 15 million but it is a lot.
> That is where you can come to the conclusion that something like a
> quarter to a third of the U.S. population likely is infected.
>
> \[Slide\]
>
> There tends to be, I find, in people who are not familiar with this
> disease and with sexually transmitted diseases in general a skepticism
> from time to time about whether that proportion of the population
> really acquires an STD. These tend to be looked at with some
> emotionality from a lot settings and the concept that many of us get
> it doesn\'t set well with some people psychologically, socially,
> politically and sometimes at the gut level. I will just make the point
> that human papilloma virus infections is probably acquired by 70 or 80
> percent of us but within our first two to four lifetime sexual
> partners so that is even a more normative event to acquire HPV.
>
> But that having been said, what these data show is the seroprevalence
> in the NHANES I study of SHV in whites by age. I show the \'78 data
> because the 1991 data were not analyzed below age 12 or 15 so we
> didn\'t have the data down here. What it shows is that whereas HSV-1
> seroprevalence rises on a more or less linear basis as age increases,
> HSV-2 infections are essentially absent before the sexually active
> years and the acquisition rate obviously declines to very low levels
> after the sexually active years. So, after someone reaches their late
> 30s they become, as has been used in the sexually transmitted disease
> epidemiology modeling world, sexually dead. So, all of the
> acquisitions are basically occurring in the sexually active years. So,
> that is just one piece among many of the evidence for those of you who
> might be skeptical that, yes, HSV-2 infections are sexually acquired.
>
> \[Slide\]
>
> Many of you have seen these data before and in a way, there is this
> almost too cute sort of slant to them, but I think they are important
> to take into account. This is one question on health-related random
> digit dialing survey, conducted by the American Social Health
> Association a few years ago, in which a number of health-related
> questions were asked. People were sought who were age 18-40. So, it is
> the younger half of the population.
>
> This is simply one of many questions that was asked. It is listed
> verbatim here. I can read you a list of items\--it is exactly the same
> approach used for political polling, the same sort of confidence
> intervals and so on. The sample size is around a thousand. I can read
> you a list of items that people may or may not consider traumatic. For
> each one, please tell me how traumatic it would be for you personally,
> \"very,\" \"somewhat,\" \"not very traumatic,\" or \"not traumatic at
> all.\" No surprise, people said getting HIV or AIDS would be very
> traumatic. The proportion saying it was very traumatic was virtually
> 100 percent. But two-thirds reported that they would consider it very
> traumatic if they acquired genital herpes, and that was more than the
> proportion than rated it very traumatic to break up with a significant
> other, to get fired from a job or to fail a course in school.
>
> Now, in a way that is crazy because this is a disease that, although
> it has its serious outcomes, the vast majority of infections are, in
> fact, mild. In fact, they are so mild that the majority of infections
> are entirely subclinical. Many of those can be converted into
> clinically recognized cases by proper counseling for people to
> recognize subtle symptoms. But it is probably not an accurate
> reflection of how bad the disease is, but it is a reflection of how
> people who recently acquired the disease or are afraid of getting it
> look at it.
>
> \[Slide\]
>
> This slide shows that although you may say, well, that is one data set
> but that makes the point of what about others? This is an entirely
> separate kind of data set that essentially comes to the same
> conclusion.
>
> After 1997 the national STD hotline, conducted by American Social
> Health Association on behalf of CDC combined with the national AIDS
> hotline, so it was a single hotline so the statistics are a little bit
> less easy to break out in this fashion since that time but the last
> year these data were available, 1997, if you limit the logged calls in
> terms of what they are about to disease specific calls, eliminating
> non-specific ones\--what is an STD; do condoms work, etc.\--and
> looking at disease-specific calls, herpes generated almost as many
> calls as all the rest of these combined.
>
> HPV and warts was, in the middle 1990s, the most rapidly rising
> category so it wouldn\'t surprise me if more recent data would show
> these two running more closely to one another, and who knows which
> would be first, but the point is the viral STDs in general and genital
> herpes in particular generate far more concern than the traditional
> bacterial STDs on which I have spent the bulk of my professional
> career.
>
> \[Slide\]
>
> Clinical spectrum of disease\--I hope this is also a review. First
> episode infection is divided into those who have true primary
> infection. These are people who have never been infected with either
> HSV-1 or HSV-2 and they tend to have the clinically most severe
> disease. I say \"tend\" because most of these are subclinical. Even
> people who are HSV-2 seropositive and HSV-1 negative, which means when
> they acquired HSV-2, it had to be a primary infection\--most of those
> or many of those, in fact, have no previous diagnosis or symptoms.
>
> That said, among the people who development symptoms, these tend to be
> clinically the most severe. These are the folks who present with
> multiple bilateral lesions, systemic symptoms and so on, and a more
> prolonged course. Non-primary first episode infections are people who
> are infected typically with HSV-2 in the face of chronic, often
> undiagnosed and unaware HSV-1 infection, often acquired years before.
> These tend on average to be shifted toward a less severe clinical
> course and probably more subclinical infection.
>
> Very important, many people present and already at the time of
> presentation have type specific antibody to the virus type that is
> causing the acute clinical syndrome, meaning that they have been
> infected for at least some weeks and, statistically, the vast majority
> have been infected for months or years. That is, they are experiencing
> the first clinical outbreak in spite of an infection that was acquired
> some time previously. This phenomenon actually explains a large
> proportion of the magical transmission theories that we have all heard
> about\--toilette seats, hot tubs and shared towels\--because what it
> means is that people who show up with infection who are not currently
> sexually active or at risk for an STD because they are in a reliable
> monogamous setting and, of course, in that monogamous setting the
> other possibility is that transmission only just occurred in a
> relationship that had been going on for a substantial period of time.
> But in both cases clinicians tend to help patients reach for
> face-saving explanations that we now know simply don\'t occur. So,
> that is an important issue to understand from an epidemiology as well
> as a clinical management perspective.
>
> Recurrent infection, of course, by definition is a second or
> subsequent recurrent outbreak that is clinically recognized, and most
> of the important information in understanding the epidemiology and
> clinical aspects of this disease in the past 15 years has been to
> understand that subclinical infection overlaps all these categories
> and is subdivided into those who are truly asymptomatic and those who
> have unrecognized disease. Most are in this category. Data show that
> persons who are seropositive and unaware, and even who say they have
> had no symptoms, if counseled about even subtle genital symptoms to
> look for and then are given a green light to be seen clinically within
> a day or two as opposed to an appointment ten days later when symptoms
> appear, in fact, 60 percent or so appear with symptoms that are
> culture positive for herpes within about three months.
>
> \[Slide\]
>
> Much of these data, though not exclusively, I owe to my colleagues
> Anna Wald and Larry Corey who have made entire careers of studying
> this disease, and much of these data come from their facility. So,
> this is sort of the plenary study on the recurrence rate of 450-some
> persons followed for something over a year on average. Men had an
> average of five, women an average of four episodes in the next year of
> recurrences. I believe the true recurrence rate probably is the same
> in men and women. Carefully counseled people in a herpes research
> clinic\--men may be able to recognize subtle disease than women
> because of anatomical location and visibility. For a woman it is hard
> to know perhaps whether a labial itch is a lesion or not. Almost 40
> percent had at least six recurrences in the next year and a sizeable
> minority had at least ten recurrences in the coming year.
>
> I actually intended to bring a slide, and I guess I just forgot to
> include it in my slide set and it wasn\'t in my laptop, about the
> natural course over the years. The same data set has been looked at to
> look at recurrences and, actually, over the course of about eight
> years and beyond eight years the number of patients followed over time
> became too small to draw very many conclusions. But the average rate
> of decline was 0.7 to 0.8 recurrences per year.
>
> The problem with those date is it is not linear, so people probably
> tend to have fairly frequent recurrences in the first year. There is
> probably usually then some decrement that goes on for many years. The
> same pattern appears to apply for subclinical shedding. So, we have
> fairly poor data both for subclinical shedding and for clinical
> disease beyond eight to ten years. I think that is an important thing
> to keep in the back of our mind. It is true that we don\'t see very
> many people in STD clinics who are, for example, age 50 who say, \"I
> got herpes at age 25 and here I am, 25 years later, still having two
> or three episodes per year.\" But the frequent recurrent rate and
> certainly the potential for transmission goes on, as ball park
> thinking, for at least a decade and what happens after that is harder
> to know. The recurrence rate is much lower for genital SHV-1.
>
> \[Slide\]
>
> This slide shows data on that. These were presented by Dr. Wald at
> IDSA a couple of years ago and have just been published, within the
> last month. The bottom line is when you follow HSV-1 infected persons
> for an average of 2.5 years, 40 percent almost had no recurrences that
> are clinically recognized; a third had only one; and only a quarter
> had four or more. So, it is very different than HSV-2 and the days to
> first recurrence are quite prolonged. As you can see, there is a
> decrement down to an average of less than one recurrence per year for
> many people after the first couple of years. So, the bottom line is
> that people with this disease can be told with some assurance that
> they might have no recurrences though probably most people have one or
> two over the next year or two and maybe very little disease
> thereafter.
>
> \[Slide\]
>
> There is a lot of folklore about triggering recurrent outbreaks. It is
> interesting that for oral labial infection with HSV-1 the very fact of
> the name, cold sore or fever blister, reflects the role of
> intercurrent infections in stimulating outbreaks. We certainly know
> that sunburn or other actinic injuries can do it. Local trauma can do
> it. Ophthalmologists and ENT docs have learned that people with
> recurrent oral herpes often are being treated prophylactically with
> antiviral drugs at the time of surgery to prevent postoperative
> complications. Admittedly, I don\'t know the extent to which those
> procedures have been systematically documented as effective, but they
> are believed to be effective by many of those providers.
>
> In contrast to folk lore, there aren\'t very many well documented
> triggers for HSV-2. The studies that are weak in this area but in
> general those that have attempted to look at diaries of stressful
> events plus recurrent outbreaks and overlying objective psychological
> scoring methodologies have not been able to show much of a link
> between the things that patients often cite, such as stress, diet,
> menses and that sort of thing. I think it is important to remember the
> power of the human mind\'s capability of linking sequential events in
> a causal fashion, and I would ask anybody to contemplate whether it is
> herpes or myocardial infarction or a sprained ankle, whether they can
> look back and say, \"oh, I haven\'t been stressed at all in the last
> week.\"
>
> \[Slide\]
>
> The biomedical complications\--I stress biomedical because of the
> psychological complications I am going to talk about in a little
> bit\--are a separate category, and I think everybody recognizes the
> predominant, frequent impact of this disease. It is psychosocial
> rather than purely biomedical although, obviously, they are
> interacting. But just to remind you of that spectrum, this is a
> protean disease that causes more than just the occasional genital
> sore. So, localized neuropathic manifestations, particularly the first
> set of infection, bladder paralysis, sphincter incompetence and things
> like that; meningitis, either acute or recurrent. For those who don\'t
> know, the historic syndrome of what used to be called Molleret\'s
> meningitis or benign lymphocytic meningitis is, in fact, in at least
> 80-90 percent of cases recurrent HSV-2 infection of the central
> nervous system. HSV-2 as opposed to HSV-1 tends to cause meningitis.
> HSV-1 tends to cause encephalitis. There is a little bit of overlap
> but in an immunocompetent patients those distinctions hold fairly
> sharply.
>
> Erythema multiforme, Stevens-Johnson syndrome\--it is now known that
> recurrent erythema multiforme is in the vast majority of cases a
> complication of genital HSV-2 infection and preventing erythema
> multiforme in those cases is highly successful with suppressant
> antiviral therapy.
>
> There is a range of perinatal and maternal morbidity, and Dr. Zane
> Brown is here and will undoubtedly address this if he has a chance to
> make some comments. The non-genital auto-inoculation syndromes, such
> as ocular infections and whitlow are an occasional issue, particularly
> the first episode disease; chronic, localized disease, in AIDS
> patients; and I will talk a little bit more about the HIV transmission
> issue in just a minute.
>
> \[Slide\]
>
> In fact, here is the start of that theme. Dr. Wald and her colleague,
> Katie Link, did a masterful review and meta analysis of the
> literature, published a year ago in JID, and this is one figure from
> that paper. They found, I think it was, 20 or 30 studies that had
> looked at the association of HSV-2 infection with HIV prevalence or
> incidence, and within that there were nine studies that were either
> prospective cohort or nested control studies that had the opportunity
> to look at incident HIV infection as a function of preexisting HSV-2
> antibody while also controlling for a variety of all of the things you
> would expect would influence it\--sexual behavior, intercurrent STDs,
> and so on, and so on.
>
> The results of those nine studies are illustrated here, and the
> overall meta-analytic conclusion was that there is, on average, about
> a two-fold increase of HIV infection, of incident HIV in the presence
> of HSV-2 antibody compared to the absence of HSV-2 antibody after
> controlling for a number of sexual partners, frequency of sexual
> intercourse, use of condoms and other similar predictors.
>
> \[Slide\]
>
> These data are, to me, among the most dramatic. They are preliminary
> and remain that way. They come from the Rikai, Uganda study and I owe
> Larry Corey thanks for letting me use this slide which he, in turn,
> got from Mary Wawar and Tom Quinn and others.
>
> I am privileged to be reviewing abstracts for the upcoming
> international society for SV research meeting that is occurring in
> Ottawa in July, and I have seen that these investigators have analyzed
> these data now with about double the number of couples reflected and,
> without betraying the confidence that is implicit in seeing
> pre-published work in that context, suffice it to say that it looks
> like these earlier results are not going to be undermined in any
> important way.
>
> One hundred seventy-four HIV discordant monogamous couples, followed
> over time, looking at the HIV acquisition rate in those couples while
> those couples kept diaries of episodes of sexual intercourse, all
> these people lacked other risks for HIV, other than their sexual
> cohabitation. What this looks at is the risk of HIV seroconversion
> according to the viral load, using a particular earlier assay that
> gave these particular numbers and looking at that by viral load in the
> HIV-infected persons per number of episodes of intercourse over time.
>
> I think you can see obviously that if the HIV-exposed person, HIV
> negative exposed person was HSV-2 seropositive the risk of HIV
> transmission was dramatically higher than if that person was HSV
> negative. In fact, the transmission rate was statistically similar in
> a person who was sexually exposed to someone with a maximal viral load
> if the exposed person was HIV negative and in someone who was HSV-2
> positive but exposed to someone with an undetectable HIV viral load by
> that assay. So, in this subset the importance of HSV-2 was a stronger
> predictor of HIV transmission than was HIV viral load.
>
> \[Slide\]
>
> So, I have concluded when I have spoken to practicing clinicians in
> the past couple of years that, other things being equal, HSV-2
> infected persons have twice the chance of acquiring HIV on a
> population basis. HSV-2 may be the post important STD. Not that the
> transmission efficiency for HIV is enhanced as much as it might be
> with, say, syphilis but HSV-2 is so much more prevalent in the
> population. The population attributable fraction likely is maximal for
> this particular disease.
>
> Now, there is some controversy about when and how type-specific
> serological testing should be used as a screening tool in asymptomatic
> persons. My own feeling is that that debate unequivocally is over in
> people at high risk for HIV. We need to know of they are HSV-2
> positive because it may help them understand that they are at double
> the risk of acquiring HIV if exposed. I think understanding this and
> its implications for the public health aspect may be at the pinnacle
> of what we need to be thinking about for this disease and prevention
> and, of course, control strategies for it which is, of course, at the
> core of why you are here today.
>
> \[Slide\]
>
> Subclinical shedding of this virus is extremely common. It is really
> unfair to try to summarize essentially your entire career in a single
> slide but here it goes. You can sort of summarize that it is present
> in people who test themselves every day for weeks on end. It is
> present 1-10 percent of the days if you use PCR, up to 30 percent of
> asymptomatic days in people with symptomatic recurrent genital herpes.
> The maximum frequency, the group in the 5-10 percent of the days or
> 20-30 percent by PCR is in the first year after acquisition of this
> disease. It then declines. But it probably settles by culture in most
> people at the rate of roughly 2-3 percent of asymptomatic days by
> culture and roughly double that number of days by PCR for at least
> several years. The time course is probably similar to the clinical
> recurrence rate that we have already discussed. At least 95 percent of
> the people who are HSV-2 seropositive have some days when the virus is
> present in the absence of both detectable symptoms and things that
> even a trained observer can recognize as clinical disease.
>
> Interestingly, the frequency is just as prevalent in people who are
> seropositive without history of clinical disease as it is in people
> with clinical disease who test themselves in between symptomatic
> outbreaks. Most episodes are symptomatic but unrecognized, although
> that is a little bit challenged by evolving data regarding PCR because
> there are more people who are PCR positive and culture negative who
> truly don\'t have symptoms. This accounts for most transmissions. All
> STDs are transmitted selectively, like people whose clinical syndrome
> has shifted toward the subclinical end. It is sort of a no-brainer.
> People with painful genital sores, genital discharge, lower abdominal
> pain don\'t have intercourse as often as people without those
> symptoms. That is not exactly a surprising finding. It does underlie
> the importance of why active steps of partner notification are
> important for all STDs. Subclinical shedding is substantially reduced
> by suppressive antiviral therapy, both in terms of frequency of
> shedding and the amount of virus that can be detected and, as with
> clinical disease, it is uncommon with genital HSV-1 disease.
>
> \[Slide\]
>
> Psychosocial impact\--I could spend the whole lecture on that. The
> fact that there is a psychosocial impact is at its core one of the
> reasons why we are all here today, at least some aspects of it. I
> would simply summarize specifically on the transmission issue because
> your focus is going to be on what is the impact clinically, public
> health and psychologically on suppression of this disease with the
> goal of preventing transmission.
>
> Every study of psychosocial impact or every survey of patients, and
> the quality of these studies is highly variable; the design is highly
> variable in terms of what they did and how they recruited patients or
> spontaneous respondents to web-based surveys, for example, are
> potentially highly biased. Nevertheless, there is great consistency.
>
> Fear of transmission to partners is consistently among the top three.
> It is usually number one or two of the stated sources of concern,
> anxiety or stress by the patients. Then typically in these studies
> that particular issue\--\"I don\'t want to infect my partner and I\'m
> afraid that I\'ll do it, and I don\'t know how to prevent that\"\--is
> typically cited by a third to 90 percent of the people participating
> in these surveys.
>
> \[Slide\]
>
> Just as a minor reflection, this is just a single web site. There are
> many out there. It is called Antopia, and I am not sure where the name
> Antopia comes from but Antopia has a \"dating service.\" MPwH I
> believe means matching partners with H, H meaning herpes or HPV. This
> is a quote from their web site yesterday, quoted to the point even of
> what is bold and what is colored in various ways. So, MPwH is a social
> resource and dating site for people with herpes and HPV. Right now it
> is May 13, 2003 and we have 36,000 registered members and 163 are
> currently logged in. Signing up is free; no obligation; your privacy
> and confidentiality are assured.
>
> Simply, you don\'t have these sorts of things appearing\--even if you
> make the argument that the people who participate in them are shifted
> towards those who are most concerned and not typical, you have to have
> lots of people to generate this sort of business.
>
> \[Slide\]
>
> I am not talking about therapy intentionally, except I do want to make
> the point that if you clinically suppress recurrent herpetic disease
> you have a significant impact to the good on psychological measures.
> This looked at herpes-related quality of life, 20 or so questions
> related to all the things that people with herpes might be concerned
> about plus general questions about quality of life that weren\'t
> directly herpes related. Going higher means that over time you have an
> improvement in the score, that is, less psychological stress and
> improved quality of life. In five different regimens with different
> drugs in Dr. Patel\'s analysis for suppressant antiviral therapy
> compared to people on placebo there was a marked improvement in people
> who had clinical suppression of HSV compared to people who were on
> placebo, and over time, if you note, there is a general upward trend.
> The scores continued to improve with time. It was not a transient
> effect in people on antiviral therapy.
>
> \[Slide\]
>
> So, if people are so concerned about transmission, what are the data
> on transmission? Well, there are several studies out there. I am going
> to summarize only one because, (a) it is one I am the most familiar
> with and, (b) because it is probably the most comprehensively done one
> in a prospective fashion. It also served, I believe, as part of the
> genesis of sample size calculations for the study behind the
> sponsor\'s proposal today.
>
> This was a retrospective\--you know, the Chiron vaccine studies have
> got to be the most successful scientific outcome of failed research.
> It generates all kinds of great analyses. The Chiron vaccine studies
> of HSV-2 serum negative persons enrolled monogamous partners of
> persons with herpes or STD clinic patients at high risk, 500-and some
> and almost 2000; followed them for 18 months with history, exams, HSV
> serologies, lesion cultures when lesions appeared; repeated safer sex
> counseling\--we need to keep it in mind because these studies are
> shifted toward the null in terms of the likely transmission rates
> because of this need.
>
> Outcome measures\--primary measures HSV-2 infection as measured by
> seroconversion; the secondary outcomes in this analysis for HSV-1
> infection; clinical disease. The vaccine and placebo recipients were
> combined because the vaccine didn\'t work and the results were
> identical in the two groups. The acquisition rates were similar in
> both studies, with some very minor differences. So, the results in
> both studies were combined in Dr. Langenberg\'s analysis.
>
> \[Slide\]
>
> In that data set there were 155 incident HSV-2 infections, giving good
> numbers to work with, of which 37 percent were symptomatic and 63
> percent were asymptomatic seroconversions. There were 19 incident
> HSV-1 infections. The infection rate per year was five percent, five
> infections per 100 person years, that is, five percent of uninfected
> people acquiring HSV-2 per year, essentially similar in both the
> partners study and the STD population study.
>
> As predicted and as we pointed out earlier in the broad epidemiologic
> data, women had a higher risk of acquiring infection than did men.
> This is an interesting side issue, HSV-1 infection did not change the
> rate of HIV infection. So, the people who were HSV-1 seropositive at
> enrollment and those who were HSV-1 seronegative at enrollment had
> identical rates of acquiring HSV-2. It is fascinating to me, however,
> that this result is entirely inconsistent with the results from the
> now GlaxoSmithKline, then SmithKline Beecham, HSV-2 vaccine studies
> which Dr. Stanbury may talk about later, where, with an essentially
> identical study design, it in fact was shown that HSV-1 appeared to
> protect against HSV-2 acquisition\--similar design; similar sample
> size. How that debate as to whether HSV-1 is protective is going to
> sort out over time remains a conundrum to me.
>
> \[Slide\]
>
> Other results from the studies are that 13 percent of the incident
> symptomatic infections were atypical. Trained observers who are
> looking to find herpes missed the diagnosis pretty frequently. In
> fact, if you jump down here, missed diagnosis in either
> direction\--thinking it was herpes when it wasn\'t or not thinking it
> was herpes when it was because they presented with these sorts of
> things\--by the investigators and the clinicians who are highly
> trained and experienced in this disease was in the 20 percent range.
> With other, more recent data, it is even higher than that. So, it is a
> disease that can be difficult to recognize.
>
> Many of the asymptomatic seroconverters subsequently developed
> clinically evident disease. That is truly an underestimate. Some of
> these people seroconverted, for example, at 12 or 13 months in an
> 18-month study and only had one more follow-up visits thereafter. So,
> over a long period of time this undoubtedly would be greater.
>
> Interestingly, half the HSV-1 infections were genital, not oral. The
> incident infection was associated with young age and women but not in
> men. Incident infection was two to three times more common in
> non-whites than in whites. That also reflects general epidemiologic
> factors that I haven\'t otherwise discussed. As we said, HSV-1 did not
> influence acquisition rate but it did ameliorate incident HSV-2 with
> more asymptomatic infections. The study design probably reduced the
> actual real-world infection rate because of the need for ongoing
> strict safer sex counseling as part of the protocol.
>
> \[Slide\]
>
> Other factors in herpes transmission, avoidance of sex if symptomatic
> I have highlighted because I am going to briefly mention them. My time
> is about up and I will be quite quick at this point. For those of you
> who are watching the clock, I apologize.
>
> Other things that are associated with transmission are that more
> recent infections are more transmissible than more prolonged
> infections. A shorter duration of relationship, apparently independent
> of duration of infection, is associated with increased transmission
> rates, presumably having to do with such things as frequency of
> intercourse and perhaps\--who knows?\--less judgment in terms of when
> to have intercourse in people whose sexual relationships are driven
> more by passion than by conscious thought. That is my hypothesis for
> that.
>
> Certainly sexual practices can influence when they interact with virus
> type; circumcision status perhaps; pregnancy perhaps; immune
> deficiency and/or HIV status. There have been either conflicting data
> or speculation around these issues without a lot of data so I won\'t
> go into them in any more detail.
>
> \[Slide\]
>
> There are two condom studies out there. Both are also spin-offs from
> the Chiron vaccine study. Anna published this one a couple of years
> ago. It is cited in your handout. Basically, in the monogamous couples
> of the Chiron vaccine data set with 25 percent common use used as a
> cut-off because that was the median\--it was sort of where the natural
> break point was in terms of numbers of people available for
> analysis\--clearly reduced transmission from men to women but there
> was no evidence of protection of women to men. These data were
> misinterpreted in some sources, as you can see, even though this odds
> ratio makes it look like there is actual risk of transmission, the
> broadness of the 90 percent confidence interval really just tells you
> the sample size was inadequate to draw conclusions at all.
>
> \[Slide\]
>
> This slide is data that have now been analyzed by Dr. Langenberg and
> by Dr. Wald, presented in abstract form and I understand are being
> prepared for or perhaps are submitted for publication, looking at the
> high risk group recruited from the STD clinic with 18-month follow-up.
> In this group the breakpoint in terms of the portion who used condoms
> was at a different level. It was plus/minus 65 percent. But in this
> analysis there was demonstrated protection, with a roughly 40 percent
> reduction in HSV-2 seroconversion rate in common users versus
> non-users in exposed men.
>
> \[Slide\]
>
> So, in the next slide I draw the conclusion that although it is very
> hard to study condom use in a definitive fashion because of the whole
> nature of how you do those studies, and so on and so on, I think we
> can draw the firm conclusion that condoms are partly effective.
> Previous controversy not withstanding, they are probably equally
> effective or nearly so for protecting women from male infection and
> females from male infection. Of course, condoms fall down in their
> efficacy in use effectiveness and overall acceptability. One might
> guess better performance in female condom because of greater surface
> area covered but no data are available.
>
> \[Slide\]
>
> In the interest of time I will just say there are good data to support
> the notion that couples who are aware of a herpes discordance in a
> relationship and who avoid sex when symptoms are present do have lower
> acquisition in transmission rates in those relationships.
>
> \[Slide\]
>
> The counseling of persons with herpes\--these are again from the CDC
> 2002 treatment guidelines, with the exception that in terms of what
> people ought to be counseled I have inserted in highlight the term
> antiviral therapy, question mark, because that is what your focus is
> going to be today.
>
> \[Slide\]
>
> My final slide is simply to make the point that when I wear my public
> health hat as someone responsible for SV prevention in a metropolitan
> area of 1.7 million people, and with some interest in and work at
> national and global levels as well, these are what I think are the six
> key issues, according to my lights. Some of you might lump these and
> come up with fewer and some might split them and come up with more but
> it is not a bad representation of what I think are the core current
> public health issues in genital herpes. I have highlighted the ones
> that I think have some relationship to your discussions today.
>
> Preventing sexual transmission and how to best do it is a core issue.
> The relationship of HSV-2 to HIV and its prevention is a core issue.
> The under-diagnosis of genital ulcer disease\--I would actually say
> that I think in terms of under-recognition and under-attention to this
> disease, I think the public health community in general is probably
> more lax than the practicing community. Few health departments are
> paying the attention to this disease that it needs or deserves. The
> role of and when and how to use type-specific serological testing is
> an issue of ongoing debate. I will say I believe it is grossly
> under-used but I think that is a core issue. Under-treatment, leaving
> aside the transmission issue, is a big issue that, in turn, relates to
> clinicians\' lack of understanding of the psychosocial impact and, of
> course, preventing the single most frequent devastating outcome,
> neonatal herpes and attendant maternal morbidity, is the last.
>
> Thank you very much for your attention.
>
> DR. GULICK: Thanks for the overview, Dr. Handsfield. We have time for
> a couple of questions, if there are questions, for Dr. Handsfield from
> committee members. Dr. Mathews?
>
> DR. MATHEWS: That was a great overview, Hunter. Is there evidence of
> uniform type-specific immunity?
>
> DR. HANDSFIELD: Well, yes but, first of all, it does not cross
> specificity. There is not cross immunity between HSV-1 and HSV-2. The
> general consensus is that it is extraordinarily rare at the clinical
> level for people to get ping-ponged, that is, new HSV-2 infections if
> they are already HSV-2 seropositive.
>
> Now, there are no absolutes in biology of medicine and it would be
> very difficult to know if, for example, the occasional patient who,
> three years into a pattern of recurrences occurring three or four
> times year, now all of a sudden has six or eight occurrences a year,
> did that person get a new infection on top of it? There is no evidence
> that that happens. If it happens it is very rare. We do know from the
> Chiron and extrapolating from the GlaxoSmithKline vaccine studies that
> neutralizing antibody alone does not provide protection against
> exogenous infection. But the notion that there is strong type-specific
> immunity that involves some combination of cellular and other
> mechanisms we don\'t understand I think is epidemiologically solid,
> but there are others in the audience who could probably answer your
> question with more scientific precision than I just have.
>
> DR. GULICK: Dr. Kumar?
>
> DR. KUMAR: Would you be able to comment on why it is more common,
> HSV-2, among African-Americans?
>
> DR. HANDSFIELD: Yes, I intentionally avoided that issue because though
> I think it is epidemiologically interesting, I think it can be
> distracting to get too much into racial issues for a whole variety of
> reasons that you are very well familiar with. That said, whatever
> drove the prevalences to very high rates, after you adjust for age,
> sex and geography, fairly consistently African-Americans have much
> high HSV-2 seroprevalence rates than do whites, Asians and some other
> ethnic groups, and Hispanics and native Americans tend to be in the
> middle. Whatever the reason that got it there, once it gets to that
> point the average sexually active person is more likely to encounter
> an infected person. So, sustained rates do not imply ongoing levels of
> sexual risk-taking that you might assume just that the prevalence is
> high.
>
> Now, why they got there to begin with clearly has to do with issues
> that are fairly poorly understand by sexual partner networks, partner
> selection and that sort of thing. The whole issue of overall higher
> HSV rates in African-Americans compared to whites probably relates to
> such things as higher mortality rates and higher incarceration rates
> in African-Americans that change the male-female ratios in communities
> and affect sexual partner networks, and a whole host of other very
> complex issues. So, that is a fairly inadequate answer but I think
> that is about as far as the science allows us to go with it.
>
> DR. GULICK: Yes, Dr. Guinan?
>
> DR. GUINAN: I wonder about the source of asymptomatic shedding. Where
> have these cultures been taken? Theoretically, the virus could shed
> anywhere along the distribution of the nerve, which is a long way.
> Traditionally, you know, the vagina in women has been cultured and
> maybe the labia, but in men it is not clear to me that there are
> samples taken from suspect areas that might be shedding. Are there
> well-established negative studies that it doesn\'t shed in some places
> and does in others?
>
> DR. HANDSFIELD: In the interest of time I didn\'t go into the
> methodology behind those studies. Briefly, what is done is that
> patients are trained to self-collect specimens, attempting to get a
> cervical specimen in women which really means putting a swab at the
> end of the finger and attempting to reach the cervix for at least a
> high vaginal and introital sweep and perianal sweep, and those are
> collected every day and go to the laboratory. Couriers come and pick
> them up, and that sort of thing.
>
> In men, and Anna, correct me if I am wrong, I think the technique is a
> swab in the urethra, under the foreskin or around the glands and up
> and down the shaft, and a third swab also perianally. As a side note,
> a modest proportion of subclinical shedding in heterosexual men occurs
> perianally, having to do undoubtedly with that broad neural
> distribution that you suggest.
>
> So, that is the basic technique. The frequencies of subclinical
> shedding tend to be slightly lower in men than in women, but that is
> probably an artifact of the notion that, first, cultures may be less
> sensitive on dry skin and PCR for that matter and, second, because men
> probably recognize subtle lesions more readily than some women do and,
> therefore, more men with recurrences classify themselves as
> symptomatic than women do.
>
> DR. GUINAN: Scrotum, for example, might be a source and, of course,
> condoms don\'t cover scrotum so it would make sense that in
> asymptomatic\--
>
> DR. HANDSFIELD: Anna, have you tested scrotum? Is scrotum one of the
> sites that you have been surveying?
>
> DR. WALD: Not routinely.
>
> DR. HANDSFIELD: Not routinely?
>
> DR. GULICK: I am sorry, we need you to go to the mike and identify
> yourself and answer the question. Thanks.
>
> DR. WALD: Anna Wald, from the University of Washington. In men, we
> have them mostly swab normal-appearing penile skin for asymptomatic
> shedding and also the perianal area. Urethral swabs in general are
> negative and we have moved away from those. We have looked at scrotum
> in a small number of men and it did not yield virus, but it was a
> small sample.
>
> DR. GULICK: I would like to ask one last question and then we need to
> move on. I was intrigued by your recommendation that people at high
> risk for HIV actually have an HSV-2 serology done. Two questions from
> that. One, what is the mechanism of action that increases the
> acquisition of HIV? Number two, what would you do with that result
> practically?
>
> DR. HANDSFIELD: As far as the first question, I am not an
> immunopathologist so I am probably not the best to answer but I think
> the general notion is, as you well know, that shedding is associated
> with lesions; they are simply not visible in an inflammatory reaction
> at the surface, and those inflammatory reactions bring CD4-laden
> inflammatory cells to the surface so that there is a biological
> enhancement of potential infection above and beyond, and in addition
> to the potential mechanical mucosal disruption. I think there is a
> general consensus that something like that is going on. Others may
> elaborate in more detail than I can.
>
> What would you do? Well, I guess I would answer the same way I would
> answer what do you do with HIV testing and counseling to begin with.
> There is a lot of controversy about how good it is in helping people
> understand their risk and helping them prevent transmission. But what
> we do know is that it can\'t hurt. So, from a public health
> standpoint, I think it is clear that people who are HIV susceptible
> and HSV-2 infected, that some individuals, not all and maybe not even
> a high proportion, we don\'t really know, will, with that knowledge
> say\--I mean, it will help some people click and the person who is
> sort of on the fence about where and how he or she is going to select
> partners, whether to use condoms or not, maybe now clicks over and
> that is the deciding factor that helps them reduce their risk.
>
> So, my argument is that it cannot hurt and very likely, on a broad
> population level, will help. So, the quick answer is I would counsel
> them accordingly about their increased risk and use that to help them
> protect themselves.
>
> The other issue is should HIV-infected people also be tested? That is
> actually a reasonable issue as well. Whether those people would be
> more efficient HIV transmitters is less clear from the available data.
> Then the issue is will it help clinicians be alert for clinical
> disease that will lower their treatment threshold for certain
> syndromes. I think that probably depends a little bit on the
> dedication and clinical acumen of that particular provider as much as
> anything else.
>
> DR. GULICK: Thanks. We need to move forward. Thanks again for the
> presentation. Next up is the presentation by the sponsor,
> GlaxoSmithKline. Dr. Cocchetto will be introducing this.
>
> **Sponsor Presentation**
>
> **Introduction**
>
> DR. COCCHETTO: Good morning, Dr. Gulick, Dr. Birnkrant, members of the
> committee, FDA and guests.
>
> \[Slide\]
>
> On behalf of GlaxoSmithKline, thank you for the opportunity to share
> the results of a major clinical study with valacyclovir, also known as
> Valtrex. My name is David Cocchetto and I am a member of the team at
> GlaxoSmithKline that studied the ability of suppressive therapy with
> Valtrex to reduce the frequency of transmission of genital herpes.
>
> \[Slide\]
>
> Over the next 45 minutes my colleagues and I will summarize this work.
> I will briefly summarize the regulatory history of this study and show
> the statements that GSK is seeking in product labeling. Following my
> introductory remarks, Dr. Stuart Harding will present the design,
> methods and results of the clinical study. Finally, Dr. Clarence Young
> will provide concluding remarks.
>
> \[Slide\]
>
> Dr. Handsfield has presented an informative overview of genital
> herpes, including information on transmission. The current approaches
> to reduce transmission of herpes are abstinence, avoidance of sexual
> contact during symptomatic episodes of genital herpes, and use of
> condoms during sexual contact even if symptoms are absent.
>
> However, as you have heard, these approaches are incompletely
> effective. Further, no prophylactic vaccine or topical microbicide is
> currently licenses or likely to be registered in the next three to
> four years. Therefore, an unmet need exists for additional approaches
> to reduce transmission of genital herpes.
>
> \[Slide\]
>
> Valtrex is currently approved for use in the United States for several
> indications, as listed here. One of the approved uses is suppression
> of recurrent episodes of genital herpes. Suppressive therapy with
> Valtrex was approved by FDA for immunocompetent individuals in
> September of 1997, and for patients with HIV infection in April of
> 2003.
>
> \[Slide\]
>
> For study HS2AB3009, which I will refer to as the 3009 study, GSK and
> FDA have had a proactive, constructive dialogue about this study since
> the topic was first introduced in 1995. We appreciate the time and
> expertise of FDA in providing their guidance on the design of this
> study. Extensive feedback was obtained in a meeting with FDA in
> September of 1996. That meeting, as well as subsequent dialogue,
> enabled GSK to design a single adequate and well-controlled trial to
> evaluate Valtrex. Ultimately, the study was completed in March of
> 2002, and a supplemental application was submitted on October 31.
>
> In GSK\'s pre-study discussions with FDA we received three main items
> of guidance regarding the design and conduct of this study, and I will
> now summarize these items for you.
>
> \[Slide\]
>
> FDA\'s first item of pre-study guidance pertained to the primary
> endpoint. FDA advised strongly that the primary endpoint be
> acquisition of clinically symptomatic, laboratory-confirmed genital
> herpes in the susceptible partner. Importantly, this primary endpoint
> is able to demonstrate clinical benefit to the susceptible partner.
> FDA advised that a single large clinical study should yield strong
> evidence in order to be convincing. That is, 70-80 percent reduction
> in transmission. At GSK, we adopted this primary endpoint and designed
> the study to detect a 75 percent reduction in transmission of genital
> herpes.
>
> \[Slide\]
>
> FDA\'s second item of pre-study guidance to GSK was that a robust
> analysis of clinical safety is required for Valtrex in this relatively
> health population receiving suppressive therapy. We responded to this
> advice in the 3009 study itself where we collected clinical safety
> data for the 743 source partners receiving Valtrex for eight months.
> In addition, in other clinical studies of suppressive they we
> collected clinical safety data for over 1,500 additional patients who
> have received Valtrex for 6-12 months. All of these safety data have
> been provided to FDA in previous submissions.
>
> \[Slide\]
>
> Finally, FDA emphasized the importance of GSK assessing the efficacy
> of Valtrex in addition to current public health recommends for safer
> sex counseling and use of condoms. We designed the study to provide
> all patients with safer sex counseling and encouraged use of condoms
> during all sexual acts. Therefore, our objective was to demonstrate
> the incremental benefit of the addition of Valtrex to safer sex
> counseling and use of condoms.
>
> In summary, we designed the 3009 study to incorporate each of FDA\'s
> main items of pre-study guidance to GSK. Subsequent speakers will
> present results showing that suppressive therapy with Valtrex is safe
> and effective for reduction in transmission of genital herpes.
>
> \[Slide\]
>
> We are seeking an addition to the prescription drug labeling for
> Valtrex based on the 3009 study. On this slide, in white text, I am
> showing the current FDA approved indication statement for genital
> herpes. We propose to add the yellow text based on the 3009 study.
>
> Further, a description of study 3009 is proposed for the clinical
> trial section of the labeling, and this description has been provided
> in your briefing document.
>
> \[Slide\]
>
> Let me move on and introduce Dr. Harding. Dr. Harding will present a
> summary of the study design, methods and results. Thank you.
>
> **Study Design, Methods and Results**
>
> DR. HARDING: Thank you, David. Good morning, everyone.
>
> \[Slide\]
>
> As Dr. Cocchetto said, I am going to describe to you the conduct and
> results of study 3009 but, before doing so, I would like to make some
> introductory remarks.
>
> \[Slide\]
>
> First, we were set a considerable challenge in being able to
> demonstrate what was described as a substantial reduction in
> transmission between partners, between 70 and 80 percent and with
> symptomatic clinical disease as the endpoint.
>
> Second, the study was demanding and personally intrusive for the
> couples participating. Furthermore, it was difficult to find
> serodiscordant couples who were in a stable relationship. As a result,
> it took over three years to screen and recruit couples, and involved
> over a hundred sites internationally.
>
> Finally, I would like to thank Dr. Larry Corey, of the University of
> Washington, for helping us develop a protocol, reviewing the endpoints
> and interpreting the results. He served as chairman of the endpoints
> committee in his laboratory under the direction of Dr. Rhoda Ashley
> Morrow who performed the virology assays. He and Rhoda are here today
> and are available as experts to join the discussions.
>
> What I will demonstrate to you in the course of this brief overview of
> the study is that we achieved our objective with a 75 percent
> reduction in the transmission of symptomatic genital herpes.
>
> \[Slide\]
>
> The scope of my presentation covers the following topics.
>
> \[Slide\]
>
> So let me begin with the rationale for the study. First, there is the
> proven efficacy of Valtrex in suppressing the recurrences of genital
> herpes. Second, as you have heard from Dr. Handsfield, shedding of
> HSV-2 occurs not only around the time of an episode but in between
> episodes, such that it is being estimated that up to 70 percent of
> transmissions occur in the absence of lesions. It is the virus that is
> shed that is the source of transmissible infection. We also know that
> Valtrex reduces viral shedding. Therefore, taking all these points
> into consideration, it is hypothesized that daily suppressive therapy
> with Valtrex will reduce the frequency of transmission of the herpes
> virus.
>
> \[Slide\]
>
> Moving on to design considerations\--
>
> \[Slide\]
>
> \--these are some of the major factors we considered and I will deal
> with them one by one. Before I do so, I would like to emphasize that a
> trial design that would allow one to demonstrate reduced transmission
> requires stringent criteria to make it both manageable and
> interpretable. When we applied these criteria we found that there was
> really only one design that allowed us to test the hypothesis.
>
> First, the study population actually comprised a couple. Let me orient
> you straightaway to the concept of the source partner and the
> susceptible partner. The source partner had to have recurrent genital
> herpes, confirmed by HSV-2 seropositive status and had to be a
> candidate for suppressive therapy with Valtrex. This is an important
> consideration since we have a unique situation where one person is
> treated to potentially benefit another. For this clinical trial we
> felt there had to be a potential benefit for the source partner as
> well. So, it was the source partner who was given study drug. The
> susceptible partner had to have no history of genital herpes and had
> to be seronegative for HSV-2. It was the susceptible partner who is
> monitored for the acquisition of HSV.
>
> In order for us to study this in as controlled a setting as possible,
> we stipulated a monogamous relationship. We did not want the
> susceptible partner having sexual contacts with others not on study
> drug. To limit the number of variables we enrolled heterosexual
> couples only.
>
> \[Slide\]
>
> As I just mentioned, the source partner had to be a candidate for
> suppressive therapy and was allocated Valtrex or placebo. We selected
> source partners with nine or fewer recurrences per year, which
> encompasses about 80 percent of those with symptomatic disease and for
> whom an approved dose of Valtrex is 500 mg once daily.
>
> As for the duration of dosing in this study, eight months was chosen
> based on several considerations. I have already mentioned the
> demanding and personally intrusive nature of the study procedures. In
> addition, we were concerned about a possible increase in partner
> switching over time and a reduction in acquisitions with time, as
> shown in the prior Chiron vaccine study.
>
> What we did do to encourage enrollment and provide an ongoing
> commitment during the study was to offer open-label Valtrex at the end
> of the study for a further 12 months. This also gave us the
> opportunity to obtain further long-term safety data.
>
> \[Slide\]
>
> Moving on to sample size calculations, the transmissibility of HSV-2
> is quite variable. Depending upon the population studied, the range is
> somewhere between 1/40 and 1/1,000 or more sexual contacts.
> Transmission acquisition has been reported between 3.5 and 10 percent
> over the period of a year. Considering that our population might be a
> somewhat low risk one and that the study was of only eight months
> duration, we estimated that the rate of acquisition in the absence of
> treatment would be about three percent. In looking for 75 percent
> reduction in transmission this would translate to 0.75 percent rate of
> Valtrex.
>
> Now, calculation based on these estimates yielded the number of
> susceptible partners acquiring symptomatic clinical disease to be 28
> to provide 90 percent power to differentiate between active and
> placebo. Given our assumptions of acquisition rates, we would need
> 1,500 couples to be enrolled.
>
> \[Slide\]
>
> Moving on to stratification and randomized, we already knew that women
> were more susceptible than men in acquiring the disease and it
> appeared that antibodies to HSV-1 might afford some degree of
> protection against acquisition of HSV-2, especially in women. So, we
> stratified treatment based on gender and HSV-1 serostatus of the
> susceptible partner. Our original intent was to recruit more female
> susceptibles in order to capture more cases of transmission, but had
> to abandon this due to difficulties in recruiting adequate numbers.
>
> \[Slide\]
>
> Having stratified enrollment by gender and serostatus of the
> susceptible partner, it was the source partner who was allocated
> Valtrex or placebo as shown here. I would like to point out that there
> were equal numbers of Valtrex and placebo for each block but we
> didn\'t require equal numbers block to block. The centralized
> randomized and stratification system was used.
>
> \[Slide\]
>
> It was very important that couples understood the principles of how
> the herpes virus could be spread and how they could help prevent
> transmission. This is clearly laid out in a very informative American
> Medical Association\'s educational booklet, \"genital herpes, a
> patient guide to treatment.\" A copy of this booklet was given to each
> couple. For non-English speaking subjects translations of this booklet
> were provided.
>
> \[Slide\]
>
> In addition, all were counseled at screening, enrollment and each
> follow-up visit on how to practice safer sex. The principles of safer
> sex, we emphasized, were to avoid sex whenever the source partner has
> signs or symptoms of genital herpes and use condoms for every sexual
> contact, whether vaginal, oral or anal.
>
> In addition to safer sex counseling, source partners were treated if
> they had an episode of genital herpes whether they were on active or
> placebo. Study medication was stopped and they were given open-label
> Valtrex, 500 mg twice daily for five days. However, it should be noted
> that the couples remained in the study,, with the source partner
> returning to double-blinded study medication at the end of the five
> days.
>
> So, taking these factors into consideration, we were doing all we
> could to ensure prevention of transmission. Any benefit of Valtrex
> suppressive therapy would be above and beyond these measures.
>
> \[Slide\]
>
> Now moving on to study methods, I have already made mention of some of
> these in my introduction. For example, I have already indicated that
> this was stratified and randomized, double-blind, placebo-controlled
> and that it was carried out in a large number of centers around the
> world. In fact 96 centers contributed couples who participated. The
> study population was otherwise healthy and 18 years of age and older.
>
> \[Slide\]
>
> For both partners there was a monthly clinic visit. For both there was
> a review of a diary. For the source partner whether they had had any
> signs or symptoms of genital herpes or any adverse events. For the
> susceptible partner both any signs and symptoms of genital herpes and
> a record of the type and number of sexual contacts and whether condoms
> were used. Diary interviews were performed separately to allow more
> frank evaluation. Both partners were counseled on safer sex practices
> and condoms were offered. The susceptible partner had a blood draw for
> serology and the source partner returned the study drug for drug
> accountability.
>
> \[Slide\]
>
> Regardless of the monthly visits, if a susceptible partner thought
> they had signs and symptoms of genital herpes they were to go to the
> clinic as soon as possible for examination, swabs and serology. On
> days one, five and ten of the suspected episode one swab was taken for
> culture and one for PCR. All samples of swabs and sera were sent to
> the University of Washington, with the exception of culture swabs from
> Canada which were sent to a Canadian lab. If a clinical diagnosis of
> genital herpes was suspected, they were given treatment appropriate
> for an initial episode according to approved product label. However,
> the couple remained in the study until a definitive diagnosis was made
> based on the lab tests. If the diagnosis was confirmed they were
> considered to have completed the study.
>
> \[Slide\]
>
> The primary endpoint was, as agreed with FDA prospectively, the
> acquisition of symptomatic genital herpes infection by the susceptible
> partner. The diagnosis was based on the susceptible partner having
> signs and symptoms commensurate with genital herpes confirmed by one
> or more laboratory tests, culture, PCR and/or seroconversion. Any
> positive culture for a primary endpoint was assessed for sensitivity
> to acyclovir as transmission of resistant virus would have been of
> considerable concern. Each case where there were signs and symptoms
> was to be reviewed by an endpoints committee.
>
> \[Slide\]
>
> The endpoints committee was convened at the end of the double-blind
> portion of the study when all the laboratory data were available. The
> purpose was to determine whether each case met the criteria for being
> considered a primary endpoint. It is important to note that the
> committee remained blinded to treatment during the review process and
> that the committee worked to written guidelines and minutes were
> recorded.
>
> \[Slide\]
>
> The secondary endpoints were as described on the next two slides. For
> the susceptible partner the time to acquisition of symptomatic
> infection is another way to look at the primary endpoint but has the
> benefit of comparing groups throughout the study and takes account of
> duration of study participation. We were also interested in the
> proportion of couples with and time to overall acquisition. This now
> includes those who acquired infection without symptoms, as
> demonstrated by seroconversion alone, added to those with the primary
> endpoint.
>
> The secondary endpoints of the source partner, which formed the basis
> for our hypothesis, were the time to first recurrence of genital
> herpes and the effect of Valtrex on viral shedding, which was carried
> out in a substudy and which I will describe in just a moment.
>
> \[Slide\]
>
> Other secondary endpoints are shown here. First is the proportion of
> couples with HSV-2 seroconversion. Note that this could have included
> those with symptoms or not, and a subset of this which is those with
> asymptomatic seroconversion alone. We also planned to assess any HSV-1
> genital acquisitions but there were none. We also looked at the time
> to first oral outbreak of herpes in the source partner. I am not
> planning to show the results of any of these other endpoints in my
> presentation but would direct you to the briefing document which has
> this information.
>
> \[Slide\]
>
> As I said, the effect of Valtrex on HSV-2 viral shedding was assessed
> in a substudy. This involved 89 source partners from three U.S. sites.
> The subjects were still blinded to treatment so may have been on
> Valtrex or placebo. Swabs were collected every day for 60 days for
> quantitative PCR assay.
>
> \[Slide\]
>
> Now for the results which you have all been patiently waiting for.
> These are presented under three broad headings, a description of the
> study couples; the results for the primary endpoint with subanalyses;
> and the results for secondary endpoints. I will start with the study
> couples.
>
> \[Slide\]
>
> If you recall, the aim of our program was to enroll 1,500 couples. We
> enrolled 1498. Of interest is that over 4,000 couples came forward to
> take part in the study but more than 2500 were found ineligible. The
> most common reason was that the susceptible partner was already HSV-2
> seropositive. Of the couples randomized, 1,484 comprised the
> intent-to-treat population, with 743 source subjects randomized to
> Valtrex and 741 to placebo.
>
> \[Slide\]
>
> Now for subject accountability, 78 percent of the subjects completed
> the full eight months in the study and reasons for discontinuation are
> given in the table. There were more consents withdrawn on placebo than
> on Valtrex, which anecdotally appeared to be due to recurrences in the
> source partner, but there were equal numbers lost to follow-up or
> dissolution of the relationship. The other reasons category included
> relocation, pregnancy, adverse events and protocol violation.
>
> However, some data were available from 96 percent of the
> intent-to-treat population because all but 58 couples returned for one
> or more visits and sometimes as many as six or seven. Having these
> data was particularly a value in the time to event analyses.
>
> \[Slide\]
>
> Recruitment by region is shown on this slide and shows that over half
> the couples were from the U.S.A., with over 60 percent recruited from
> North America including Canada.
>
> \[Slide\]
>
> Moving now to demographics, this set by the stratification variable,
> gender and HSV-1 serostatus. The majority of susceptible partners were
> male, which is in keeping with the higher prevalence of the infection
> in women who formed the source. HSV-1 serostatus, of note almost 70
> percent susceptible partners were already HSV-1 seropositive.
>
> \[Slide\]
>
> Ages and race were well matched between groups, with a median age of
> 34 years and 90 percent of subjects white.
>
> \[Slide\]
>
> The Valtrex and placebo groups were also well matched for the items on
> this slide, the number of recurrences of genital herpes in the source
> partner, the duration of infection in the source partner, the duration
> of the monogamous relationship and the frequency of vaginal sexual
> intercourse. However, about 50 percent, as you can see at the bottom
> of the slide, claimed never to have used condoms in the month prior to
> randomization.
>
> \[Slide\]
>
> I will now deal with the primary endpoint. What I will do, I will take
> you through the endpoint evaluations, the proportion of clinical
> acquisitions, the time to clinical acquisition and some subanalyses of
> this primary endpoint.
>
> \[Slide\]
>
> First let me show you how the numbers play out. Of the original 1,484
> couples in the ITT population, 58 never returned, leaving 1,426 for
> whom we have data; 71 susceptible partners had some sign or symptom
> thought suitable to be put forward for consideration by the endpoints
> committee. The remaining 1,355 remained asymptomatic.
>
> \[Slide\]
>
> Of the 71 referred to the endpoints committee, 20 were confirmed as
> true clinical acquisitions or primary endpoints, 15 by seroconversion
> with or without culture and/or PCR and five by culture or PCR alone.
> Fifty-one were rejected. Of these, the majority had no confirmatory
> laboratory result. However, there were three symptomatic subjects who
> seroconverted but were rejected by the committee. The reasons for
> rejection for two of them were that the symptoms were considered
> unrelated to genital herpes. The third was considered a protocol
> violator in that the source subject had only eight doses of study
> drug. There were also 18 HSV-2 seroconversions from the asymptomatic
> group, making a total of 36 seroconversions and 41 overall
> acquisitions.
>
> \[Slide\]
>
> Looking now at the primary statistical analysis which was a
> proportions analysis, of the 20 confirmed primary endpoints, 16 were
> on placebo and four on Valtrex. These represent 2.2 percent and 0.5
> percent of their respective populations, as shown on this slide. This
> difference is statistically significant with a relative risk of 0.25.
> In other words, there was a 75 percent reduction in the risk of
> transmission of genital herpes when the source partner was on Valtrex
> compared to placebo. This then met our a priori expectation and
> confirmed our result as being both substantial and clinically
> meaningful.
>
> \[Slide\]
>
> Looking at the time to acquisition for these primary endpoints using a
> Kaplan-Meier plot, as shown here, again there is a clear and
> statistically significant difference between Valtrex and placebo in
> favor of Valtrex. Of note is that the difference becomes apparent
> almost immediately after randomization and that the rates of
> acquisition remain linear throughout the study, with no indication of
> tailing off with time. I will mention here that we have viral cultures
> from ten of the subjects with primary endpoints and all isolates were
> sensitive to acyclovir. In other words, their IC-50 values were below
> 2 mcg/ml.
>
> \[Slide\]
>
> I am now going to show you some subanalyses of the primary endpoint,
> this one by gender. As expected, the majority of acquisitions were in
> females. There were 12 in total of the 20, this despite the smaller
> number of female susceptible partners enrolled in the study. The
> difference between males and females was statistically significant but
> the difference is in favor of Valtrex regardless of gender.
>
> \[Slide\]
>
> We had also expected more acquisitions in HSV-1 seronegative partners
> but there wasn\'t a major difference, as shown here. The trend was for
> proportionally more acquisitions in seronegative subjects but the
> numbers were small and not significant. However, again differences
> were observed in favor of Valtrex regardless of HSV-1 serostatus.
>
> \[Slide\]
>
> Finally, here is a display of acquisition by condom use. The chart
> here shows the frequency of acquisitions of symptomatic genital herpes
> for the placebo group according to whether the median use of condoms
> during the study was \"never,\" \"sometimes\" or \"nearly always.\"
> The incidence reduces from 2.8 percent for those who never used
> condoms to half that, 1.4 percent, for those who nearly always used
> them.
>
> \[Slide\]
>
> Now I have added the data for Valtrex and the message is the same.
> Note that there were zero acquisitions in the sometimes and nearly
> always categories. This emphasizes the importance of couples
> practicing appropriate protective measures and shows that the benefit
> of Valtrex is in addition to the practice of safer sex. In a covariate
> analysis the effect of condoms in reducing transmissions approached
> statistical significance, with a p value of 0.06.
>
> \[Slide\]
>
> Now for the secondary endpoints and I will deal with the following,
> first I will look at recurrences in the source partner; then viral
> shedding from the source partner in the substudy. If you recall, the
> hypothesis was that if we could reduce recurrence and viral shedding
> we should also be able to reduce transmissions. Finally, I will show
> you the effect of Valtrex on overall acquisitions. Again to remind
> you, these were all HSV-2.
>
> \[Slide\]
>
> Here we have a graph of the proportions of source partners for genital
> herpes recurrence at eight months, 47 percent for Valtrex and only 13
> percent for the placebo-treated subjects. This is a highly significant
> difference and similar to that reported in previous studies.
>
> \[Slide\]
>
> Now we have the results from the viral shedding substudy which showed
> a reduction in shedding by Valtrex. I will give you the results for
> total shedding, which are those obtained from every day of swabbing
> which is of 60 days duration. These included days on which there might
> have been an outbreak. I will mention results from an analysis when
> those days are excluded. Eighty-nine subjects were enrolled in this
> substudy and the numbers are somewhat unbalanced, 50 on placebo and 39
> on Valtrex. This was because randomized to the main study, if you
> recall, was centralized, not by site. It was also dependent upon the
> source partner\'s agreement to undergo the extra study procedures
> necessary.
>
> The results were very much as expected from the literature, as we have
> just heard, with HSV DNA being detected by PCR on at least one day in
> over 80 percent of those on placebo compared with almost 50 percent on
> Valtrex. HSV DNA was detected in almost 11 percent of days for those
> on placebo compared with almost three percent on Valtrex. That is a 73
> percent reduction on Valtrex. The number of DNA copies was reduced on
> Valtrex from 4.2 on a log scale to just 1.7. That is greater than 99
> percent reduction. All these differences were clearly statistically
> significant.
>
> Very similar results were obtained if one excludes days when there was
> an outbreak. There was still 90-95 percent reduction in DNA copies/mL
> on Valtrex compared to placebo.
>
> \[Slide\]
>
> Just to remind you before I get to overall acquisitions how that group
> is defined. It is those with a primary endpoint, some confirmed by
> seroconversion with or without culture and some by culture or PCR
> alone, and to those you add those with seroconversion and the total is
> 41.
>
> \[Slide\]
>
> So here we have the proportion of susceptible partners with overall
> acquisition of HSV-2 infection. Twenty-seven of them were in the
> placebo group and 14 in the Valtrex group. This represented a relative
> risk of 0.52 or a reduction in risk of 48 percent.
>
> \[Slide\]
>
> The time to event analysis for this group, shown here, is more
> powerful statistically as it adds time of acquisition to the numbers
> of acquisitions. The reduction in risk on Valtrex was, as in the
> previous slide, 48 percent for the relative risk of 0.52. As with the
> primary endpoint, the difference in rate was noted early and remained
> linear throughout the study. So, the secondary analyses fully support
> our hypothesis and add strength to the primary analyses.
>
> \[Slide\]
>
> I will now briefly review the safety results obtained in the study.
> Remember that these pertain to the source partner who is receiving
> Valtrex or placebo. These results are from the 8-month double-blind
> portion of the trial. I will mention results from the 12-month
> open-label extension at the end.
>
> \[Slide\]
>
> This slide summarizes the adverse events reported through the study.
> As you can see, there is very little difference between Valtrex and
> placebo. None of the serious adverse events was classified as drug
> related. Discontinuations due to an adverse event were slightly more
> frequent on Valtrex but none of these was serious or unusual. Reasons
> included headache, gastrointestinal upset and one case of urticarial
> rash.
>
> \[Slide\]
>
> Here you see a graphical depiction of those adverse events reported by
> five percent or more of subjects. The most common events were
> headache, upper respiratory and gastrointestinal, and there was
> nothing unexpected from previous experience in clinical trials.
>
> \[Slide\]
>
> Laboratory tests included those listed above as being of greater
> potential interest, reflecting hepatic, renal and hematologic systems,
> were unremarkable and there was no indication of any difference
> between Valtrex and placebo.
>
> \[Slide\]
>
> Finally, here is a summary of the data we have up to January 31st of
> this year from 831 source partners who continued for further 12 months
> on open-label Valtrex after the main study had completed. This
> represents about 95 percent of those opting to continue to receive
> drug. The dose of Valtrex was 500 mg once daily as in the main part of
> the study.
>
> As you see, the pattern of events is similar to that reported in the
> double-blind phase and, again, we have no new safety signals for what
> for some of them is now 20 months of continuous use of Valtrex.
>
> \[Slide\]
>
> Finally, in conclusion study 3009 clearly met its objectives. By that,
> I mean that we set out with a hypothesis that Valtrex would reduce
> episodes of recurrent genital herpes in the source partner and would
> reduce viral shedding. These would result in a significant reduction
> in transmission of genital herpes to an uninfected partner. The study
> demonstrated this with a reduction of 75 percent in the acquisition of
> clinical infection by a susceptible partner and a 48 percent reduction
> in overall disease acquisition. This benefit is seen over and above
> that afforded by counseling on safer sex practices, the use of condoms
> and, I should add, the treatment of outbreaks in the source partner.
> The safety profile of Valtrex was similar to that described in the
> product label which by now has been well characterized.
>
> Thus, I hope to have demonstrated to you that the data are
> scientifically sound and clinically relevant, and that the reduction
> in transmission of herpes virus to a partner is an additional benefit
> of suppressive therapy when combined with safer sex practices.
>
> Thank you, and I will now pass it over to Clarence Young to make some
> concluding remarks.
>
> **Concluding Remarks**
>
> DR. YOUNG: Thank you, Stuart. Good morning, everyone.
>
> \[Slide\]
>
> My name is Clarence Young and I direct clinical development activities
> at GlaxoSmithKline for anti-infectives. I have also had the experience
> in my career of caring for patients with genital herpes and also
> counseling these patients.
>
> Dr. Harding has taken you through the results for study 3009. My task
> over the next few minutes is just to summarize what these data mean
> for both patients as well as healthcare providers.
>
> \[Slide\]
>
> First of all, it is important to note that study 3009 is a landmark
> study which provides a new option for the management of patients with
> genital herpes. As Dr. Handsfield outlined in his talk, various
> strategies have been undertaken to prevent the transmission of genital
> herpes but to date none of these strategies has been completely
> effective, and the availability of a prophylactic vaccine is still
> several years away.
>
> This study, 3009, was the first demonstration that an antiviral agent
> can actually decrease the transmission of genital herpes between
> sexual partners. This study also indicated an association between the
> reduction in viral shedding and the transmission of genital herpes.
> These data may be especially relevant for HSV-2 uninfected women of
> childbearing potential who are at great risk for acquisition of
> genital herpes in the course of pregnancy.
>
> \[Slide\]
>
> The benefits of Valtrex therapy that were observed in this study were
> in addition to safer sex practices and condom use and the results, as
> Dr. Harding had mentioned, are truly unique in that the benefits of
> Valtrex therapy accrued not only to the HSV-2 infected source partner
> with genital herpes who received Valtrex therapy but also the HSV-2
> uninfected susceptible partner who did not receive Valtrex. These
> benefits were without any added risk to the partner who received
> Valtrex.
>
> The study, therefore, provides a new option to address what has been
> shown, and as you saw earlier in Dr. Handsfield\'s presentation, to be
> a major patient concern, which is transmission of genital herpes.
>
> \[Slide\]
>
> Now, GlaxoSmithKline has had a long-standing interest in the education
> of patients and families, as well as healthcare providers, regarding
> genital herpes, its management and various treatment options. It is
> important to ensure that the patients as well as healthcare providers
> have a very clear understanding regarding study 3009, how the study
> was designed; what the results of the study showed; and what the
> implications of these results are to avoid any misinterpretation of
> the study results. GlaxoSmithKline will work with FDA as well as with
> external stakeholders in order to ensure that the benefits of Valtrex
> therapy and, more importantly, the benefits of safer sex practices and
> condom use are communicated both accurately and effectively.
>
> \[Slide\]
>
> Since Valtrex is already available for suppression of genital herpes
> recurrences, it is reasonable to ask why additional information is
> required in the prescribing information. Well, feedback from
> healthcare providers has indicated that the availability of this new
> indication for Valtrex will provide another reason for healthcare
> providers to initiate a conversation with their patients regarding
> sexually transmitted diseases and safer sex practices. Others view
> this as another tool in the toolbox which they will use as part of
> their management approaches to their patients with genital herpes.
> Awareness of these data by patients may influence their decision to
> actually pursue suppressive therapy. Finally, the availability of
> labeling will enable GSK, external stakeholders and patients to have a
> definitive source of accurate and balanced information on the results
> of study 3009 with the benefits of FDA oversight.
>
> \[Slide\]
>
> We cannot say that based on the results of this study the use of
> Valtrex will impact in any way the prevalence of HSV-2 infection in
> the United States, or that the study addresses all of the questions
> which one might have regarding the benefits of Valtrex therapy in
> special populations. What we can say is that the results from study
> 3009 clearly provide an opportunity to make a difference in the lives
> of patients.
>
> \[Slide\]
>
> Finally, GSK would just like to acknowledge the participation by the
> hundreds of individuals in this very time consuming and demanding
> study. We also would like to acknowledge both the study personnel as
> well as clinical investigators. Some of them are here with us today.
> Thank you very much for your attention and for the opportunity to
> share the results of study 3009 with you today. Thank you.
>
> DR. GULICK: Thanks to Drs. Cocchetto, Harding and Young for the
> sponsor presentation. As mentioned earlier, we are going to defer the
> question and answer period until after the presentation from the
> agency, which brings us to our break. It is 9:55 so we will reconvene
> at 10:10.
>
> \[Brief recess\]
>
> DR. GULICK: We will move now to the agency presentation. We will start
> out with Dr. Haverkos.
>
> **FDA Presentation**
>
> **Study Design**
>
> DR. HAVERKOS: Good morning.
>
> \[Slide\]
>
> I am Dr. Harry Haverkos. I am the primary reviewer on the application,
> and I will be joined by my statistical colleague, Dr. Smith, in
> presenting the FDA review.
>
> First of all, I would like to congratulate the sponsor on conducting
> this large, multinational trial, really a landmark study looking at a
> medication to reduce sexual transmission of herpes simplex.
>
> \[Slide\]
>
> Our presentation will be divided into several areas. I will present
> some comments on study design and Dr. Smith will get to present the
> efficacy results. I will then come back up and discuss a little bit of
> the virology, safety and some of the behavioral results. We will then
> list our conclusions and finally read for you the questions that we
> would like the committee to deliberate on for us.
>
> \[Slide\]
>
> As reported before, this application was submitted in October and has
> an NDA due date of September. They propose the dosage of 500 mg a day
> of valacyclovir to reduce the risk of transmission of genital herpes
> with the use of suppressive therapy and safer sex practice.
>
> \[Slide\]
>
> Valacyclovir is approved for several indications involving herpes
> simplex, treatment of initial genital herpes with one gram b.i.d. for
> ten days; treatment of recurrent genital herpes too mg b.i.d. for
> three days; and as chronic suppressive therapy of recurrent genital
> herpes at one gram a day or 500 mg a day as an alternate dose.
>
> \[Slide\]
>
> This single study was submitted. It is multinational, randomized,
> double-blind evaluating valacyclovir in HSV-2 discordant monogamous
> couples. As mentioned, the sample size sought was 1,500 couples. Over
> 4,000 were screened and the patients were randomized to valacyclovir
> versus placebo for eight months of therapy. During the study all
> subjects were encouraged to use condoms and abstain from sex during
> any outbreaks.
>
> \[Slide\]
>
> Inclusion criteria were gone through before. These were monogamous
> heterosexually active couples. The source partner had to be HSV-2
> antibody positive and have clinical episodes. They excluded patients
> who had greater than ten symptomatic recurrences a year. I am
> concerned about some of the ethics about not providing suppressive
> therapy to that group, but it was needed that a person be a candidate
> for suppressive therapy. It was not clearly defined in the protocol
> but generally is considered as somewhere between five and six
> recurrences in a year. The susceptible partner had to be in a
> relationship with no other partners, and be HSV-2 antibody negative
> and report no clinical herpes outbreaks.
>
> \[Slide\]
>
> The primary endpoint has discussed and we will be discussing this
> point I think over and over again. It is the proportion of susceptible
> partners with a clinical episode confirmed by the laboratory. The
> laboratory, of course, could be by culture, PCR and/or serology.
>
> \[Slide\]
>
> The monitoring that occurred during the study is listed on this slide.
> Safer sex counseling was provided at each visit. The source partner
> came in monthly, and during those monthly visits they reviewed the
> diary card for any symptoms or recurrences that the source partner
> had. If they developed an outbreak they were to return to the clinic
> immediately to be evaluated and to be started on therapy.
>
> Susceptible partners also came back monthly and for those partners two
> areas were reviewed, the diary cards of the sexual exposures and
> practices and also looking for any signs of herpes in the previous
> month. They too were expected to return for any suspect lesion for
> open-label therapy.
>
> \[Slide\]
>
> For virology, as mentioned, confirmation was defined by either
> culture, DNA of suspicious lesions and monthly serologies were
> followed. Mostly all of the samples were sent to a single lab in
> Seattle. However, there were five cultures that were sent to a lab in
> Vancouver.
>
> \[Slide\]
>
> There were a couple of issues raised I guess by the virologist during
> our review. In a study with a fairly small number of endpoints I think
> you really want to make sure that you miss one, two or three
> endpoints. The samples, as mentioned, were collected at over 100 sites
> in more than 20 countries from around the world and then were
> transported to Seattle. As mentioned, a few Canadian samples were sent
> to Vancouver.
>
> Concerns are about some protocol violations. There was failure to
> report at the first sing of genital herpes so some cultures were
> missed. There were a few samples that were contaminated, a few samples
> that were lost in transit. Even though herpes is quite a stable virus,
> there was some concern raised by our virologist about what effect
> transit might have on some of these results.
>
> \[Slide\]
>
> As mentioned, there was a long history of discussion between the FDA
> and the sponsor. As mentioned, there were three topics of discussion.
> I think our three may be a little different than their three but that
> probably just reflects more history. The primary endpoint was one of
> the primary areas of discussion, and we will talk about that again on
> the next slide.
>
> Source partner inclusion\--again, the study was initially looked at as
> predominantly a serologic study, serologic endpoint. But the FDA
> wanted really clinical endpoints and so wanted to have the history of
> clinical herpes of source partners be candidates for suppressive
> therapy and less than ten recurrences in the past year was the agreed
> upon inclusion criteria.
>
> There was some discussion of whether two studies would be better than
> one. If one studied different populations would it be easier to
> interpret the results and write the label? In the end, the company I
> think decided to do one large, multinational study.
>
> \[Slide\]
>
> The primary endpoint agreed upon is that shown first. We will also be
> presenting some data on some secondary endpoints, predominantly the
> endpoint of HSV-2 seroconversion which historically was how the study
> was initially proposed. Finally, acquisition of meeting one or both of
> the two endpoints.
>
> I just want to point out question six is actually going to deal with
> that issue so I think it is very important that we understand the
> different endpoints.
>
> \[Slide\]
>
> My last slide before turning it over to Dr. Smith is just to give you
> a little history of the study. It was initiated in February of 1998.
> As mentioned, over 4,000 couples were screened. There were a couple of
> amendments along the way that occurred. Two of them I think may be
> part of the discussion. A shedding substudy was added about six months
> into the study. We will look at some of those results. Then, in May of
> 2000, because recruitment hadn\'t quite lived up to expectations,
> sites were added outside of North American and Europe to include
> Australia. Eastern Europe was added to those originally recruited from
> western Europe, and south America. The initial stratification to try
> to get more female susceptible partners was waived in order to recruit
> more couples.
>
> With that, let me turn the podium over to Dr. Smith who will present
> the efficacy results.
>
> **Efficacy Results**
>
> DR. SMITH: Thank you.
>
> \[Slide\]
>
> I am going to go over the demographic and baseline characteristics and
> then primary and secondary results, and robustness of the analyses to
> discontinuations, and finally regional differences.
>
> \[Slide\]
>
> One thousand four hundred and ninety-eight out of 4,030 screened
> couples were randomized. The primary reason for screening failure was
> the lack of HSV-2 discordance within couples. So, the susceptible
> partner was HSV-2 seropositive or had symptoms of it.
>
> \[Slide\]
>
> Demographic characteristics were very similar in both treatment groups
> so I will summarize them overall. Two-thirds were male and one-third
> of the susceptible partners were female. The median age was 35 years;
> 90 percent of the susceptible partners were white; five percent
> Hispanic; three percent black; one percent Asian and less than one
> percent other races.
>
> \[Slide\]
>
> One percent has sexual relations with other partners in the last three
> months. The median duration with the source partner was two years and
> 22 percent had been treated for an STD.
>
> \[Slide\]
>
> Ninety-seven percent had sexual intercourse with the source partner in
> the last month and the median number of contacts in the last month was
> seven.
>
> \[Slide\]
>
> This summarizes the condom use for vaginal/anal intercourse at
> baseline. Approximately 50 percent of the patients had never used
> condoms at baseline in both treatment groups. Thirty percent said they
> nearly always used condoms and about 20 percent said they sometimes
> used condoms.
>
> \[Slide\]
>
> In terms of HSV-1 status for female susceptible partners at
> randomization, approximately 80 percent were positive in both
> treatment groups. About 20 percent were negative and only two were
> atypical.
>
> \[Slide\]
>
> For male susceptible partners, slightly less, about 65 percent were
> positive. About 35 percent were negative and five were atypical.
> Again, these were very similar in both treatment groups.
>
> \[Slide\]
>
> Now I will summarize efficacy evaluations.
>
> \[Slide\]
>
> The primary analysis looked at clinical evidence of HSV-2 or
> symptomatic HSV-2 acquisition and 0.5 percent of valacyclovir patients
> had clinical evidence of transmission compared to 2.2 percent of the
> placebo patients. The p value was 0.011 and the odds ratio was 0.24,
> representing approximately a 75 percent reduction. The 95 percent
> confidence interval of the odds ratio went from 0.06 to 0.76.
>
> The other two selected secondary endpoints are HSV-2 seroconversion
> and overall HSV-2 acquisition, which consists of HSV-2 seroconversion
> or symptomatic HSV-2 acquisition. Some may argue that HSV-2
> seroconversion may be a better endpoint because subclinical infections
> may become symptomatic HSV-2 later on.
>
> Here we have 1.6 percent of the valacyclovir patients with HSV-2
> seroconversion 3.2 percent of placebo patients. In this case the odds
> ratio was 0.49, approximately 50 percent, representing about a 50
> percent reduction with valacyclovir treatment. The p value was 0.06.
> Similar results were obtained for overall HSV-2 acquisition. This was
> primarily driven by the HSV-2 seroconversion results. In this case we
> have 1.9 percent of valacyclovir patients compared to 3.6 percent of
> the placebo patients. In this case the odds ratio was 0.5.
>
> \[Slide\]
>
> This is what it looks like graphically. We have a bigger difference
> for the primary endpoint when you compare placebo patients to
> valacyclovir patients. Again, the odds ratio is approximately 0.25.
> Here we have about a 50 percent reduction for these other two selected
> secondary endpoints, and the p values are of borderline significance.
> In these analyses withdrawals were regarded as being
> transmission-free.
>
> \[Slide\]
>
> When we look at condom use during the study what we have are over 50
> percent of the patients never used condoms during the study compared
> to 30 percent who nearly always used condoms in both treatment groups,
> and about 15 percent who said they sometimes used condoms. This is
> calculated a little differently. In this case during the study what
> they have calculated is the median usage over months one through eight
> so that basically with nearly always using condoms 90 or more percent
> of the patients who nearly always used condoms were classified in this
> category. So, this represents greater than 90 percent usage at
> baseline or at a particular visit.
>
> However, because we are using the median to calculate this during the
> study, it is possible that at one visit they could have nearly always
> used condoms; at the next visit they might never have used condoms;
> and at the third visit they might have always used condoms at months
> one, two and three and, in that case, the median would have been
> nearly always used condoms. If they never used condoms, that is really
> zero percent of the time. So, in that case the true median would be
> about 60 percent rather than 90 percent. So, what we got here during
> the study is a little different than what we had at baseline.
>
> In addition, condom use can fluctuate from month to month and patients
> who nearly always used condoms over months one to eight might never
> have used condoms just prior to an episode. So, we have to take all of
> this in mind and the study wasn\'t designed specifically to look at
> condom use.
>
> \[Slide\]
>
> Here we have the primary endpoint separated out by condom usage. On
> the left-hand side we have valacyclovir patients. In this case one
> percent of the valacyclovir patients who never used condoms had
> clinical evidence of transmission compared to 0/91 patients who
> sometimes used condoms and 0/211 who nearly always used condoms. We
> have the 95 percent confidence intervals plotted just to indicate that
> even though we didn\'t observe any events we have a confidence
> interval here that ranges from zero percent to over three percent, and
> here we have more patients so we have a smaller confidence interval
> that goes from zero to 1.5 percent.
>
> Then, when we look at placebo patients we can see that almost three
> percent of the patients had clinical evidence if they said they never
> used condoms through the majority of the visits during the study
> compared to two percent who sometimes used condoms and approximately
> 1.5 percent who never used condoms. So, we also see a main effect of
> condom usage and the more condom usage, the less transmission. The p
> value for the main effect of treatment, adjusted for condom usage, was
> 0.011 and the p value for condom usage was 0.08, close to significant.
> Again, keep in mind that this study was not designed specifically to
> look at condom use.
>
> \[Slide\]
>
> To illustrate the effects in a little more detail we also were looking
> at overall acquisition rates in addition to clinical evidence. So,
> what we have in the dark shaded regions on the graphs down below is
> what we saw in the previous slide. Over and above that we have the
> rates of overall acquisition which can include either clinical
> evidence or HSV-2 seropositive incidence rates.
>
> So, in this case when we look at the lightly shaded regions for
> valacyclovir we can see that about two percent who never used condoms
> had overall acquisition and over three percent who said they sometimes
> used condoms, and we have the rates for nearly always using condoms of
> approximately two percent\--no real trend for overall acquisition with
> valacyclovir.
>
> When we look at placebo patients we do seem to see another decline
> when we look at overall acquisition rates, as is the case when we look
> at the clinical evidence of transmission. In this case the clinical
> endpoint is close to statistically significant. It is hard to read
> here but it is 0.08 and for overall acquisition the p value is 0.84.
> These p values represent the effect of condom use.
>
> \[Slide\]
>
> Now I will talk about the robustness of efficacy analyses to
> discontinuations.
>
> \[Slide\]
>
> On the first slide we have the results for the primary analysis. Shown
> here are the percentage of patients with clinical evidence of having
> HSV-2 transmission. In this case we have withdrawals and the main
> point of this slide is to show that the withdrawal rate, which is
> greater than 20 percent in both treatment groups, is much larger than
> the percentage of patients with the primary endpoint.
>
> \[Slide\]
>
> So, we wanted to look at reasons for withdrawal. In this case, the
> principal reasons include withdrawal of consent, loss to follow-up,
> relationship breakup and the partner withdrew. Withdrawal of consent
> was somewhat higher in placebo patients than in valacyclovir patients.
> It ranged from three to six percent. Six percent of both treatment
> groups reported loss to follow-up; five percent reported a
> relationship breakup, approximately five percent; and two percent in
> both treatment groups had partners who withdrew.
>
> \[Slide\]
>
> None of the susceptible partners withdrew to adverse events or lack of
> efficacy. Less than one percent of the source partners withdrew due to
> adverse events, although it was slightly higher for valacyclovir,
> approximately two percent. Less than one percent of the source
> partners withdrew due to lack of efficacy.
>
> \[Slide\]
>
> So there were various sensitivity analyses that we used to look at
> this. One very conservative analysis took all of the withdrawals and
> considered them to be treatment failures. In this case, the percentage
> of withdrawals far outnumbered the primary endpoint cases. So, what we
> have is very little difference between the two treatment arms. In both
> cases we have approximately 22 percent of valacyclovir patients
> compared to about 24 percent of placebo patients, and a p value of
> 0.30. There is no difference when you include all the withdrawals or
> discontinuations and treat them as treatment failures.
>
> So, what we are getting here are more reasonable estimates when we
> just include a small fraction of the withdrawals and treat them as if
> they were treatment failures. When we assume that 10 percent of the
> discontinuations were treatment failures we see approximately four
> percent of placebo patients and we can see approximately three percent
> of valacyclovir patients. In this case the p value is 0.11. When we
> count five percent of the discontinuations as treatment failures we
> see about double the rate for placebo compared to valacyclovir. This
> looks very similar to the HSV-2 seropositive results, and the p value
> here again is 0.05 so this is what it takes to reach statistical
> significance. In the primary analysis none of the discontinuations
> were counted as treatment failures. They were all concluded to be
> successes so this is what we see here, with the p value again being
> 0.011.
>
> The Kaplan-Meier analysis was 0.008. The Kaplan-Meier adjusts for the
> length of follow-up and also it assumes not informed of censoring. For
> example, in Valtrex patients the risk for patients who discontinue is
> the same as the risk of transmission for patients who complete the
> study. The same thing in placebo patients, the risk for patients who
> discontinue is the same as the placebo patients who complete the
> study.
>
> \[Slide\]
>
> Now I would like to talk about regional differences.
>
> \[Slide\]
>
> We see a histogram of the different countries, major geographic
> regions. In this case, the percentage of patients with a first episode
> of genital HSV-2 in susceptible partners is plotted and we see that by
> far the biggest differences seem to occur in Australia and Canada.
> These are all placebo patients so we have almost nine or ten percent
> of Australian patients and in Canada it is about three percent, and we
> have no Valtrex cases except in the U.S. South America has only 43
> patients but eastern Europe and western Europe comprise about 20
> percent of the sample and there are no cases, no patients who had the
> primary endpoint in all of eastern and western Europe. The p value for
> the effect of geographic region was 0.01. So, the main effect of
> geographic region was very significant statistically.
>
> \[Slide\]
>
> This is a backup slide which actually has the numbers of confirmed
> cases in each country.
>
> \[Slide\]
>
> When we plot the overall acquisition rates we see a similar pattern,
> with the highest rates in Australia, followed by Canada. However, in
> Europe we do see cases. In fact, we see more placebo cases in eastern
> Europe than valacyclovir cases. In western Europe, it looks like they
> are approximately the same. In the U.S., it looks like the rates ar
> approximately the same. The U.S. has 803 patients.
>
> This is a little different because for the clinical evidence in the
> primary analysis the U.S. results tended to look approximately the
> same as the overall analysis with all countries combined. The other
> thing is that in Europe it looks like there are as many cases, roughly
> as many cases as there are in the United States. which is very, very
> different from what we saw with the primary endpoint.
>
> \[Slide\]
>
> This is backup slide, which is in your handout, which has the actual
> numbers of patients.
>
> \[Slide\]
>
> I looked at several different demographic and other sexual behaviors
> to see if that could explain the regional differences. The only thing
> I was able to see was that it looks like in eastern Europe there is a
> much higher percentage of patients who said they nearly always used
> condoms, over 60 percent, compared to all the other geographic regions
> where it is just slightly over 20 percent or less than 20 percent.
> However, it doesn\'t seem like in eastern Europe the rates of HSV-2
> seroconversions are any lower. Also, the overall acquisition rate in
> eastern Europe was similar to the U.S. and western Europe and eastern
> Europe.
>
> \[Slide\]
>
> So, my summary and conclusions are that the percentage of dropouts was
> over 20 percent, and this was much higher than the percentage of
> susceptible partners classified as having clinical evidence of a first
> episode of genital HSV-2.
>
> The primary reasons for discontinuation include withdrawal of consent,
> loss to follow-up and the ending of relationships.
>
> \[Slide\]
>
> The statistical significance of the primary endpoint depends on the
> assumptions about how many discontinuations should be counted as
> treatment failures. This can be statistical significance or it could
> also mean clinical significance, i.e., is there a 75 percent
> reduction, which is actually harder to achieve than statistical
> significance.
>
> No transmissions were reported in Europe where approximately 20
> percent of the patients were enrolled. This rate is similar to the 20
> percent discontinuation rate so it is possible that if there were no
> real treatment differences in Europe then we could also do a
> sensitivity analysis where we counted those European patients as
> treatment failures and we would have an equal amount in both groups,
> and then we would add that on to the percentage of discontinuations
> and we would have less robust analyses.
>
> \[Slide\]
>
> The largest treatment effects were observed in Australia and Canada.
> The U.S. results were similar to the results for the primary endpoint
> for all countries combined. The differences between valacyclovir and
> placebo were not as significant for HSV-2 seroconversions and overall
> acquisitions, particularly in the United States.
>
> \[Slide\]
>
> Now I would like to have Dr. Haverkos talk about viral shedding,
> substudy results, safety and behavioral results and conclusions.
>
> **Viral Shedding Substudy, Safety and Behavioral**
>
> **Results and Conclusions**
>
> DR. HAVERKOS: Thank you, Dr. Smith.
>
> \[Slide\]
>
> First of all, the viral shedding substudy, 89 patients were recruited
> and 85 source patients were followed intensively for two months. As
> mentioned before, they filled out daily diary cards recording any
> signs or symptoms of recurrence. They collected samples at home and
> did a self-exam, and then every two weeks came into the clinic for
> review of the diaries, clinical exams and additional viral cultures.
>
> \[Slide\]
>
> I think that the results shown are supportive of an effect in
> suppressing virus. As seen here the valacyclovir group shed 2.9
> percent of the days or cultures taken compared to about 11 percent in
> the placebo group, and during the times of shedding the valacyclovir
> group had lower levels of virus present, about a one log drop.
>
> I think Dr. Guinan asked some questions earlier about differences,
> male and female. I have not seen those results and maybe the company
> can address her question in the comment period.
>
> \[Slide\]
>
> Moving on to safety, currently the drug has warnings in the label
> about thrombotic thrombocytopenic purpura and hematuria syndrome and
> death that has occurred in some patients with advanced HIV disease and
> immunosuppressed for other reasons, transplant recipients receiving
> valacyclovir up to eight grams a day. So, there are some significant
> side effects seen with this but generally at much higher doses than
> people are going to propose to use for this indication. Adverse events
> commonly reported with use of valacyclovir include nausea, headache,
> vomiting, dizziness and abdominal pain.
>
> \[Slide\]
>
> Looking through the data presented, there were no deaths. There were
> no reports of TTP/HUS in the study. Twenty-six subjects developed
> serious adverse events. There were 17 discontinuations and there were
> 16 pregnancies, and we are looking at those last three bullets on the
> next three slides.
>
> \[Slide\]
>
> If you look at the serious adverse events, they are pretty similar
> between the two groups. A patient discontinued to glomerulonephritis
> was a patient that, right at the beginning of the study, developed
> some symptoms of arthralgias that ended up in a diagnosis of lupus and
> during that process the patient was discontinued from valacyclovir.
>
> We have one cancer in each column. We have an intestinal obstruction
> attributed to another medication that the patient was taking. Then we
> can see some parallels, some spontaneous abortions; uterine fibroids;
> Bartholin\'s cyst infection; ovarian cyst; a couple of localized
> infections. I think one with meningitis came in, was treated with
> cephtriaxone and was signed out as a viral meningitis though it was
> not clear that herpes cultures were done or herpes was ruled out in
> that case but the patient\'s symptoms resolved over four days and the
> patient was discharged. There were a couple of orthopedic problems in
> each group and then a syncope, a vasovagal attack. So, nothing jumping
> out that one could attribute to valacyclovir and serious adverse
> events.
>
> \[Slide\]
>
> If you look at the discontinuations, there were 12 in the valacyclovir
> group, most of them for symptoms that were attributed to headache and
> GI disorders. There were two rashes and two where they had renal
> problems, one glomerulonephritis associated with lupus and hematuria
> that did not meet any other conditions for TTP and was being worked up
> for kidney stone.
>
> \[Slide\]
>
> As I mentioned, there were eight pregnancies in both groups. Trying to
> look at what impact, if any, valacyclovir might have on these
> pregnancies, there were four women, source patients randomized to
> valacyclovir, two healthy infants were delivered and two developed
> spontaneous abortions. There were seven in the placebo group, as you
> see here, and three health infants and three spontaneous and one
> elective abortion. There was one susceptible partner who was treated
> with valacyclovir for a suspicious HSV initial event who elected
> abortion, and then there were four other susceptible partners who did
> not receive drug and for which data was not presented.
>
> \[Slide\]
>
> Moving on now to the behavioral aspects, just for review, the
> guidelines put out by the public health service, specifically the CDC,
> to manage herpes are quite extensive. They are included in your
> packet. It is mentioned that for critical management of herpes
> counseling be done. The goals of counseling are to help patients cope
> with infection and to prevent sexual and perinatal transmission. They
> are encouraged to inform their partner before initiating a sexual
> relationship and are reminded that transmission can occur during
> asymptomatic periods as well as during outbreaks.
>
> \[Slide\]
>
> In addition, partners or couples are encouraged to abstain from sex
> when lesions or prodromal symptoms are present. They are encouraged to
> use condoms which, when used consistently and correctly, can reduce
> the risk, again reemphasizing that sex partners might be infected even
> if no symptoms occur, and encouraging testing of partners for herpes.
>
> \[Slide\]
>
> These guidelines are pretty much based on a variety of studies from
> the Seattle group, including a study in JAMA in 2001 which the authors
> claim was the first one to prove that condoms actually prevented
> transmission or reduced transmission among HSV partners. This was a
> reanalysis of an ineffective vaccine trial, alluded to by Hunter
> Handsfield and others earlier, in which over 500 monogamous
> heterosexual discordant couples were followed for 18 months. There was
> about six percent transmission, and condom use was reported as
> protective, interestingly, for women but not for men.
>
> \[Slide\]
>
> Now let\'s look at some of the data. If one asks how effective was the
> STD counseling provided in this study, what behavior change was
> actually found, as you see here, at baseline about 50 percent of
> couples said they never used condoms and in the month prior about a
> third said they nearly always used condoms. As mentioned earlier, when
> we calculate the nearly always used condoms during the study, it is
> based really on a median use of the eight months. So, if a couple
> reports five months using condoms all the time and then there is a
> month or two where they only use it sometimes or never, they still are
> classified as nearly always.
>
> But if you look at the effects of counseling, as you can see, condom
> use during vaginal sex actually decreased slightly. \"Nearly always\"
> now is reported by 30 percent of couples, and a higher percent
> reported never using condoms. In oral sex, which was reported by over
> 70 percent of the partners, only seven percent in both groups reported
> nearly always using condoms for oral sex.
>
> I must say, there is some difficulty interpreting the oral sex data
> because it is not clear in the reports in which direction the oral sex
> occurs. Is it man or woman, woman or man? So, it becomes difficult to
> know exactly what exposures, particularly during symptomatic periods,
> in one of the partners\--whether risk or direct contact was made.
>
> \[Slide\]
>
> Looking at some of the behavioral data, as we have mentioned, the
> condom use collection or report can best be described as poorly
> defined. For oral sex I think was even more difficult to look at the
> data, particularly if one tries to then look at this issue of
> abstinence either of sexual behavior or specifically of oral sexual
> behavior during outbreaks. No analysis was conducted.
>
> I am always struck as I read these studies of couples by what kind of
> data we collect and what we don\'t collect on couples. We collect data
> on duration and whether they have had a history of STD, but among
> heterosexual couples we don\'t have data like on marital status;
> whether people are living together; whether or not the couples have
> any children, which might give us some better definitions for being
> able to decipher who these couples are.
>
> There was no analysis of the effects of counseling or, you know, how
> the data were collected on behaviors by different languages; how a
> number of these things were done considering the fact that it was
> multinational and multilingual, how different cultures might look at
> some of these definitions of oral sex or reporting different
> behaviors. Finally, there were a number of missing diaries.
>
> \[Slide\]
>
> In summary, I think we think the study was well done and does show
> that it does reduce clinical HSV-2 outbreaks among source partners and
> transmission to susceptible partners among these couples.
>
> The viral shedding substudy I think clearly supports that valacyclovir
> does reduce transmission among such couples, and no new safety issues
> were identified to date in our review.
>
> \[Slide\]
>
> On the other hand, if one looks at the efficacy of the counseling and
> behavioral interventions, clearly subjects continued not to use
> condoms during every sex act, and very little during oral sex acts,
> and looking over the histories, there were individuals that did not
> abstain from sex during symptomatic recurrences despite counseling
> monthly. This behavior area may be an area that we can make some
> additional progress in, in addition to what we are finding with the
> medication.
>
> \[Slide\]
>
> With that, let me move on to the questions. I will just read them
> briefly. We will start out with one that, hopefully, will be fairly
> straightforward, does the information presented by the applicant
> support the use of valacyclovir to reduce the risk of transmission of
> genital herpes among monogamous heterosexual couples?
>
> If you agree with that, we will them move on to the other questions.
> If you don\'t, then we will talk about what additional studies need to
> be conducted.
>
> \[Slide\]
>
> After that one I think we get into some questions on how we are going
> to use this drug in practice and how we are going to fit it into
> public health guidelines. Does the information presented support the
> use of valacyclovir to reduce the risk of transmission of genital
> herpes among populations other than monogamous heterosexual couples?
>
> \[Slide\]
>
> Third is this issue of screening in 3009. Over 4,000 couples were
> screened. Only 1,500 were enrolled. Many of them, even though they
> didn\'t know they were infected, were. So, please discuss the
> implications of screening susceptible partners for herpes prior to
> initiating therapy of the source partner with valacyclovir.
>
> \[Slide\]
>
> Number four is a more philosophical question but one I know bothers
> some people in public health, what will marketing of valacyclovir for
> reduction of genital herpes have on the impact of use of condoms and
> following other STD guidelines?
>
> \[Slide\]
>
> Fifth moves on to another issue which I guess deals with duration of
> therapy and resistance. Although patients in the registrational trial
> were treated for eight months, it is likely to be used for longer
> periods of time. What additional studies would you suggest to evaluate
> the potential for longer-term adverse events, including development of
> resistance to valacyclovir?
>
> I guess I would kind of like to add a thought. When would you consider
> stopping to use this drug in a relationship? For example, what if the
> relationship breaks down? What if you get into another partner who is
> already infected? What if transmission occurs? If you get into a
> relationship and start this at age 20 and you stay in that
> relationship for 50, 60 years, how long should one continue the
> medication and should there be some monitoring, or whatever, in the
> process?
>
> \[Slide\]
>
> Finally the six question, getting back to this issue of the primary
> endpoint, in future studies for treatments for herpes simplex what do
> you recommend that we use as a clinical endpoint? And, if we have
> time, which we probably won\'t, there is extra credit. One can try to
> address other STDs because I know we have other STDs that other
> manufacturers out there are interested in looking to see what impact
> this might have on HIV and other STDs.
>
> So with that, I will conclude and turn it back over to Dr. Gulick.
>
> DR. GULICK: You have one more slide, I bet you.
>
> DR. HAVERKOS: Excuse me, I am sorry.
>
> \[Slide\]
>
> Dr. Smith and I would like to thank the collaborators and those who
> have provided us with all materials and told us what to say today.
> Thank you very much.
>
> DR. GULICK: Thanks, Dr. Haverkos and Dr. Smith. Just a brief
> announcement, Dr. Handsfield mentioned that he would be willing to
> share his slides with people. He will post them on the FDA web site
> and he is also available if you want to get his e-mail address.
>
> At this point we are going to go into a question and answer session.
> Although we just saw the questions reviewed for the committee, I want
> to stress that we are going to focus on those during the afternoon
> period. The period now for questions and answers is really questions
> of content or clarification either for the sponsor or for the agency
> and their presentation. Dr. Kumar is jumping right in.
>
> **Questions from the Committee**
>
> DR. KUMAR: This is a question for the sponsor. If I understood the
> prevalence rate of herpes in African-Americans, it is about 47
> percent, and if we just take African-American women it is about 55
> percent. But the study, if you look at the population that was
> enrolled, only three percent were African-Americans. Could you comment
> on why that was and what did you, as the sponsor, do to encourage more
> participation of African-Americans?
>
> DR. COCCHETTO: Sure, happy to comment on that. Let me ask Dr. Young to
> comment on that question.
>
> DR. YOUNG: First of all, as noted in Dr. Harding\'s presentation, this
> study was conducted multinationally so we actually did have sites that
> were spread throughout the world. Now, we had selected investigators
> that were in the U.S. as well as in Canada and actually did have
> access to diverse populations. Although I would acknowledge that we
> did enroll the percentages of African-American patients that you had
> identified, we had no restrictions on enrollment in terms of
> demographics. This is how the data actually played out. Those are the
> data.
>
> DR. KUMAR: Dr. Young, about 860 patients came from the U.S. sites.
>
> DR. YOUNG: That is correct.
>
> DR. KUMAR: If I understood the data.
>
> DR. YOUNG: That is correct.
>
> DR. KUMAR: Can I just follow-up?
>
> DR. GULICK: Yes.
>
> DR. KUMAR: In the FDA briefing document there was some mention that
> some specimens were lost or contaminated. Would you comment on
> cultures from the European countries, from West Europe and East
> Europe? Could you give us a sense of how much of these specimens were
> lost or contaminated during transport here?
>
> DR. COCCHETTO: Sure. We did look carefully at that issue of handling
> of specimens. Let me ask Stuart Harding to comment on that, transport
> and our accountability for specimens.
>
> DR. HARDING: Of those cases reviewed by the endpoints committee, 71
> cases, there were six subjects in which there was a sample, or
> sometimes more than one sample that was missing or contaminated, or
> whatever. But when you consider that for a suspected cases samples are
> taken for culture and PCR on days one, five and ten and serology on
> day one and ten, and then there is continued follow-up with serology,
> we don\'t think that that would impact the results.
>
> For your question about transport around the world and particularly
> from Europe, I am not aware that there was any problem with that
> transport. According to Dr. Ashley Morrow the samples typically
> arrived in very good condition and chilled. If you need more
> information I think she would be pleased to give you some.
>
> DR. KUMAR: That is fine, I just wanted to get a feeling for that. Can
> I ask one last question?
>
> DR. GULICK: Sure.
>
> DR. KUMAR: Again, this is for the sponsor. Could you comment, on
> valacyclovir four patients developed herpes. Could you give me some
> sense of their clinical presentation and how long was the follow-up
> that you had on those four patients?
>
> DR. COCCHETTO: Let me just make sure I understand. You are asking for
> some clinical information on the four primary endpoints within the
> valacyclovir group?
>
> DR. KUMAR: And how long they were followed.
>
> DR. COCCHETTO: And how long they were followed. Again, I would ask Dr.
> Harding to comment.
>
> DR. HARDING: I can\'t recall exactly but we do have the case
> narratives for each of those four, if you want us to show them.
>
> DR. GULICK: Yes.
>
> DR. HARDING: If we could have those? I can give you some summary
> details at least for the demography, and stuff. There were two male,
> two female, for example, ages 29-35, all from the U.S.
>
> \[Slide\]
>
> This is one of them. I don\'t know if you want me to read that or if
> you can read it from where you are.
>
> DR. GULICK: Why don\'t you guide us through it?
>
> DR. HARDING: The randomized date was in October, 1999 and the date of
> the end clinical endpoint was June, 2000. The subject reported dysuria
> approximately four days before noticing a large erythematous papule on
> her external labia on June 13, 2000. On exam, four additional
> erythematous lesions were identified. There were confirmatory labs;
> culture taken on June 15th was positive.
>
> \[Slide\]
>
> Again, an American one, as we said. Randomization May 6, \'98 and in
> August, end of August, subject returned to the clinic on September 2nd
> with a suspected genital herpes outbreak. Subject stated that
> prodromal symptoms started on August 31st, with lesions appearing on
> September 2nd. The office visit included tender palpable lymph nodes
> in the bilateral groin; fatigue, malaise and general rash. The
> confirmatory lab, culture and PCR on September 2nd were negative but
> the serology became atypical on October 13th and then converted fully
> to positive on December 2nd.
>
> \[Slide\]
>
> Another one, randomization in June, \'98; clinical endpoint December,
> \'98. Subject returned to clinic on December 2nd with complaints of
> sore throat, genital tenderness and genital lesion that started on
> September 2nd. The confirmatory labs were both culture and PCR.
>
> \[Slide\]
>
> The last one was randomized April 21st. On April 29th the subject
> presented at clinic on May 1st, complaining of dysuria lasting two
> days. The labia was erythematous with no discrete lesions and
> extensive cervicitis. Culture and PCR were positive. In addition,
> serology on May 20th was positive. So, these are all fairly typical
> primary cases.
>
> DR. KUMAR: Dr. Harding, I may not have asked my question clearly. What
> I wanted to know is not so much what the clinical presentation was but
> really what happened to them. Did they respond to a treatment? What
> were they treated with and did they respond? I recognize that you had
> not collected any resistance data. So, I was just trying clinically to
> see what happened to these four patients.
>
> DR. HARDING: Well, they were all given one gram twice a day of
> valacyclovir for ten days. But at that stage they were free to leave
> the study if we had the confirmatory labs.
>
> DR. KUMAR: Can you give us a sense of whether they responded to the
> treatment that was given to them?
>
> DR. HARDING: Can anyone help me as to whether we recorded that? I am
> getting shakes of the heads. This wasn\'t an analysis that we
> collected.
>
> DR. GULICK: I guess what you are getting at is, just because of the
> issue of resistance, it would be nice to know if they responded to the
> therapy and healed the lesions.
>
> DR. KUMAR: Yes, that is all that I wanted to know. Is there any sense
> of what happened once they got treated, and how quickly did they
> respond, and any such information.
>
> DR. HARDING: Dr. Young has reminded me that all the isolates were
> susceptible but, of course, we didn\'t determine that until later. But
> we are not aware of transmission of resistant isolates in
> immunocompetent subjects anyway so I don\'t think this was a
> consideration.
>
> DR. GULICK: So, the short story sounds like we don\'t have clinical
> information available on that.
>
> DR. HARDING: We don\'t have that sort of detail. Obviously, expecting
> very small numbers it wouldn\'t have really helped us over and above
> all the details we have on treatment of episodes.
>
> DR. YOUNG: Just one additional comment, it is not unusual in our
> clinical studies on suppression to actually have individuals who may
> develop recurrences on active therapy. Typically, when these
> individuals are actually treated with what would be considered to be
> the standard doses they do resolve their lesions. So, it is really not
> an unusual circumstance.
>
> DR. KUMAR: But we are not sure, Dr. Young.
>
> DR. YOUNG: Not in this study. I am just making a general comment.
>
> DR. KUMAR: We do recognize that but I think particularly for this
> group of patients that would have been important, with four patients
> that got it, it would have added a sense of comfort to clinicians like
> me.
>
> DR. GULICK: Dr. DeGruttola and then Dr. Sherman.
>
> DR. DEGRUTTOLA: I have a couple of questions about the withdrawals
> first, directed first to the FDA but then also to the sponsor. As was
> correctly pointed out, the analyses are sensitive to assumptions about
> withdrawals so my first question is, is there any information about
> when these withdrawals took place? Obviously, for those toward the end
> of the study the assumptions have less impact on the analyses.
>
> Also, was there any effort to find out more about who withdrew, not
> just the reasons for it but what the characteristics of people who
> withdrew were, and did those characteristics predict outcome and
> differ by treatment arm? Because that would be the case, again\--where
> the characteristics predict outcome and differ by treatment
> arm\--where the non-informative censoring assumptions would break down
> and could have an impact on the results.
>
> So, two questions to start. Distribution, when they took place and who
> they were.
>
> DR. SMITH: As far as when they took place, the applicant has, I
> believe, a Kaplan-Meier plot about the time to discontinuation in
> their package. Generally, it looked like\--
>
> DR. GULICK: Could you give us the page number on that?
>
> DR. SMITH: I can\'t give you the page number right away.
>
> DR. GULICK: Anybody who has the page number could give it to us.
>
> DR. COCCHETTO: Page 46.
>
> DR. GULICK: Thanks.
>
> DR. DEGRUTTOLA: So, it looks like it is pretty even over time, except
> right at the beginning.
>
> DR. SMITH: Yes, so it looks like it is very even in terms of time to
> withdrawal, similar to the proportions analysis. Patients who had
> unknown outcomes in terms of the primary endpoint, they tended to
> withdraw earlier than other patients who discontinued. We didn\'t
> really get into that, you know, present, absent or unknown, as far as
> the primary endpoint was concerned but those patients who were unknown
> were counted\--it was dichotomized; they were not counted as a
> separate category.
>
> Basically, in terms of the types of withdrawals and withdrawal
> characteristics, I am not familiar with the withdrawal
> characteristics.
>
> DR. GULICK: Does the sponsor want to comment on this?
>
> DR. COCCHETTO: Yes. Dr. DeGruttola, we share your curiosity about the
> withdrawals, as well as Dr. Smith\'s, and we did look at those pretty
> carefully. If you put up D7, just so everyone can see the same
> graphic\--
>
> \[Slide\]
>
> \--that is the Kaplan-Meier plot. Let me ask Roger Liddle, who is the
> head of our statistics group for this trial, to make some comments to
> address your question, Dr. DeGruttola, from looking at patient
> characteristics as well as the time course of discontinuations.
>
> DR. LIDDLE: Thanks. My name is Roger Liddle. I am vice president of
> biostatistics and data management for GlaxoSmithKline. Thanks for the
> opportunity to just take a few minutes to cover a couple of slides.
> Let me jump to D2.
>
> \[Slide\]
>
> We have covered already overall. We see a very similar discontinuation
> rate between the two treatment arms, with 22 percent on placebo and 21
> percent on Valtrex. In the bottom part of the slide you see that over
> the course of time this is sort of similar, maybe just a quick summary
> to the slide you have already seen but if you look at the three-month
> period, less than three months, three to six or more than six, there
> was somewhat of a tendency to withdraw earlier from the study, but
> between the two treatment groups the pattern was very consistent.
> Let\'s go to D3, please.
>
> \[Slide\]
>
> I think with respect to that, what is the impact and what are the
> various analyses, and how dependent are they on the different analysis
> methods? The key sensitivity analyses that we performed, one was time
> to event which certainly has some appeal because we get to use the
> data right up until the time of discontinuation. With the as-treated
> analysis, we really focused on those patients who completed the entire
> study. The imputation approach, which was also referenced in the FDA
> presentation\--here, what we have chosen to do rather than say 100
> percent or five percent or whatever else the discontinuations, here
> what we did was we took the placebo rate for transmission and we
> applied that rate to the discontinuations. So, if we saw something
> between two and three percent on the placebo arm, that would
> correspond to four or five additional events. So, we added those four
> or five additional events to each treatment group. So, we sort of
> imputed the placebo transmission rate for each of the treatment arms.
>
> In all three of those cases, the intent-to-treat, the as-treated, the
> time to event and that imputation, in all three cases the statistical
> test was robust for those and we did see a significant, less than
> 0.05, p value in all three of those cases. Let\'s go quickly, if we
> can, to D9.
>
> \[Slide\]
>
> These are the p values that I just referenced. You see the primary
> analysis was the 0.011 which has been referenced a couple of times
> this morning. Time to event is the 0.008. Perhaps not surprising,
> because we are using all the data it does give you a bit more power.
> The as-treated analysis was 0.012. If you use that placebo rate, it
> came out as somewhere between four and five events. So, we have shown
> the results both for four and five events added to the two treatment
> groups.
>
> In a sense, this itself is being a little bit conservative because we
> have ignored in this imputation approach the fact that we do have some
> data for those patients. They did not get the transmission and we have
> actually imputed the placebo rate as if it was the entire eight
> months. If you actually said, well, they were on average in the study
> for three months and used a sort of time-dependent transmission rate
> it would be more like three events. So, again, it would still be
> significant. So, in this sense it is perfectly appropriate to look at
> a variety of the sensitivity analyses but in this case they were all
> robust to that.
>
> I think the question about was there information in those
> discontinuations, I have one additional slide I would like you to talk
> you through very briefly, slide D27.
>
> \[Slide\]
>
> This is actually fairly recent work. We, obviously, were still trying
> to understand if there was information in these discontinuations. What
> we have done is we took a variety of baseline characteristics that are
> listed over on the left-hand side of this, and we have looked at them
> to see if they were predictive of discontinuation. There, what you
> will see is that the first five were not predictive of discontinuation
> and, therefore, would not likely drive some bias because of the
> discontinuations. So, we sort of didn\'t worry about those.
>
> The four at the bottom were of some concern but then, of course, the
> next question is are they predictive of primary outcome? If they are
> unrelated to the primary outcome, and the HSV-1 for the susceptible
> partner was not predictive of the primary outcome, again we don\'t see
> that as a concern.
>
> That still leaves us with three baseline characteristics that were
> potentially of interest and could conceivably result in some bias in
> the results. For two of those, the country where we analyzed it as
> U.S. versus noon-U.S., and the duration of relationship\--as I said,
> they were somewhat related to discontinuation and they were somewhat
> predictive of the primary outcome, with U.S. being more likely to
> transmit and shorter relationships being more likely to transmit but,
> in fact, there was not evidence of a differential rate in the
> discontinuation. So, while that may have had some effect on the
> overall transmission rate, it should not have a bias in favor or
> against one treatment arm versus the other.
>
> That leaves us really with one variable which was potentially of
> interest and could have had some bias. That was the duration of the
> HSV-2 in the source partner. But in this case it is interesting to
> note that because Valtrex was associated\--sorry, let me get this
> straight\--this does imply a potential bias against Valtrex and for
> placebo. The reason for that is that HSV-2 infection is correlated
> with clinical acquisition. The duration of the HSV-2 infection is
> correlated with clinical acquisition and is also correlated with a
> higher discontinuation rate for the placebo arm. So, if in fact that
> baseline characteristic, if there is information there, it means that
> placebo patients were a bit more likely to drop out and were more
> likely to have been transmitters. Therefore, at least based on this
> analysis that we went through in some detail, we felt there were no
> red flags or cause for concern based on a fairly comprehensive look at
> baseline characteristics. Thank you for your patience.
>
> DR. DEGRUTTOLA: Thank you very much, that was very helpful and very
> useful. I have a couple more questions. One is to the agency, given
> the fact that, as Dr. Liddle just mentioned, at least in the
> Kaplan-Meier analysis you can use the information up until the time
> the subject discontinues, why were the primary analyses that you
> presented based on odds ratios rather than the time to event analyses,
> and could you comment on the appropriateness of the time to event
> analyses, given that in some cases\--I think in all cases there was a
> higher degree of statistical significance, not greatly but it was
> greater?
>
> DR. SMITH: We found that the Kaplan-Meier analysis was slightly more
> powerful but we didn\'t find a tremendous deal of difference between
> the two approaches and since the primary analysis was done on the
> proportions we just tried to look at the proportions that correspond
> to the primary analysis. But we would expect similar sensitivity for
> the Kaplan-Meier analysis if you counted withdrawals randomly.
>
> The other problem with the Kaplan-Meier analysis is it depends on
> which withdrawals from, say, the five percent you choose as failures.
>
> DR. GULICK: Can you speak up a little bit?
>
> DR. SMITH: Sorry. If you choose five percent of the discontinuations
> and treat them as failures, then you have a little bit of a problem
> where they are all going to have different failure times. So, it
> depends on which ones you randomly choose.
>
> DR. DEGRUTTOLA: I agree, if you were going to do sensitivity analyses
> you might want to make different kinds of assumptions, or would have
> to make different kinds of assumptions. But it sounds as if in general
> you considered the Kaplan-Meier analyses appropriate and informative
> even though all of them have issues with withdrawals.
>
> Dr. Smith presented analyses showing that there was a significant
> geographic effect on the risk of developing the endpoint. But was
> there was there an analysis done of the impact of geographic region on
> the treatment effect?
>
> DR. SMITH: Yes, we did analyses looking at treatment by geographic
> region interactions. In that case we didn\'t find any statistical
> significance so it was mainly the main effect of geographic region
> regardless of which treatment they were on.
>
> DR. DEGRUTTOLA: And one final question just to clarify, for the
> primary analyses patients were followed after drug discontinuation and
> included in analyses and then intent-to-treat ways. Is that correct?
>
> DR. SMITH: Patients were followed for eight months, the duration of
> the double-blind study. After that we didn\'t look at events after
> eight months because all the patients were put on open-label
> treatment.
>
> DR. DEGRUTTOLA: But if there were treatment discontinuations prior to
> eight months, were those patients no longer followed?
>
> DR. SMITH: They were no longer followed, to my recollection, after
> they discontinued from the study.
>
> DR. DEGRUTTOLA: Could they discontinue\--maybe this is a question for
> the sponsor, could patients discontinue treatment but continue to be
> followed in the study? Or, once they discontinued treatment was
> follow-up discontinued?
>
> DR. HARDING: Obviously, the typical case was when they discontinued
> they were not followed. There was a small number of subjects who did
> remain with follow-up. In fact, we tried to get serology after
> discontinuation where possible.
>
> DR. DEGRUTTOLA: And is that true for partners as well, if they changed
> partners or treatments that they were no longer followed?
>
> DR. HARDING: If the susceptible partner changed partners, yes, there
> were some instances where they continued but, according to the
> protocol, they should have discontinued because they are no longer
> monogamous.
>
> DR. GULICK: Dr. Sherman and Dr. Fish.
>
> DR. SHERMAN: Thanks you. Two points of information just to help
> clarify some things for myself, for the sponsor, can you explain why
> in your design you limited the number of episodes permitted per year
> to nine or less?
>
> DR. COCCHETTO: Sure. The regimen of Valtrex evaluated in this trial is
> currently approved for suppressive therapy for patients with nine or
> fewer recurrences per year. So, in order to be able to compare a
> single regimen of Valtrex versus placebo we focused on that group of
> patients.
>
> DR. SHERMAN: Wouldn\'t you have had a somewhat higher yield in
> patients that presumably shed higher levels of virus?
>
> DR. COCCHETTO: Let me ask Dr. Harding to comment on the proportion of
> patients who have those particular histories of recurrences.
>
> DR. HARDING: As I said in my presentation, the vast majority, about
> eight percent of subjects, do have nine or fewer recurrences so this
> was the predominant population. But we did have two other
> considerations as to why we didn\'t choose people with ten or more
> recurrences. One was the fact that they would be more likely to
> actually want treatment as opposed to have the possibility of placebo
> so it was bordering on whether this was ethical. The other is that if
> they had such frequent recurrences they may be more easily able to
> discern whether they were on active or placebo and, therefore, break
> the blind because it would be pretty obvious if they started taking
> Valtrex.
>
> DR. SHERMAN: Okay. The second question relates to actually one of the
> slides that Dr. Handsfield showed in his discussion of the sexual dead
> zone after about age 40. If the rate of transmission is about 2.5-3.0
> percent per year in untreated patients, how come we don\'t see in
> stable monogamous couples continued effect of infection on and on and
> on because it is going to take many, many years, 30 years or more, at
> that rate to continue to completely infect the stable partner
> population? This question is relevant to how long does one ultimately
> continue treatment. Is there a time period where pretty much the risk
> of transmission ends?
>
> DR. HANDSFIELD: I am not sure we know definitive answers to those
> questions. I have given you the clues that one might suspect that
> subclinical shedding because symptomatic recurrences probably wane
> over long periods of time, after several years, and it is a fair
> assumption that subclinical shedding may as well. So, a longer
> duration relationship may become less risky from that standpoint over
> time. That is hypothetical; it hasn\'t been sufficiently studied.
>
> There has also been speculation, and Dr. Corey or others can answer
> this part better than I can, about whether there might be some level
> of non-measurable immunity, that is, not measured by current
> approaches to antibody levels or perhaps even cell-mediated immunity,
> but, nevertheless, as has been analogous and suspected for some HIV
> cases, low level exposures might, in fact, result in some level of
> protection that is not detectable by those methods, which also might
> be expected to have its effect in couples over time. So the exact
> physiologic explanation for the epidemiologic observations I think is
> not something we have definitive answers for, but that is my
> epidemiologist\'s response but perhaps others have comments on it.
>
> DR. SHERMAN: But would it be fair to say, and perhaps a representative
> of the sponsor can answer this, that at some point it doesn\'t appear
> that suppressive treatment may, in fact, be indicated?
>
> DR. HANDSFIELD: I will comment, if I can continue, and then I will sit
> down. I think that begins to get to issues that are not yet on the
> table but clearly will be, and that is, what are some of the
> extrapolations that can or should be made from a public health
> standpoint? The notion that viral shedding is the most common in the
> first months to a year or two after acquisition, therefore,
> differential benefit might be seen in people with shorter-term
> relationships and/or more recent acquisitions I think is certainly the
> implication of what you are asking and I think that is potentially a
> valid implication. That doesn\'t, however, undermine the high value,
> regardless of the public health benefits, in those individuals who
> have ongoing relationships who are looking for that level of assurance
> or protection that they may want over a long period of time.
>
> DR. GULICK: Let me caution us not to get into the discussion period
> just yet and let\'s stick to questions of clarification at this time.
> We have plenty of time to grapple with some of the questions a little
> bit later on. Dr. Corey, do you want to add something?
>
> DR. COREY: If I might comment, it is a great question but, you know,
> you are asking about an area in any infectious disease and especially
> for genital herpes and we actually don\'t know a lot of information
> about the exact issues of transmission. As an anecdotal case, both in
> the Chiron study and this study, we have had people who have had in
> monogamous relationships for greater than eight years and ten years
> who actually transmitted on study at that period of time. So, for a
> long duration. Yet, when you look at relative risk factors, certainly
> shortness of the relationship increases the relative risk by, let\'s
> say, a factor of 2.5 to 3. And, duration of genital herpes, long
> duration, decreases the risk factors.
>
> Now, how much of that is due to biological factors that relate to
> frequency of subclinical shedding that decreases over time; how much
> of it relates to behavioral factors that are associated with sexual
> practices that go with duration of relationships, and how much is the
> other new factor which is essentially innate resistance, just like in
> HIV where there has been among high exposed seronegative men and women
> T-cell immunity associated with no seroconversion? Chris Posavad, from
> our group, has recently reported that now with some HSV seronegatives.
>
> So, on a population basis we have a complex interplay here that we
> actually can\'t really play out in a definitive way from a counseling
> point of view, unfortunately, at least in my opinion.
>
> DR. GULICK: Additional questions of clarification? Dr. Fish and then
> Dr. Englund.
>
> DR. FISH: I have three questions, if I may. Understanding that the
> primary endpoint related to genital HSV-2, and on slide 28 you
> mentioned it was culture, PCR or serology that was utilized, I thought
> I heard the sponsor say that there were no cases of HSV-1. Is that
> correct?
>
> DR. COCCHETTO: That is correct.
>
> DR. FISH: And how is that known?
>
> DR. GULICK: Sorry, we need people to go to the mike to answer.
>
> DR. HARDING: There were no primary acquisitions of HSV-1 genital
> herpes in the susceptible partners. There were four asymptomatic
> seroconversions. Does that answer the question?
>
> DR. FISH: So, no clinical endpoints but four seroconversions to HSV?
>
> DR. HARDING: Yes. The serodiscordancy for HSV-1 was only 13 percent
> where, of course, it was 100 percent for HSV-2. So, although nowadays
> a fair number of primary acquisitions of genital herpes are HSV-1, I
> think because the gradient, if you like, was much smaller in our study
> we didn\'t actually have one but we did look for it.
>
> DR. GULICK: Can people hear in the back of the room? All speakers,
> please speak loudly and into the mikes.
>
> DR. FISH: The second question relates to the counseling design. Was
> there a specific script given to the investigators in terms of
> counseling about condom use, or was this left to investigator
> discretion?
>
> DR. HARDING: There was no specific script. They all had the American
> Medical Association booklet, which was state-of-the art at that time,
> 1997. They were instructed in the protocol and at investigator
> meetings to make sure that people could recognize the signs and
> symptoms because that obviously is a big feature, and then the
> abstinence and the condom use. The fact that counseling was given was
> checked off in the CRF so at each visit they had to verify that they
> had done that.
>
> DR. FISH: Thank you. Then a last question for the agency, there were
> approximately 25 percent fewer primary endpoints than anticipated,
> 20/28 that they thought one might see in the 1500 who were entered.
> Can you comment in terms of how this might affect, if at all, the
> robustness of the analysis?
>
> DR. SMITH: Well, given more endpoints, the analysis, had there been
> the same difference between the two treatment groups, would have been
> more robust to discontinuations because there were so many more
> discontinuations than endpoints. That is why we had a lot of trouble
> with the sensitivity because of the fact that the discontinuations
> just swamped the treatment effect.
>
> DR. GULICK: Dr. Englund?
>
> DR. ENGLUND: I have some questions about the seroconversions as the
> secondary endpoint, and specifically on slide A44 for the sponsor,
> because in fact serology was an entry point for the study, I am
> interested in these 36 seroconversions as a secondary endpoint. Did
> those include the patients that were culture and/or PCR positive that
> were serology negative at the time, perhaps of a timing issue? In
> other words, do the seroconversions include all those that had
> symptomatic clinical disease documented by other laboratory
> parameters?
>
> DR. HARDING: Perhaps if we have slide A44 it would be helpful.
>
> \[Slide\]
>
> So, you have your 36 seroconversions and, as you see, 15 were from the
> primary endpoint. The culture or PCR came first but seroconversion was
> detected later. For the five that were determined to be endpoint based
> on culture or PCR, three of them left the study there and then and
> there was no adequate duration of follow-up for seroconversion but,
> obviously, we would have expected them to convert given time. Then,
> there were the three seropositives from the cases referred to the
> endpoints but without culture or PCR positives.
>
> So, the overall acquisitions is probably the best endpoint to look at
> as a secondary endpoint compared with the primary because that now
> includes the cultures or PCRs taken at the time. It wasn\'t that
> patients were always followed for long enough to ascertain
> seroconversion. Does that answer your question?
>
> DR. ENGLUND: Well, it does because one of the questions when you are
> looking at the secondary endpoint is that you want to make sure that
> you aren\'t missing any, and you are saying you probably aren\'t but
> you don\'t have the data on several patients.
>
> DR. HARDING: That is why I included the overall acquisitions because
> that includes not only the seroconversions but those for which we have
> culture and PCR. If you just look at seroconversions, you may have
> missed some who withdrew from the study having had a positive culture.
>
> DR. ENGLUND: I have another question in which perhaps you might be
> interested. This is regarding resistance and I would just like to ask
> perhaps one of our other experts here, but to my knowledge there has
> never been resistant HSV transmitted from an immunocompetent person to
> another immunocompetent person, whether it is HSV-1 or HSV-2. Is that
> correct?
>
> DR. HARDING: That is my understanding.
>
> DR. GULICK: Dr. Mathews?
>
> DR. MATHEWS: I wanted to return briefly to the issue that Dr.
> DeGruttola raised about whether there was a differential dropout
> because there were a couple of other risk factors that I didn\'t see
> on the slide that probably are relevant, and those are whether the
> dropout was differential by condom use, either at baseline or on
> study, and also by the reported frequency of intercourse. Do you have
> any analyses that looked at those factors?
>
> DR. COCCHETTO: I am looking to my colleagues to see if one of them can
> help us with that. Roger?
>
> DR. LIDDLE: I may be able to answer but it won\'t be totally
> satisfying. I think in the analysis that I presented we were looking
> at baseline characteristics. We were trying to understand what
> differences in the patient population when they walked in the door
> could drive some bias induced both by the differential dropout rate
> and some effect on overall acquisition. So, we were not looking at
> variables that we were monitoring during the study, such as the condom
> use during the study or the frequency of sexual activity during the
> study.
>
> DR. MATHEWS: Well, you probably have the data, right? I mean, the
> effect size for condom use in one of the analyses you presented was a
> relative risk reduction of about 0.5 so it is not a trivial protective
> factor. So, I would suggest those be looked at by the agency as well
> as the sponsor.
>
> Secondly, dealing with the point Dr. Sherman made about how long the
> period of risk might last, you might have some data in this trial by
> looking at what happened to the effect size for the treatment by
> antecedent duration of the partnership, recognizing that there were
> not a lot of endpoints but if you even made one cut point in the
> duration of the partnership was there modification of the magnitude of
> the effect?
>
> DR. LIDDLE: We did look at the duration of the relationship and there
> was some impact. The shorter duration of relationship was associated
> with an increased chance of discontinuation and was associated with an
> increased chance of our primary outcome of transmission.
>
> DR. MATHEWS: So, if you were to estimate the relative risk reduction
> for those who had, say, partnerships of two years or greater versus
> less than two years, those kinds of analyses, was there evidence of an
> effect size difference?
>
> DR. LIDDLE: We did not calculate relative risk factors so I actually
> can\'t comment on how big a difference that was. There was somewhat of
> a relationship; I don\'t think it was huge. Can anybody help me with
> that?
>
> DR. COCCHETTO: Dr. Wald is pressing to comment.
>
> DR. GULICK: Please state your name and your affiliation.
>
> DR. WALD: Anna Wald, University of Washington. Although short duration
> of relationship was a risk factor for HSV-2 acquisition in this study,
> there was no interaction between the valacyclovir effect and the short
> duration of relationship.
>
> DR. LIDDLE: This is Roger Liddle again, if I can just follow-up, I
> think the relative risk was a factor of about 2.5 so it was a fairly
> significant change, duration of relationship related to acquisition
> rate, the relative risk was a factor of 2.5.
>
> DR. MATHEWS: I would suspect you didn\'t have a large power to detect
> an interaction given the number of events.
>
> DR. LIDDLE: I am sure that is true.
>
> DR. MATHEWS: One last question relates to the condom use. Dr. Haverkos
> showed us cross-sectional data on the frequency of reported condom use
> before starting the study and on study. It might be helpful to know
> cross tabulation. For example, the people who were never using condoms
> before the study, what proportion of them started using them? The
> analyses you showed were just cross-sectional and didn\'t show a lot
> of change, but was there mobility when you look within subjects across
> time?
>
> DR. SMITH: I think we looked at that and we didn\'t see that much of a
> difference. I can\'t remember if we have it on a backup slide but we
> could maybe look for that, if we have it.
>
> DR. MATHEWS: This will come up later in the discussion but if, in a
> setting like this where there was a conscious intent to educate and
> encourage condom use, you really don\'t see any effect it raises
> questions about, if the indication is granted, how effective any
> educational programs along with it will be.
>
> DR. GULICK: Let\'s hold that thought for the discussion but that is an
> important point.
>
> DR. COCCHETTO: Can I add something to that?
>
> DR. GULICK: Let\'s actually not add anything at this point in the
> interest of time. This is one of the questions we will be facing in
> the afternoon so let\'s not.
>
> DR. COCCHETTO: Let me just say we have looked at those data.
>
> DR. GULICK: Okay, thanks. Dr. Potter?
>
> DR. POTTER: Yes, actually I was concerned about the fact that there
> were 4,000 people, there were attempts to recruit 4,000 with 1,500
> actually included. It was mentioned that for most of them it was
> because the partner was already seropositive. But I wanted to know
> about the rest of that group. You know, what proportion was because
> they were already seropositive? What were the reasons for refusal?
> Because this would reflect the typical user as opposed to the more
> perfect user that takes part in a study like this.
>
> DR. GULICK: So, the causes of screen failures, the proportions?
>
> DR. POTTER: Yes.
>
> DR. HARDING: What I said was that the most common reason was the lack
> of serodiscordancy. In fact, overall it was about 30, 34 percent so it
> wasn\'t the majority. As the study went on and recruitment got more
> difficult, more advertising was done and people came forward, thinking
> that they might want to participate in the study or they might just
> want a free serology test. So, there was about another 20 percent and
> the source partner was not confirmed to have HSV-2 by serology. That
> has not accounted for about 54 percent of the subjects. I think there
> was another big chunk, probably about 30 percent, who, when they found
> out what was required of this study with all this personal, intrusive
> stuff and the duration of the study, they refused to participate. In
> fact, there were three sorts of major reasons, not just lack of
> discordance.
>
> DR. POTTER: My real question was about that last group. If they were
> the people who would have had more trouble complying with the regimen,
> you wouldn\'t have data on that I guess. And, the same thing happens
> later\--I am not sure of the direct link here but track of compliance
> with the Valtrex itself during the course of the study. In other
> words, if people refused to participate, was there a proportion that
> refused because they thought they couldn\'t follow the regimen that
> carefully and then, during the study was there track of compliance to
> see how forgiving the method is? Does that make any sense?
>
> DR. GULICK: Dr. Cocchetto?
>
> DR. COCCHETTO: I think so. You can help me further. On the first part
> of your question, at the point of screening where couples were
> considering the trial they considered the entirety of the trial. So,
> they would include consideration of their ability to adhere over an
> eight-month, double-blind period to study medication, as well as the
> need for monthly follow-up visits, laboratory specimens and so on. We
> don\'t have specific data on which component of that drove their
> decision-making. Anecdotally, as Dr. Harding has said, the personal
> intrusiveness seems to be the dominant factor pre-study. During the
> study we did use a straightforward table count methodology to track
> medication compliance and we could share that with you perhaps this
> afternoon.
>
> DR. POTTER: Thank you.
>
> DR. GULICK: Yes, Dr. Guinan?
>
> DR. GUINAN: Thank you. I would like to see gender stratification
> breakdown on the substudy on viral shedding and the results. Thank
> you.
>
> DR. GULICK: Was that clear?
>
> DR. HARDING: We have not done that analysis as yet.
>
> DR. GULICK: Other members of the committee who haven\'t had a chance
> to ask questions who would like to? Dr. Fletcher?
>
> DR. FLETCHER: I have two that I think are quick. First, the say, at
> least in the sponsor\'s briefing booklet, that amendment IV is
> presented, it says the sample size was revised in order to observe 28
> confirmed endpoints. As I read it, and I think this kind of follows
> Dr. Fisher\'s comment, I was expecting to see 28 endpoints and there
> are not. So, was there agreement between the sponsor and the agency
> that there did not have to be 28 endpoints?
>
> DR. HARDING: Yes, the protocol started off with 1,500 but actually,
> strictly speaking statistically, it is the endpoints that matter and,
> therefore, I think the protocol was amended to reflect that degree of
> finesse. What happened in practice was we were having considerable
> difficulty enrolling subjects, as you have heard, and then in May of
> 2001 we had achieved 23 possible endpoints because, obviously, there
> was ongoing review as faxes came in, information and so on. So, giving
> the sites sort of six weeks to complete their period between screening
> and enrollment, and then another eight months for subjects we reckoned
> we would probably achieve over that sort of ten-month period another
> five endpoints because that was our estimated rate, and it turned out
> that we had about 1,500 couples; we anticipated 28 endpoints but we
> didn\'t achieve them.
>
> DR. FLETCHER: Then my second question, again just to make sure I am
> clear, what the sponsor is requesting on the dosing is no statement
> regarding duration so 500 mg once daily but nothing on the duration of
> therapy. Is that correct?
>
> DR. COCCHETTO: In our proposed labeling for duration it is quite
> explicit about the nature of the 3009 study in stating that the study
> was conducted for an eight-month, double-blind period. We have also
> proposed a statement elsewhere in the labeling to be clear that
> efficacy beyond that eight-month duration has not been demonstrated.
>
> DR. GULICK: Are there other members of the committee who haven\'t had
> a chance to ask questions\--I will come back to you, Dr. Guinan\--who
> would like to ask questions?
>
> \[No response\]
>
> I have a few and then I will come back to you. One of my questions
> concerns the endpoint committee. I am trying to get a feeling for
> actually how the cases were evaluated in terms of what was available
> to the endpoint committee\--history, pictures, what kinds of things
> were looked at?
>
> DR. COCCHETTO: We are fortunate to have Dr. Corey here who chaired the
> endpoint committee. I will ask Dr. Corey to comment.
>
> DR. GULICK: Great!
>
> DR. COREY: As Dr. Harding said, there was both real-time monitoring
> and then a formal evaluation at the end of the endpoint committee. The
> charts were all reviewed for any clinical signs and symptoms of
> genital herpes. All the laboratory data from the cultures and PCRs
> were made available and a serial line listing on each individual case
> was given on the serologies. So, the endpoint committee did all these
> evaluations in a blinded fashion. The definitions, of course, were
> agreed upon prior to the onset of the study. We actually reviewed the
> definitions before our formal endpoint meeting and agreed there would
> be laboratory confirmation that would be critical, essentially
> necessary to require a case, and the focus was were the signs and
> symptoms compatible with genital herpes from the narrative as it
> relates to the finding? Was it conceivable that these signs and
> symptoms were related to the laboratory confirmation of the test?
>
> Of all the endpoints, actually there was really 100 percent unanimity
> on the endpoint committee on all except one endpoint, which we ended
> up classifying as an asymptomatic acquisition in a case that clearly
> had HSV-2 seroconversion, had some very vague symptoms and signs that
> were related to the general area that were prolonged itching that the
> majority of the members felt could not be associated convincingly
> enough at the time of the signs and symptoms with the seroconversion
> to be called a clinical endpoint. It certainly was a total overall
> acquisition. That was the only endpoint that had any dispute or
> difference among the six members of the endpoint committee.
>
> DR. GULICK: Just so I understand, the investigator would do a clinical
> evaluation; write up a history of what went on; serologic testing
> would be done; and then the endpoint committee would receive\--
>
> DR. COREY: That, as well as the fact that there was 100 percent
> monitoring by the sponsor on those narratives. So, the narratives were
> really confirmed not only by the investigator but by the monitoring.
> They were written up and the narratives were made available with all
> the laboratory testing, as well as what the clinician diagnosed and
> whether medication was dispensed for an incident case.
>
> DR. GULICK: As I understand, of the 51 endpoints that were rejected,
> in all but three it was because the serologic test was negative?
>
> DR. COREY: Correct.
>
> DR. GULICK: We heard about the other three and why they were
> different.
>
> DR. COREY: Correct.
>
> DR. GULICK: Thanks. My next question is about resistance. Did I
> understand correctly that ten viral isolates were available to be
> tested for resistance? Yes.
>
> DR. GULICK: So, it was from the source patient obviously, and that is
> pretty much the extent of the resistance information that is
> available?
>
> DR. COCCHETTO: Well, let\'s clarify that further. Dr. Harding, do you
> want to comment on those ten specifically?
>
> DR. HARDING: There were ten cultures from the susceptible\--
>
> DR. GULICK: Susceptible?
>
> DR. HARDING: And one from Canada which is currently being tested for
> resistance.
>
> DR. GULICK: And no evidence of resistance in any of those cases?
>
> DR. HARDING: Not at all.
>
> DR. GULICK: Then, one question for the agency. Reading through the
> background material, apparently the agency initially suggested that
> two studies would be preferred. What we have seen here is one large
> study. I wonder if you could comment on the discrepancy between those
> two recommendations.
>
> DR. BIRNKRANT: I believe the original recommendation for more than one
> study was to be able to capture a more diverse patient population, and
> it was left to the applicant to decide whether to do one or two
> trials.
>
> DR. GULICK: Thanks. Dr. Guinan, I am going to go back to you. I bet I
> got your question, didn\'t I? Anyone else who hasn\'t had a chance to
> ask a question? Dr. Stanley, I have forgotten you.
>
> DR. STANLEY: No, you all have clarified all the questions I had.
>
> DR. GULICK: Super! We will have additional time for questions in the
> afternoon. At this point I would like to go to the open public hearing
> part of the agenda. We have four people who have signed up previously
> to speak at the open public hearing, actually five. The first one is
> Dr. James Allen who is from the American Social Health Association.
>
> **Open Public Hearing**
>
> DR. ALLEN: Thank you, Mr. Chairman. I am James Allen, President and
> CEO for the American Social Health Association, also known as ASHA. We
> appreciate the opportunity to comment on approval of valacyclovir
> suppressive therapy to reduce the risk of transmission of genital
> herpes. ASHA is a nonprofit organization that has focused on education
> and prevention of sexually transmitted diseases since 1914.
>
> We have operated a National Herpes Resource Center for the last 24
> years. Through this center and our associated services, such as the
> National Herpes Hotline, the National STD Hotline, Internet-based
> services, local support groups and involvement with an international
> patient advocacy movement, we interact with tens of thousands of
> people affected by herpes every year. Because of this background and
> the work that we do, ASHA would like to address the issue of
> preventive antiviral therapy to reduce the risk of transmission of
> genital herpes from a patient advocacy perspective.
>
> Our comments today reflect our strong history of patient advocacy and
> the information and concerns we have gleaned from contact with people
> living with herpes. ASHA fully supports approval of the
> GlaxoSmithKline application for valacyclovir suppressive therapy in
> reducing the risk of transmission of genital herpes.
>
> As a prelude to this statement, ASHA discloses that we have received
> charitable grants from GlaxoSmithKline, as well as from other
> pharmaceutical companies, to support our herpes educational activities
> and resources. These monies have been provided for specific activities
> to be conducted by ASHA such as operation of the Hotline or Resource
> Center or convening of a scientific meeting, but we have not used
> these funds for promotion, either directly or indirectly, of products
> or services related to the pharmaceutical companies providing this
> support. The message and information provided by ASHA are determined
> by an independent scientific and medical review and are not related in
> any way to funding from specific manufacturers.
>
> One of the most prominent concerns expressed repeatedly to ASHA by
> people with genital herpes and their uninfected partners is the risk
> of transmission. Quite apart from the physical aspects of recurring
> signs and symptoms, genital herpes can create continuing anxiety and
> psychological distress. From a patient perspective, it is extremely
> difficult to adjust to the uncertainty of this infection\--the fact
> that one might be infectious to others even at times when no signs or
> symptoms are present. Affected people and their partners want to know
> what they can do, what preventive steps they can take. Unfortunately,
> the options for reducing risk have been limited. An effective vaccine
> for the herpes simplex virus does not exist and prevention
> alternatives for this chronic, lifelong infection are not perfect or
> reliable.
>
> ASHA encourages infected persons and their partners to consider any
> and all of the options available. We advice infected people to
> disclose this information to their partner, to have open communication
> and discussions, and to abstain from sexual contact if symptoms or
> signs of infection are present. Each of these has an important place
> in the prevention message. ASHA promotes consistent and proper condom
> use as well, with the important caveats that condoms should not be
> relied upon during symptomatic periods and that condoms are never 100
> percent effective.
>
> Clearly, however, more choices are needed. People with genital herpes
> have long wanted to know whether antiviral medications would be
> helpful in reducing risk of transplantation, and for years we have
> informed them we have no data. The results of the herpes suppression
> transplantation study, which you have heard today and that was
> presented by Dr. Lawrence Corey of the University of Washington at the
> Interscience Conference on Antimicrobial Agents and Chemotherapy in
> September, 2002, however, provide convincing evidence that suppressive
> therapy is effective at reducing both the frequency of clinical
> recurrences and the risk of transmission of infection to an uninfected
> partner. This information significantly substantiates the claim that
> reducing the risk of herpes transmission should be a labeled
> indication for valacyclovir. Such a step will give physicians and
> people with genital herpes another option to consider as a risk
> reduction method.
>
> In conclusion, ASHA believes that people with genital herpes and their
> partners should have more information about risk reduction options,
> beginning with the counseling they receive from their healthcare
> providers, and they need more choices to consider when faced with the
> need to reduce to a minimum any risk of transplantation of herpes
> infection to a partner. Given the information currently available,
> ASHA urges the Food and Drug Administration to approve the
> GlaxoSmithKline application for valacyclovir as suppressive therapy to
> reduce the risk of transplantation of genital herpes. Thank you.
>
> DR. GULICK: Thank you very much. Next is Mr. Gray Davis who is
> Director of the HIV Prevention Trials Network. Oh, I am sorry, that is
> clearly a grave error, Ms. Gray Davis, Dr. Gray Davis. Thank you.
>
> DR. DAVIS: You will get it right soon!
>
> DR. GULICK: Thank you.
>
> DR. DAVIS: I guess we have established that my name is Gray Davis and
> I am the Director of HIV Prevention Trials for Family Health
> International. I am here today not as a representative of any
> organization but as a private citizen with a background in the field.
>
> GlaxoSmithKline did not ask me to come, nor are they supporting my
> attendance in any way, nor were they informed that I would be here. In
> the past I worked for Burroughs Welcome Company and then for Glaxo
> Welcome as the international project leader for acyclovir, which is
> the parent compound to valacyclovir.
>
> I am here to talk about the importance of prevention. Managing an
> epidemic requires more than just having an effective treatment for
> outbreaks. It requires prevention interventions, diagnostic tools and
> counseling techniques. Given that at least 11 million people got
> infected with HSV-2 between 1980 and 1990, and since little has
> changed in the way we manage this disease, we are likely to see
> another 15 million people infected between 1990 and 2000. This is of
> particular concern since, as with other STDs, women are more severely
> affected and bear the burden of some of the more devastating outcomes
> of genital herpes.
>
> Today we have an opportunity to have a major impact on the
> transmission of this infection. By approving Valtrex for prevention of
> transmission you will give clinicians one of the much needed tools to
> combat this disease. Provision of an effective prevention strategy
> will empower people, especially women, to make decisions and take
> control of their lives. Women can encourage their partners to wear
> condoms but they can\'t always enforce that. This will be an
> intervention with equal opportunity for everyone.
>
> The availability of Valtrex will substantially enhance the provider
> options on how to control this disease. The very act of writing a
> prescription will provide a window of opportunity for counseling.
> Patients can be encouraged to talk to their partners, to use condoms,
> to avoid sex during an outbreak, and to take daily therapy. Each of
> these strategies are complementary and provide additional tools in the
> toolbox for prevention. None should be considered exclusive of the
> others.
>
> Why has genital herpes gotten so out of control? Perhaps because it is
> an STD we are uncomfortable talking about it. Both clinicians and
> patients may be reluctant to bring up the subject because society has
> labeled people with STDs as somehow dirty, or stupid, or deserving of
> what they got. Why would you want to talk about something like that?
>
> Clinicians have said that the reason they didn\'t want to bring up the
> subject of herpes was because they knew the patient would get upset
> about it; they didn\'t know what to tell the patient; and they
> weren\'t confident of the test. After all, 50 percent of the time
> cultures are falsely negative. Once diagnosed, there wasn\'t much they
> could do for the patient anyway. So, rather than bring up the subject,
> they elected not to talk about it. Why tell the patient that they have
> a disease they don\'t know they have? However, how can you control an
> epidemic if 80-90 percent of the people who are infected don\'t know
> that they are infected?
>
> Today we have many of the needed interventions to reduce the spread of
> this infection. Reliable, accurate diagnostic tests that can identify
> infected individuals are now available. Clinicians can accurately
> diagnose patients in their office using a diagnostic test as well as
> by drawing blood to send to a central lab for both diagnosis of HSV-1
> or HSV-2. Thus, accurate diagnostic tests are now available to
> everyone.
>
> We also know what to say once a patient is diagnosed. Hotlines,
> written materials and web sites are available to both clinicians and
> patients to help them understand the disease and to provide accurate,
> non-judgmental information. As you heard earlier from Dr. Allen, the
> American Social Health Association has a hotline available five days a
> week from 9:00 a.m. to 7:00 p.m. This hotline is free of charge and is
> an excellent resource for both clinicians and for people with herpes.
> Clinicians can now refer their patients who need more lengthy
> consultation to a reliable source for information, and patients have a
> place to call for anonymous accurate information. The counselors at
> ASHA will spend as much time as needed to provide the best support for
> the caller. Written materials provided by ASHA and other organizations
> are also available.
>
> Lastly, information is available on the web for anyone who wants to
> know more about this disease. The American Herpes Foundation and the
> American Medical Association have information and CME courses for
> clinicians. Another site, herpesdiagnosis.com, provides information
> for both clinicians and patients on how to diagnose and manage this
> disease. It also provides check lists for the clinicians regarding
> what to tell the patient, and for the patient regarding what questions
> to ask the clinician.
>
> So, now we can accurately diagnose this infection and we can
> accurately provide counseling to the patient. The next step is to
> provide a therapeutic intervention. The availability of Valtrex for
> reduction in transmission enhances our armamentarium for the control
> of this disease. As stated earlier, it is just another tool in the
> clinician\'s toolbox. We can now accurately identify those infected.
> We can educate about the natural history of the disease. We can teach
> patients to recognize recurrences. We can help them find ways to talk
> to their partners. We can instruct them to wear condoms, and we can
> offer an easy daily therapy to reduce transmission.
>
> Whenever the FDA is asked to approve a drug they have to weigh the
> benefits of therapy against the potential toxicities. Rarely is there
> a case in which the benefits of therapy so far outweigh the potential
> risks. Valtrex has an impressive safety profile which makes your
> decision today much easier. You can concentrate on whether or not the
> benefits of this medication warrant its approval.
>
> Some decision-makers seem to think that herpes is a benign infection
> with no severe sequelae. However, as with much of the history of
> herpes infections, the more we know about this disease the more we are
> surprised to find out how our beliefs are wrong. Neonatal herpes
> affects one in 3,000 births in the United States. That is about four
> babies a day. The best way to prevent neonatal herpes is by preventing
> the mother from becoming infected in the first place.
>
> As Dr. Handsfield presented earlier this morning, there is also the
> link with both transmission and acquisition of HIV. If we have learned
> anything from our African friends, it should be the lessons learned
> from herpes. In countries most severely affected by HIV, the herpes
> epidemic predated the emergence of HIV. In each of the countries in
> which we know the seroprevalence of herpes infections, the higher the
> seroprevalence of HSV, the higher the seroprevalence of HIV. Needless
> to say, we need to do everything within our means to prevent these
> infections.
>
> Finally, the investigators, the company and, most importantly, the
> patient should be commended for undertaking this trial. I am currently
> trying to do similar prevention trials for HIV. It is extremely
> difficult to get patients to participate in transmission studies.
> Identifying discordant couples and getting them to agree to
> participate in a placebo-controlled trial is a challenge. People are
> uncomfortable acknowledging that their relationship has placed them at
> risk of acquiring a sexually transmitted disease. Many people, while
> being aware of the risk on a certain level, have a hard time
> acknowledging it by actually participating in a trial. Other patients,
> when hearing the rationale for the study, decide to just start taking
> the medication. Why risk getting randomized to a placebo? All these
> challenges were met and overcome by perseverance, innovative
> recruitment strategies and dedicated participants. They should be
> commended for conducting such a challenging study.
>
> So, today you have the opportunity to do something to empower patients
> and clinicians to help control this epidemic. You have the ability to
> empower people, especially women, to take control of their sexual
> health, and you have the ability to approve a medication that is both
> safe and effective for the prevention of transmission of herpes
> infections. All the decisions in your life should be this clear!
>
> DR. GULICK: Thank you, Dr. Davis. Nest is Dr. Hunter Handsfield from
> the University of Washington.
>
> DR. HANDSFIELD: Thank you. I put my name in as a place holder in case
> there were issues that came up that I thought were particularly
> important that didn\'t arise, and that hasn\'t happened.
>
> In the interest of disclosure, I will say that as a public health
> official responsible for a large HSV control program, I support the
> application on both clinical and public health grounds, and I think it
> is also fair to point out that Dr. Haverkos and others at the agency
> were aware of that support when they invited me to speak this morning.
> Thank you.
>
> DR. GULICK: Thank you, Dr. Handsfield. The fourth person to sign up is
> Mark Wasserman, who is the co-leader of HELP of Washington. He is
> unable to be here today but has a written statement that was made
> available to members of the committee and it is at the registration
> table as well. It is not very long, perhaps I will just read through
> it briefly:
>
> Subject: Submission for FDA hearing on Valtrex supplemental new drug
> application. This letter for consideration by the FDA advisory
> committee is to support the GSK application for Valtrex suppressive
> therapy to reduce the risk of transmission of genital herpes.
>
> For the past 20 years, I have been a member and leader of the
> Washington area herpes support group, HELP of Washington. In that
> capacity, I have heard the personal stories of thousands of people
> with herpes who have participated in our meetings.
>
> It may be difficult for someone without herpes to grasp the shock,
> anger, depression, fear and loneliness that a person with the virus
> may well experience. One of the most often stated sources of this
> emotional anguish is the fear of spreading the disease to a sexual
> partner during the most intimate act of human nature. Even after
> people with herpes have overcome the initial emotional distress that
> accompanies a diagnosis of herpes, many continue to have difficulty
> carrying on a normal social life because of this fear of transmission.
>
> Fortunately, the new research showing that daily use of Valtrex
> significantly reduces the risk of transmission has given hope and
> encouragement to our members. For many, this information has helped
> them better deal with emotional problems of living, dating, telling
> and loving with herpes. For many uninfected partners of our members,
> the new has meant that they too can more easily accept having intimate
> relations with someone with herpes.
>
> It is important that the results of this research reach a much wider
> audience of people with herpes and their medical practitioners. FDA
> approval of the supplemental new drug application would help achieve
> that goal.
>
> Finally, from a public health medical perspective, it is important to
> curtail the spread of herpes. The new research shows that Valtrex
> helps achieve that goal. Both in the interest of reducing the spread
> of this disease and reducing the debilitating emotional distress that
> often accompanies the disease, HELP of Washington strongly urges the
> cm to approve the supplemental new drug application for Valtrex. It is
> signed Mark Wasserman.
>
> Our last person to sign up to speak at the open public hearing is
> Curtis Phinney, also from HELP of Washington. I hope that you weren\'t
> planning to read the letter that I just read.
>
> MR. PHINNEY: No, Mark had the easy part. My name is Curtis Phinney and
> I am a consumer advocate for people with viral STIs other than AIDS
> and HIV, loosely under the auspices of HELP of Washington, DC.
>
> I am currently speaking on an ad hoc basis at the Johns Hopkins
> University, Bloomberg School of Public Health in a nursing
> preceptorship program there, administered under the auspices of Keith
> Aimmerman and Dr. Ann Rampalo.
>
> When I speak to people outside of the consumer group I always like to
> say that I have five things that are important about genital herpes.
> That is, genital herpes is chronic, contagious, preventable,
> treatable, and I think perhaps most importantly very serious. I think
> that there are two things that are relevant to the committee here this
> afternoon that may not be intuitive to people outside of the consumer
> population, and one of those has been touched on already, and that is
> one of the primary concerns of newly diagnosed consumers, people who
> join the club, if you will, is the risk of transmission to an
> uninfected partner. This causes a tremendous amount of psychosocial
> morbidity associated with the condition, not only the possibility of
> infecting a current partner, but also adding to the complexity of
> attracting and retaining new partners.
>
> The other thing that I think has been touched on earlier is that there
> has been very little available, other than counseling, in terms of
> direct chemotherapy intervention for people with herpes that will aid
> in the dynamics of disclosure. People are not open and honest about
> having this condition. I came to the realization a decade ago that
> dishonesty and denial were important factors in the transmission of
> this condition. That is one of the reasons that I chose to break my
> anonymity with regard to my serostatus. It is my opinion that being
> able to offer people with this condition a tool that will prevent or
> reduce the possibility of transmission to an uninfected partner could
> have a profound positive influence on the dynamics of disclosure and
> help not only to dispel the stigma but to also give people a toe-hold
> in initiating an extremely difficult conversation, laying themselves
> vulnerable to somebody that they are nervous in the presence of
> anyway, and being able to say that this treatment will reduce the
> possibility of getting involved with me having a negative influence on
> your health.
>
> Finally, I would just like to close, I have a short paper out in the
> lobby on the impact of prophylactic treatments for people with HSV and
> HPV, and also contact information is included in that package as well.
> That is really all I have this afternoon. Thanks very much.
>
> DR. GULICK: Thank you. That concludes the people that signed up to
> speak at the open public hearing. Is there anyone else who did not
> sign up who would like to make a statement at this time?
>
> \[No response\]
>
> Then we will close the open public part of this meeting, which brings
> us to lunch. It is 12:20. We will reconvene at 1:15.
>
> \[Whereupon, at 12:20 p.m., the proceedings were recessed for lunch to
> reconvene at 1:15 p.m.\]
>
> \- - -
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> DR. GULICK: We will reconvene. Welcome back from lunch. Just a
> reminder both for the committee and people observing, there are the
> surveys about conflict of interest, if you could complete them and
> either mail them back in, or there is a box at the registration desk,
> that would be appreciated.
>
> We left one unanswered question at the end of lunch, which was posed
> by Dr. Potter about the compliance on the study. So, if we could take
> a look at those data.
>
> DR. COCCHETTO: Sure. Dr. Potter, I asked Dr. Roger Liddle to look at
> that and we want to focus initially on the information that we have on
> source partner compliance among the primary endpoints and also the
> overall acquisitions.
>
> DR. LIDDLE: Could you bring up slide E23?
>
> \[Slide\]
>
> This just shows us the compliance rates for the primary endpoints, for
> the primary infection transmissions. Obviously, more interest is on
> the Valtrex side. Three of the four transmissions on active treatment
> were in the greater than or equal to 95 percent compliance. There was
> one that was lower but it was in the 80, 85 percent range. The other
> slide that might be of interest would be E37.
>
> \[Slide\]
>
> If you are looking at overall acquisition, the same sort of
> information for all acquisitions, again, there was one patient where I
> think we actually had some missing data. If the treatment stop date is
> missing, then we sort of don\'t have the denominator to calculate the
> compliance figure. So, I think the one that shows up there is less
> than 80, a case where we had missing treatment stop date, but overall
> the compliance was pretty good among the endpoints so there is no
> strong signal there.
>
> DR. POTTER: What about overall?
>
> DR. LIDDLE: Overall? Let\'s pull up S5.
>
> \[Slide\]
>
> It is a little harder to look at this slide but I think here, if you
> look under placebo down to greater than or equal to 80 percent
> compliance, you will see 91 percent. The same figure for Valtrex is 93
> percent. The only thing sort of disturbing I guess about this slide is
> there are 40, 41 patients listed under zero with the asterisk. What
> happened here is there were patients for whom we had no stop date and,
> therefore, it is really missing so that zero really includes these
> patients for whom we didn\'t have a good compliance figure because we
> didn\'t know on what date the treatment was stopped.
>
> DR. GULICK: This information is based on pill counts? Is that correct?
>
> DR. LIDDLE: Yes, that is correct.
>
> DR. GULICK: Great, thank you. We will turn now to Dr. Birnkrant for
> the charge to the committee.
>
> **Charge to the Committee/Questions for Discussion**
>
> DR. BIRNKRANT: Well, this afternoon we are looking for a discussion by
> the committee on the interpretation of the results presented this
> morning. We are particularly interested in the relevance of the
> endpoint and the impact of the dropout rate on the trial results.
>
> In addition, we are very interested in the applicability of the data
> to other populations. We are looking for comments with regard to
> screening as well.
>
> Lastly, we are looking for the committee\'s interpretation of the data
> and the impact on public health with regard to condom use and
> abstinence during outbreaks. So, I think we can turn to the first
> question at this point.
>
> DR. GULICK: So, the first question for the committee to consider is
> does the information presented by the applicant support the use of
> valacyclovir to reduce the risk of transmission of genital herpes
> among monogamous heterosexual couples? Let\'s have some discussion
> about the information that we saw today in terms of safety and
> efficacy, and some other issues that people might want to raise. We
> will start with Dr. Pazin.
>
> DR. PAZIN: I am very impressed by the data that was presented this
> morning and that we had previously been given. I think it is a very,
> very well done study. There are a couple of comments I would like to
> make. For instance, Dr. Smith sort of alluded strongly to the people
> that are dropouts and I think for anyone who has ever done one of
> these studies with genital herpes a 20 percent dropout from 1,400
> couples is actually a pretty small dropout. I am not troubled by that
> at all.
>
> I am a little bothered by the data about Australia and Canada. It was
> so swayed towards the efficacy of valacyclovir that you can\'t help
> but wonder what if that group had not been included, would the numbers
> still be statistically significant? They wouldn\'t be as significant
> as they are, clearly.
>
> The second comment I want to make is that I have always been impressed
> by the scientific validity of many of these studies sponsored by
> industry basically, and I think this is another good example. It is a
> very, very well done study and I think perhaps the collaboration with
> the FDA helped that along. I am not as equally impressed by the
> marketing people from companies and I think I would caution them that
> everything I got said that it reduces transmission and I think that
> that is pretty well borne out. I think they like to use the words
> prevents transmission and I think that is a term that often conveys
> 100 percent or effective in preventing transmission. When you say
> effective, it sounds like it is 100 percent. I would say that the
> committee ought to caution the company to say that it is partially
> effective or partially preventive or, as they have said in the
> materials we have gotten, that it reduces transmission.
>
> The third comment I would like to comment on is something I just found
> out yesterday. I happen to stop by our pharmacy and I inquired as to
> the cost of acyclovir and the cost of valacyclovir. It turns out, in
> our hospital, acyclovir 200 mg is five cents; 800 mg is 20 cents. That
> is the daily cost. But 450 mg of valacyclovir is \$17.25, 86 times as
> much. I think the optimism that I heard about the utility of this, if
> you really get down to it, an ordinary poor person is not going to be
> able to afford this drug and I think that we should somehow\--if they
> are going to have this indication, we should somehow try to suggest
> that perhaps the cost is a consideration. I deal with patients.
> Formerly I was primarily a research doctor but now I deal with
> patients and cost is a very, very important thing. So, I just wanted
> to make those comments regarding the studies.
>
> DR. GULICK: Thanks. Other comments? Dr. Sherman?
>
> DR. SHERMAN: I am curious if the sponsor has any sort of cost-benefit
> analysis information. During lunch I was kind of jotting down numbers
> and calculations on the back of a piece of paper, looking at the
> number needed to treat for effect. Obviously, with a transmission rate
> that is in the two to three percent range, reduced to a half percent
> range, you have to treat for extended periods of time many patients to
> get that benefit. You know, I freely admit that there is a large
> number of patients infected but when I looked also at the numbers
> related to cost of the product as listed, current retail cost, you
> know, again just back of pad calculations came out to some place
> between \$110,000 and \$120,000 per case prevented, which goes beyond
> the typical accepted numbers that people use in prevention
> programs\--in evaluation of vaccines, in other interventional
> procedures.
>
> So, I am not questioning the data related to the efficacy of the
> treatment. I think that the sponsor did a great study on a difficult
> population and has presented and satisfied my concerns about efficacy
> and safety. But I think that at some place in this equation has to be
> the answer to the question that I am posing.
>
> DR. GULICK: Would the sponsor like to respond? Is there any
> cost-benefit analysis data?
>
> DR. COCCHETTO: A couple of comments. Part of the response lies in the
> patient population that was selected for the trial, as I am sure you
> recognize. We selected a patient population who were candidates for
> suppressive therapy. Let me ask Dr. Young to comment further from a
> cost-benefit perspective and your comments on numbers needed to treat.
>
> DR. YOUNG: Just to pick up on Dr. Cocchetto\'s comment, I mean, the
> way that we have actually approached this is to think of it in terms
> of an incremental benefit for prevention of transmission, in addition
> to the benefit that is already afforded to the person who is actually
> receiving suppressive therapy. So, when we think about the number
> needed to treat in that circumstance, it is probably on the order of
> one or less than one. Certainly what you do see is a reduction in the
> frequency of recurrences, again, among those individuals who would be
> receiving suppressive therapy.
>
> We have thought about the number needed to treat in order to prevent a
> transmission event, and what we have come up with is an annualized
> event rate of about 40 in terms of the number needed to treat but,
> again, the way we have thought about this really has to do with
> thinking about what the incremental benefit is for someone who is
> already benefiting from suppressive therapy.
>
> DR. GULICK: Dr. Englund?
>
> DR. ENGLUND: Well, I would just like to make a comment related to
> that, particularly from the pediatric viewpoint, and that is that one
> case of neonatal herpes\--there are different estimates as to cost and
> I am not the expert on this, but a cost estimate of \$500,000 to a
> million per case survivor is certainly typical, and that is because
> the children survive. Fifty percent have prolonged, permanent
> neurologic sequelae. There is no institutionalization currently
> available. They are requiring special ed. The state is required to
> send them to school, which costs a lot of money, even though many of
> them have very limited potential for learning. So, the cost for the
> children would be really high and if any cost-benefit analysis were to
> be made, I would strongly urge that the consideration of the children
> be considered. Particularly in this small study for a small period of
> time, it appeared to me there were 18 pregnancies during an
> eight-month study period. That is a lot of potential babies. So, the
> potential benefit to prevention of transmission to women of
> childbearing age really needs to be considered when anyone is
> considering doing this. I believe the cost and other things need to be
> considered, but I don\'t want to forget the children out of this
> analysis, which is certainly not the primary endpoint of the study but
> will be a consideration for people in my clinic and other clinics when
> there are couples that want to have children.
>
> DR. GULICK: Other general comments and then I am going to try to focus
> us a little bit? Dr. Fish?
>
> DR. FISH: I think adding to that the information that we learned this
> morning in terms of the potential increased greater transmission of
> HIV, if one HIV case is not transmitted there would also be a huge
> impact there.
>
> DR. GULICK: Dr. Guinan?
>
> DR. GUINAN: I would just like to add that for HIV patients with herpes
> simplex infection this is an important consideration because probably
> their recurrences are much greater and their asymptomatic shedding is
> probably more frequent, although there is limited data. The
> possibility that an HIV-positive person will transmit HSV to a partner
> who may be negative, you know, discordant partners for both, and I
> have seen this in heterosexual couples with a much younger female
> partner and the worry is about transmission of HSV and HIV. I think
> this subpopulation, although may be small\--it is very important
> because if the partner gets HSV infection then they are at higher risk
> for getting HIV infection. You see? So, the primary prevention of HSV
> acquisition in this discordant relationship is very important. So,
> there are subpopulations where the cost effectiveness or cost-benefit
> analysis would be, I think, quite different depending on what the
> values and assumptions are.
>
> DR. GULICK: Can I ask Dr. Handsfield or Dr. Corey about information on
> HIV-infected patients in terms of numbers of recurrence of HSV and
> amount of viral shedding, just to clarify that point?
>
> DR. COREY: Well, it is very variable. Certainly CD4 count and viral
> load are factors and, as you would expect, the lower the CD4 count,
> the higher the viral load, the more shedding. I think the most
> surprising thing, however, that has occurred and in the paper that has
> been submitted from our group, is that while therapy decreases the
> frequency of genital lesions does not decrease the frequency of total
> inactivation and subclinical reactivation. So, it is and continues to
> be a problem both in the treated and untreated populations.
>
> DR. GULICK: Thank you. Dr. DeGruttola?
>
> DR. DEGRUTTOLA: I would just like to say in response to this question
> that I think that the information presented did support use of
> valacyclovir to reduce risk of transmission of genital herpes, but the
> results are still not quite as reliable as one would hope because of
> lingering issues about the high withdrawal rate. Even though I think
> the study was done under very difficult conditions and that withdrawal
> rate may be all that can be hoped for, there are still some concerns
> there as with the geographic variation. Despite those concerns, I
> would still answer in the affirmative.
>
> But given that we did see strong evidence for the effect of
> valacyclovir on viral shedding, on number of episodes and so on\--and
> this may come later, but some further research to try to understand
> transmission better might help increase the degree of certainty that
> the question truly has been answered in the affirmative.
>
> DR. GULICK: Let me just remind the committee, we will take a formal
> vote on this question at the end of this discussion. Don\'t feel like
> you need to say what your vote is going to be at this point because
> each person will get the chance to vote, but comments are welcome.
>
> Let me try to focus us a little bit. Safety, let\'s consider safety
> for a minute. We have heard some sort of general comments. Are there
> more specific comments to make about safety in terms of what we saw?
> Dr. Guinan?
>
> DR. GUINAN: I would say that it is an impressive record of safety. The
> adverse reactions are headaches for the most part. Clinically that is
> what I see. What we don\'t know is long-term but, even so\--you know,
> what if you treat someone for 20 years for example\--those data are
> not available. My suggestion on that would only be that there needs to
> be postmarketing surveillance somehow developed for long-term use of
> acyclovir and valacyclovir for trying to understand that. In other
> words, does 20 years of therapy mean that there is a larger risk, or
> are there just these rather minor effects that we see, adverse effects
> of therapy?
>
> DR. GULICK: Let me remind the committee that that is a whole separate
> question that we are going to answer about the longer-term side
> effects. Yes, Dr. Kumar?
>
> DR. KUMAR: When acyclovir is used in high doses I know it crystallizes
> and causes stones in the kidney, and please correct me if I am wrong.
> So, I was a little intrigued by the one patient that had hematuria
> that the sponsor said may have a stone. Do we have any further
> information on that patient? There was one patient with hematuria.
>
> DR. COCCHETTO: We don\'t have further information on that patient. Dr.
> Haverkos mentioned it in his case presentation and he may wish to
> comment.
>
> DR. HAVERKOS: Well, I have the narratives and I actually went back to
> try to find that narrative again last night and I couldn\'t find it,
> but it is one that we need to look at again.
>
> DR. GULICK: Further comments about safety? If not, let\'s turn to
> efficacy. We already considered this somewhat. Are there additional
> comments about efficacy? Dr. Washburn?
>
> DR. WASHBURN: I have a question for Dr. Smith. I too am fascinated by
> this geographic breakdown. To put it bluntly, I wonder if the
> differences in the observations in Australia versus eastern Europe are
> likely to be by chance alone.
>
> DR. SMITH: I didn\'t do a formal comparison with just Australia
> compared to eastern Europe but the overall comparison between all of
> these, I think six different regions, is statistically significant.
> You know, a p value of 0.01 is quite a bit less than 0.05 although
> they do have multiple comparison issues. You know, that is a good
> question. I don\'t know.
>
> DR. GULICK: Other comments about efficacy? Could you introduce
> yourself to the committee?
>
> DR. SOON: My name is Greg Soon, FDA. Regarding your question about
> interactions that you were asking, is the effect size different
> between different regions\--I assume that is your question. If that is
> your question, then the answer is that the p value for that was fairly
> large. I don\'t remember the exact numbers but it is somewhere about
> 0.3 or 0.5 so it is pretty large. So, really we do not have evidence
> to say the true differences are different between regions, but we do
> have evidence to say that the response rates are different among
> different regions.
>
> DR. WASHBURN: Speaking naively, it just looked like the drug worked in
> Australia and it didn\'t work in eastern Europe. What I am hearing is
> that probably wasn\'t statistically significant, that I should ignore
> that, that that is background noise. I can think of it as a Poisson
> distribution; it could have been the other way around. Is that right?
>
> DR. SMITH: Yes, that is probably correct in terms of the treatment
> differences. In terms of the evaluation though, you know, there could
> be some kind of response categorization bias or response category bias
> where they have different ways of ascertaining the endpoint in eastern
> Europe and western Europe than then do in Australia and the United
> States.
>
> DR. GULICK: Dr. DeGruttola, would you agree?
>
> DR. DEGRUTTOLA: Well, I can just comment on what the FDA statisticians
> are saying and actually just reviewing the data, because of the small
> numbers, it doesn\'t surprise me that they don\'t find an interaction
> of the treatment effect itself with geographic region, but do find
> that geographic region affects the endpoint rate. So, the analysis
> that the FDA has reported on seems to me to jive with what I would
> expect from looking at the numbers.
>
> DR. GULICK: Dr. Fletcher?
>
> DR. FLETCHER: My question is for the sponsor on the efficacy issue,
> and I am wondering whether you have any information, and I realize how
> small the sample size is, but it is to the issue of correlates with
> efficacy or with the prevention of transmission. What I am
> particularly thinking is in terms of trying to provide information to
> a physician, to patients\--again if there is a recommendation for
> approval\--that would use this. It would seem to me one dose, for
> example, is not likely to be effective so there is probably some
> duration of time on therapy before there is efficacy and I am
> wondering if you have any information on that issue.
>
> DR. COCCHETTO: I think we can help to some extent with that. Let me
> ask Dr. Wald to comment.
>
> DR. WALD: Anna Wald, from University of Washington. In our shedding
> studies it appears that the amount of virus present after initiation
> of antiviral therapy decreases in about three to four days, and then
> achieves sort of a complete low baseline in five days. The same is
> also true when you discontinue therapy. There is a slow rise over
> three to four days and then it goes back to baseline levels at five
> days.
>
> DR. GULICK: Additional points about efficacy to raise? Mr. Ebel?
>
> MR. EBEL: I wanted to comment from a patient point of view on the
> efficacy question and to put it in kind of a real-world frame of, you
> know, compared to what. Obviously, we have heard already some pretty
> compelling statements from people to the extent that wanting to
> protect a sexual partner is a major concern for people who have
> genital herpes and the risk reduction measures they have at their
> disposal now are very limited. While condoms are recommended and may
> be a good option for a lot of people, I think probably we would all
> agree there is pretty limited data on that.
>
> So, I guess from a patient point of view, it seems to me that this
> range of efficacy data we are looking at, whether it is 75 percent or
> the 50 percent seroconversion protection, would be regarded by people
> with herpes as a huge gain compared to what there is.
>
> DR. GULICK: Thanks. Dr. Mathews?
>
> DR. MATHEWS: Two points. I already mentioned the issue about potential
> misclassification in terms of the dropout rates. I would suggest that
> the agency request the analyses on frequency of sexual intercourse and
> condom use at least at the baseline time point to be sure that there
> was no differential effect in dropouts.
>
> The other thing with regard to efficacy is that while the point
> estimate of 75 percent risk reduction is clearly significant and
> consistent across even the secondary endpoints, the confidence limits
> on that point estimate are very broad. They go from 0.08 to 0.75. So,
> when you go to craft an efficacy statement in terms of what the
> prevention message is and how effective this is, somehow the
> uncertainty in that estimate has to be conveyed.
>
> DR. GULICK: Dr. Birnkrant?
>
> DR. BIRNKRANT: Building on Dr. Mathews\' statement, we would also like
> the committee to discuss the relevance of the other endpoints, namely
> the overall acquisition, because this will be important to us with
> regard to labeling of the product. So, if we could get a discussion on
> the importance of including that type of data in labeling in addition
> to the primary endpoint, which is the main focus. We would also like
> to have input on the other endpoints as well.
>
> DR. GULICK: Just to remind us all, the primary endpoint was clinical
> episodes of HSV-2, and then seroconversion was a secondary endpoint.
> Overall acquisition would sum those two together. So, what do we think
> of the choice of the primary endpoint and the other two endpoints? Dr.
> Englund?
>
> DR. ENGLUND: I personally think that the serologic or total endpoint
> is actually much more important. If I were to be asked about future
> trials, that is what I am interested in. I am saying that for several
> reasons. I think we know more now than we did perhaps back then about
> the asymptomatic shedding and the high prevalence of asymptomatic
> shedding. I, as a pediatrician, see babies born, like last week, where
> the mothers didn\'t know they had it because it was asymptomatic
> shedding. That is, in fact, very, very common. So from my viewpoint, I
> would be interested in the total. And serology, I was trying to get at
> that in my earlier question, I think serology is a very good
> reflection.
>
> Furthermore, for future studies by relying on serology it might make
> it easier to do a study. This study is heroic. This is absolutely
> heroic to have people doing as many cultures as they are doing. I
> think if it were a simpler study design perhaps, maybe not, you could
> get more people involved. But disease as measured by serology, for me,
> is important because I think it would really help couples know what is
> going on and it certainly would help in terms of the babies born.
>
> DR. GULICK: Other comments on endpoints? Dr. Guinan?
>
> DR. GUINAN: Yes, I agree with Dr. Englund. I think that there is a
> great deal of asymptomatic infection, not only asymptomatic shedding
> but asymptomatic transmission in which the partner does not have any
> clinical symptoms or signs. So, this is a very important aspect of the
> epidemiology. It is not terribly important from a clinical point of
> view of treating people because they don\'t know they have it so it is
> sort of our of the clinician\'s purview. But I think if we looked at
> it epidemiologically and were interested in prevention or reducing
> transmission, that is a more logical and more accurate endpoint about
> reducing transmission.
>
> DR. GULICK: Dr. Fish?
>
> DR. FISH: Yes, I think I would agree with those comments. When I was
> first reading through the briefing document that was the question that
> came into my mind, why wouldn\'t we want to know about overall
> acquisition and knowing that there is the risk for shedding and
> increased risk for potential transmission? It does, however, diminish
> the apparent treatment effect when you look at a study that only would
> have serology-based data based on the data that was presented here
> today.
>
> DR. GULICK: The last special issue to consider with the question from
> Dr. Birnkrant is the dropout rate. We have talked a little bit about
> this already. Are there additional comments to make about the dropout
> rate versus the endpoint rate? Dr. Washburn?
>
> DR. WASHBURN: Just a quickie, I would assume that they would be
> equally distributed through the two arms of the study so they didn\'t
> bother me.
>
> DR. GULICK: Well, let me try to sum up what we have said. Consensus of
> the committee is that we found the efficacy and safety data impressive
> and the study well done. We found that the drug reduces transmission
> but would caution not to use the word prevent. It also has some side
> benefits about reducing HIV transmission and reducing shedding; the
> repercussions of the social aspects of this in terms of reducing
> anxiety among infected people in terms of transmitting to their
> partners.
>
> We did have some cautions. One was Dr. Mathews\' point about the wide
> confidence interval around the point estimate that we saw in terms of
> the data. The choice of endpoints generated some recent discussion.
> People felt that perhaps a serologic endpoint or overall capturing
> both clinical and serological endpoints was actually preferred or
> would be preferred in future studies. This may be more logical, in the
> words of Dr. Guinan. We certainly appreciate more asymptomatic
> shedding and transmission and this could be an easier endpoint to
> assess. That was Dr. Englund\'s comment on future studies.
>
> Other concerns that came up in our discussion are the low number of
> endpoints compared to the number of patients treated. We spoke of the
> high dropout rates that were observed, although some people were less
> concerned than others in terms of the overall effects on the primary
> endpoint. Dr. Mathews cautioned us about differential effects among
> the dropout populations.
>
> There are lingering concerns about geographic differences and why
> those occurred and how to explain that; some concerns about the
> demographics of the population studied. We mentioned earlier
> today\--Dr. Kumar brought out the point that 90 percent of the
> population studied were white and I think the committee felt that we
> would liked to have seen more information in other groups as well. We
> heard some caution about the duration of therapy. We are going to have
> another opportunity to discuss that in terms of long-term safety.
>
> Then, another issue that we don\'t often discuss as a committee is
> cost of medication but that was raised early, and the cost-benefit
> analysis and how does this compare with other interventions that we
> use, although several cautions about what is the relative cost of
> preventing an HIV infection or preventing complications, for instance,
> in the pediatric group. So, that remains an open question but one that
> generated some interest among the committee.
>
> With that, we are going to take a formal vote and read the question
> one more time: Does the information presented by the applicant support
> the use of valacyclovir to reduce the risk of transmission of genital
> herpes among monogamous heterosexual couples? So, a vote \"yes\" would
> be for approval and a vote \"no\" would be against approval. Mr. Ebel
> and Dr. Stone, you are not eligible to vote so I am going to go around
> the table and ask people to vote yes or no, and start with you, Dr.
> Potter.
>
> DR. POTTER: Yes.
>
> DR. GULICK: Dr. Guinan? Turn your mike on.
>
> DR. GUINAN: Yes.
>
> DR. GULICK: Dr. Pazin?
>
> DR. PAZIN: Yes.
>
> DR. GULICK: Dr. Fish?
>
> DR. FISH: Yes.
>
> DR. GULICK: Dr. Washburn?
>
> DR. WASHBURN: Yes.
>
> DR. GULICK: Dr. Mathews?
>
> DR. MATHEWS: Yes.
>
> DR. GULICK: Dr. Fletcher?
>
> DR. FLETCHER: Yes.
>
> DR. GULICK: Dr. Stanley?
>
> DR. STANLEY: Yes.
>
> DR. GULICK: She is hanging in there! Dr. Kumar?
>
> DR. KUMAR: Yes.
>
> DR. GULICK: Dr. Sherman?
>
> DR. SHERMAN: Yes.
>
> DR. GULICK: Dr. Englund?
>
> DR. ENGLUND: Yes.
>
> DR. GULICK: And Dr. DeGruttola?
>
> DR. DEGRUTTOLA: Yes.
>
> DR. GULICK: And the chair votes yes. That is unanimous, 13 votes for
> \"yes\" and no votes for \"no.\" Let\'s take a five-minute break.
>
> \[Brief recess\]
>
> DR. BIRNKRANT: That was the easy part of the afternoon.
>
> DR. GULICK: I know. Thanks for reminding us. Now the working part
> comes into play. Let\'s go to question number two: Does the
> information presented by the applicant support the use of valacyclovir
> to reduce the risk of transmission of genital herpes among populations
> other than monogamous heterosexual couples? Dr. Mathews?
>
> DR. MATHEWS: Well, to get it started, the first thing I would say is
> that I don\'t see any reason to restrict it to monogamous heterosexual
> couples. I think, at least to my mind, there is no biological reason
> why that should have anything to do with the efficacy of the
> intervention.
>
> However, I don\'t think it should be an indication for
> immunocompromised heterosexual couples, whether by HIV or anything
> else, since that was an exclusion. Although it is likely to have some
> efficacy, we don\'t know anything about whether this would be the
> appropriate dose, for example, in immunocompromised populations.
>
> I also don\'t think that it should be generalized to non-heterosexual
> couples for similar reasons. We just don\'t know whether the
> intervention would have a comparable efficacy, and also the prevalence
> of HIV in men who have sex with men would likely attenuate the effect.
> So, those are my opinions.
>
> DR. GULICK: Other thoughts? Dr. Potter?
>
> DR. POTTER: Just a very brief one, the more different kinds of methods
> you are using to prevent transmission, the better. In other words,
> this and condoms, although condoms are not used very much, literally
> because of compliance issues, the more the better.
>
> DR. GULICK: Dr. Guinan?
>
> DR. GUINAN: I don\'t really know very much about the quantitative
> aspects of HSV. I am just not familiar with the methodology. But it is
> clear that if valacyclovir reduces the quantity of virus shed, and in
> all infectious diseases we presume that there is a minimal infective
> dose for infection and it may vary with host factors so, from a
> theoretical point of view, in whatever population you use this there
> would be a decrease in quantity of virus and rate of shedding. So, I
> believe that that could be extrapolated to all populations. In other
> words, that the effectiveness, based on sexual orientation or whether
> you are monogamous or not, shouldn\'t be different.
>
> As far as whether the social circumstances are different, that is a
> question that I think we can\'t answer, but from an effectiveness
> point of view, I don\'t think you can argue that it is unlikely to
> decrease the quantity of virus in somebody who is not monogamous or
> who is not heterosexual.
>
> DR. GULICK: Dr. Mathews, a response?
>
> DR. MATHEWS: Well, I would agree that it is likely to have some effect
> but how could we estimate the magnitude of that effect? Is it 0.75 in
> an immunocompromised patient or a gay male who is predominantly having
> anal receptive intercourse? I mean, on what basis would you estimate
> how protective it would be?
>
> DR. GUINAN: Well, I certainly wouldn\'t estimate that but I would just
> say that from a logic point of view it would reduce it. Whether it
> would reduce it sufficiently to be protective at the same rates as it
> is in this study I don\'t know. But it would seem logical that it
> reduces the rate and magnitude of virus and the shedding. I think that
> is extrapolatable to gay\--I am not talking about immunocompromised
> but I would say a non-heterosexual, non-immunocompromised individual.
> I can\'t see any reason why this wouldn\'t be translatable.
>
> DR. GULICK: So, as a committee we have faced difficult questions like
> this before. We have seen data in one population and we have biologic
> plausibility, but we have no data in other populations and how do we
> translate that into what goes into the label? How do others feel about
> that? Dr. Sherman?
>
> DR. SHERMAN: I think that, as has perhaps already been said, we can
> translate this into heterosexual immunocompetent couples but not
> beyond that. The monogamous was a mechanism to do the study
> appropriately so that certainly should not be an issue in the
> equation. Everything else follows right after that in terms of people
> who are immunocompetent and have heterosexual contact.
>
> DR. GULICK: Dr. Kumar?
>
> DR. KUMAR: From everything that I have looked at in the data, I think
> this data is applicable only to heterosexual immunocompetent couples.
> I think to make the leap of faith, even though biologically it may
> make sense, especially with the issues we spoke earlier about, it is
> efficacious but not the effective method of decreasing transmission. I
> would be very uncomfortable to make that leap of faith to anything
> other than immunocompetent heterosexual couples, especially when it
> comes to immunocompromised HIV patients.
>
> DR. GULICK: Dr. Pazin?
>
> DR. PAZIN: I would just agree with that. I think immunocompetent
> heterosexual is probably as far as you can go on this study data.
>
> DR. GULICK: Any other thoughts on this or disagreement?
>
> DR. GUINAN: Yes, I disagree that you couldn\'t in an immunocompetent
> non-heterosexual\--I don\'t see that the data on shedding of virus and
> of reduction in quantity of virus\--there is no biologic known
> difference between non-heterosexuals and heterosexuals in handling
> infections if they are immunocompetent. So, I would disagree that this
> should be limited to immunocompetent heterosexual. I think that
> immunocompetent non-heterosexuals would also\--it would apply also. I
> can\'t find a logical reason why it wouldn\'t.
>
> DR. GULICK: Dr. Sherman?
>
> DR. SHERMAN: I wonder if any of the expert members on the sponsor\'s
> team have an answer to this, but I suspect that immunosuppressed
> patients have higher titers and for a given level of reduction there
> is probably some threshold level that you see a significant reduction
> in risk of transmission below that point. If that is the case, and it
> is the case with many other viruses, if we see an average, just to
> throw out a number, of a half log decline in virus and you start two
> logs higher you may have absolutely no apparent effect in transmission
> for this particular virus. I think that that would really need to be
> tested.
>
> DR. GULICK: Dr. Birnkrant?
>
> DR. BIRNKRANT: Could we also get comments on use in adolescents and
> how do we deal with the susceptible partner not being monogamous?
>
> DR. GULICK: Let\'s take adolescents first. Dr. Englund?
>
> DR. ENGLUND: Well, adolescents don\'t use condoms. We try and try and
> try and they don\'t use condoms even when they are HIV-infected and
> they know it. They don\'t tell their partners frequently and they
> don\'t use condoms. I think this HSV approach might be another way to
> try and get them up to speed to acknowledge that there is a problem.
> There is certainly double seropositivity in these and I think for my
> patients and my clinic that this will be a good approach. Not that we
> are ever going to tell them to stop using condoms; we don\'t want them
> pregnant, but they are getting pregnant every day too. So, they
> obviously aren\'t using condoms even when they tell us they are using
> condoms, which they do tell us but they aren\'t.
>
> So, I think that this is an important adjunct. I think that people of
> childbearing age range are where this drug could be focused from a
> public health point of view because of the multiple sequelae\--HIV,
> the childbearing. And, I see no problem with having this part of an
> adolescent clinic. We start usually around 11 or 12 years for this
> kind of thing. We don\'t know long-term effects. I would encourage
> that we need to have long-term efficacy and safety but I think it fits
> right in with what we are doing and gives us yet another reason to
> talk with them every month, which is what we are doing.
>
> DR. GULICK: Other comments about adolescents? The other population
> was?
>
> DR. BIRNKRANT: When the susceptible partner is not monogamous. Is that
> an issue for any of the members on the committee?
>
> DR. GULICK: Given our previous discussion about monogamous couples, I
> am guessing not.
>
> DR. BIRNKRANT: Okay. And what about Dr. Stone, being from the CDC, do
> you have any additional comments on this question?
>
> DR. STONE: I think I agree that immunocompetent heterosexual
> populations could be included. I have some reservations about men who
> have sex with men. I would have no problem including adolescents.
>
> DR. GULICK: Dr. Pazin?
>
> DR. PAZIN: This thought that a susceptible partner\--it is irrelevant.
> Obviously, it is not going to provide protection for other people who
> aren\'t using the medication. So, that just goes without saying as far
> as I can see.
>
> DR. GULICK: So, let me summarize what we said about populations. First
> of all, a reminder to us that education about herpes and transmission
> and the overall thought that there are other methods of avoiding
> transmission, including condoms, continues to be important. What is
> recognized here is biological plausibility of an antiviral agent to
> reduce the amount of virus. Then, some differences of opinion about
> how much one can extrapolate to other populations because of
> differences in the amount of virus and how much it may or may not go
> down; the differences in effect from population to population and the
> magnitude of response.
>
> As Dr. Sherman pointed out, monogamous was really a requirement for
> this particular trial and allowed the study to be done but, as many
> have echoed, it is not an important criterion for achieving benefits
> in immunocompetent heterosexual couples. That is the best data we have
> that we have seen today.
>
> There was more concern in homosexual couples, although not uniform
> opinion on whether one can extrapolate data from heterosexual to
> homosexual couples, and simply no data to guide us at all.
>
> There was endorsement among adolescents for the same reason that
> adults would benefit, and perhaps even more of an endorsement in
> adolescents given problems with condom use and opportunities to
> discuss reduction and transmission. Because adolescents are younger,
> longer-term data is going to be even more important in this group
> perhaps.
>
> Then, a consensus that it is probably not appropriate to extrapolate
> to the immunocompromised host because of concerns that viral burden
> may be higher in this population and that, again, we simply don\'t
> have the data to make those recommendations.
>
> We suggested some longer-term studies in the course of our
> conversation here. Dr. Sherman earlier said that transmission studies
> would be of interest, and perhaps relating the amount of HSV or the
> HSV titer to transmission is something that we could know about more.
>
> I guess we would like to see studies in immunocompromised groups. We
> would like to see studies in gay men and women. Again, the longer-term
> safety issues were something that is of paramount importance. Dr.
> Mathews?
>
> DR. MATHEWS: One implication I think of what we have recommended is
> that the label should I think somewhere contain a recommendation that
> people be encouraged to have HIV testing before this decision is made
> to prescribe this. I mean, the same population should have been HIV
> tested anyway, I would think, especially if they are not monogamous.
> We should find a way to put that in there.
>
> DR. GULICK: Just to remind us from the sponsor point of view, in this
> study everyone received HIV testing and that was an exclusion
> criterion? Is that correct?
>
> DR. HARDING: There was no HIV testing. They were excluded if they had
> a history of HIV. We also went through the case records after the
> study had completed to look for any indication of HIV and there was
> none, nor were there any medications used for HIV.
>
> DR. GULICK: So, by history HIV was an exclusion but serologic testing
> was not performed on the study?
>
> DR. HARDING: Right.
>
> DR. GULICK: Thanks for that correction. Dr. Fletcher?
>
> DR. FLETCHER: On your list I think you would want studies in
> adolescents as well. I am not saying, you know, a thousand patients.
> In this study it only went down to 18 years of age and while I don\'t
> think that the pharmacokinetics of valacyclovir are going to be
> different in adolescents, without data\--you know, there are always
> surprises out there. So, I think if you are going to make that
> extrapolation to adolescents there needs to be some basis to do that.
> At least from the most simple point of views, a pharmacokinetic study
> of valacyclovir in adolescents would be one way to understand whether
> the concentrations at a 500 mg once daily dose are going to be
> equivalent to those seen in adults.
>
> DR. GULICK: Does the sponsor have data on PK in adolescents with
> valacyclovir?
>
> DR. COCCHETTO: I am looking to Dr. Weller here. Steve? Stephen Weller
> is in our clinical pharmacology group and he can comment.
>
> DR. WELLER: We don\'t have specific pharmacokinetic data in
> adolescents per se since studies have been done in younger children,
> much younger children with acyclovir, historically. Children as young
> as 12, 13 years of age have been included in some of the Phase III
> trials for some of the indications but, again, specifically as
> pharmacokinetic data in adolescents, we don\'t have that at present.
>
> DR. GULICK: Dr. Pazin?
>
> DR. PAZIN: Yes, I was thinking it would be interesting to get the
> committee to vote on the concept of whether we think it should be
> extendable to homosexual couples.
>
> DR. GULICK: Okay, a non-binding kind of straw vote.
>
> DR. PAZIN: Sense of the committee.
>
> DR. GULICK: Let\'s just do it\--
>
> DR. GUINAN: Immunocompetent.
>
> DR. PAZIN: Immunocompetent homosexual partners. Do you think it should
> be extended to them or not?
>
> DR. GULICK: In other words, extrapolated on the basis of labeling,
> whether we would recommend that for labeling or not. Dr. Handsfield,
> did you want to make a comment?
>
> DR. HANDSFIELD: I would just point out that in that discussion what
> has not been raised by any of you is differences in sexual practices
> in particular because it is conceivable that at a biological level it
> is not just viral load, but what is the level of the kind of exposure
> that takes place, for example, during anal intercourse as opposed to
> vaginal intercourse and potential microscopic or overt trauma that
> might affect transmission rates. So, in thinking about that vote I
> would be inclined to factor that into your thinking.
>
> DR. GULICK: Dr. Guinan?
>
> DR. GUINAN: Well, in the study was it determined what types of sexual
> intercourse these monogamous couples had? Was it restricted to
> vaginal-penile intercourse?
>
> DR. GULICK: Unlikely to be restricted\--
>
> \[Laughter\]
>
> DR. GUINAN: What I am saying is that it is very possible that there
> was rectal intercourse among these couples.
>
> DR. GULICK: Does the sponsor have any information on what kind of
> intercourse occurred on the study?
>
> DR. HARDING: There was no restriction on anal intercourse. There was
> some but it was a very small number. We do have the numbers if you
> require them, but I can\'t recall them off the top of my head. The
> median was zero obviously.
>
> DR. KUMAR: I think your page 44, table 8, would that not give us
> information we are looking for?
>
> DR. LIDDLE: I think it looks like eight percent according to the diary
> data.
>
> DR. GULICK: Again just to clarify, the way that this was assessed was
> by patient diary? Is that how it was? So, people were expected to jot
> down what was going on over the last 24 hours in their diary?
>
> DR. COCCHETTO: That is correct. Susceptible partners maintained a
> diary that was returned with each monthly clinic.
>
> DR. GULICK: Additional comments about extrapolating to the homosexual
> immunocompetent population before we take a straw vote? Dr. Mathews?
>
> DR. MATHEWS: I just one to make one last comment about this. I don\'t
> think it is a matter of whether it is a good idea or is biologically
> plausible. It is a matter of is the evidence sufficient that it should
> go into a label and my opinion is definitely not. It should be studied
> and there should be the same kind of evidence for the MSM population,
> for the reasons that have been stated previously as well as what Dr.
> Handsfield just said.
>
> DR. GULICK: Dr. Corey, do you want to chime in?
>
> DR. COREY: I think everybody is right\--
>
> \[Laughter\]
>
> \--but I would say that there has not been a partners study published
> in the HIV literature, and certainly not in the herpes literature that
> I am aware of, that has been successful in looking at transmission
> among gay men solely, monogamous gay. So, the study design, and we
> have thought about this, we don\'t think is a possible study design to
> get enough monogamous gay men. So, you would have to think of a more
> unique design or that could be done in a unique population-based
> basis, or something. But it would certainly be a very unique study
> design as far as I am aware of in the field of STDs.
>
> DR. GULICK: Just to be clear, did you say that previous studies have
> been attempted or designed and were unsuccessful in enrolling?
> Discordant gay couples, those studies have been largely difficult to
> perform is what you are saying. Other comments? Dr. Fish?
>
> DR. FISH: I think that said, I would agree with Dr. Mathews that I am
> not sure how we would extrapolate to this patient population. It is a
> large leap of faith and whether the study can or can\'t be done, it
> seems to me like the labeling would better address the information
> that we have, letting people decide based on the information that is
> there and the data that is available, people being practitioners.
>
> DR. GULICK: Dr. Guinan?
>
> DR. GUINAN: I would just like to say I have worked for the CDC for a
> long time and was in charge at one time of developing the STD
> treatment guidelines, and all that was done on scientific studies, it
> was not until very recently that sexual orientation ever entered into
> the discussion. In other words, you didn\'t know what the sexual
> orientation of the patient was. It was whether it was effective or not
> effective. Do you see what I mean? So, it is very difficult for me to
> now differentiate those and say, okay, this is good for heterosexuals
> and to make a recommendation, for example, if CDC were incorporating
> these into the treatment guidelines, to say, oh, this is good for
> heterosexuals but we don\'t recommend it for homosexuals, or there is
> no data on homosexuals. Do you see what I mean? So, I understand
> everybody\'s concerns but to think that there are biological
> differences in the way people process these drugs because of sexual
> orientation, to me, is not plausible.
>
> DR. GULICK: Dr. Stone, could you comment on implications for
> guidelines?
>
> DR. STONE: Let me also just say as regards the applicability of this
> to gay people, I think our concerns were more specifically for
> MSM\--not all MSM but not just HIV co-infection but just the general
> sexual practices may be very different.
>
> This study population did have anal intercourse but it may be with a
> different frequency than men who have sex with men. But when the time
> comes for us to, you know, update our treatment guidelines we
> would\--I can\'t tell you now what we would do but in each section of
> our guidelines we have a special section on special populations and we
> specifically comment on HIV-infected persons. To my knowledge, we
> don\'t have anything in here about homosexual versus heterosexual
> patients or partners.
>
> Another approach would be to speak of vaginal intercourse versus anal
> intercourse and you could get away from the sexual orientation label.
>
> The other thing about this study, if you were really restricting the
> applicability, then it would be applicable almost to very few people
> because if you look at the frequency of sex in this group, they really
> were not very sexually active but I don\'t think anyone here wants to
> limit the indication for people who have sex six times a month.
>
> \[Laughter\]
>
> So, I think it is a fine line between, you know, generalizing too
> broadly and being too narrow.
>
> DR. GULICK: Any Australians in the crowd?
>
> \[Laughter\]
>
> Dr. Englund?
>
> DR. ENGLUND: I just wanted to say that it was actually the women
> though who drove the study or the vaginal intercourse. That is, before
> the study the investigators knew that. That is why the study tried to
> be stratified, ultimately unsuccessfully. When you look at page 56 and
> the table, it is 7.5 percent of the women in the placebo group and
> only 1.0 percent of the men. So, it is the women, in fact, that may
> have benefited the most, which is good news for women, but to be able
> to translate that into men only and then men having sex with men in
> addition, that is making two leaps of faith instead of just one. So,
> even though I think biologically it might be the same, I think the
> practices vary and I think we, as the advisory group, need to take
> that into account.
>
> DR. GULICK: Dr. Smith?
>
> DR. SMITH: As I recall, there was no treatment by gender interaction
> so the treatment effects in men were basically similar to the
> treatment effects in women. It is just that both treatment groups had
> a lot of fewer events. So, I would say that the results probably are
> generalizable to men among heterosexual monogamous couples.
>
> DR. GULICK: Then, if we take anatomy as the likely explanation for
> differences in transmission, receptive anal intercourse may be more
> analogous perhaps to men having an increased risk to transmit to
> women, although we don\'t know. Lots of leaps of faith here. Dr.
> Smith?
>
> DR. SMITH: There is only the median of zero. You know, the number of
> anal sexual contacts is zero for the overall population. So, it is
> almost all non-anal sex in the study.
>
> DR. GULICK: So, we have heard a lot of differences of opinion and this
> is kind of a non-binding vote but might be of interest to the agency
> if pin people down. So, let\'s just raise our hands and Mr. Ebel and
> Dr. Stone, we will invite you to vote in this one too since it is just
> an opinion thing. So, a vote for \"yes\" is that we would not
> recommend restricting the label on the basis of heterosexual versus
> homosexual. In other words, that would simply not be in the label. Is
> that phrased okay?
>
> Let me try this again. You would support the use of valacyclovir to
> reduce the risk of transmission of genital herpes, period. No caveats
> about monogamous and no caveats about heterosexual.
>
> DR. PAZIN: Is that the question?
>
> DR. GULICK: I thought it was the question.
>
> DR. PAZIN: I don\'t think you are stating it very clearly. I want to
> make a distinction between heterosexual couples and homosexual
> couples. I think that is what the discussion has been talking about.
>
> DR. GULICK: That is what I was trying to do. I am just taking the
> question and eliminating the last part. The question to the committee,
> and this is a straw vote, is does the information support the use of
> valacyclovir to reduce the risk of transmission in genital herpes,
> period? Or, if you like, in both homosexual and heterosexual couples.
> Is that clear? All in favor of including that sentiment in the label,
> raise your hand.
>
> \[Show of hands\]
>
> Two votes. All opposed?
>
> \[Show of hands\]
>
> So, you get the idea. It is a straw vote.
>
> MR. EBEL: Mr. Chairman?
>
> DR. GULICK: Yes?
>
> MR. EBEL: To me, I would just like to reiterate the confusion about
> calling the question. Are you going to follow-up now with a more
> exclusive definition of extending it, in other words, dropping the
> monogamous part but keeping the heterosexual part?
>
> DR. GULICK: Our purpose today is just to provide some discussion about
> considerations for the label for the FDA and the sponsor to go forward
> with in further discussion. We don\'t have to sort of hammer out the
> terms of the label itself. We have already voted to say that we would
> recommend approval of the drug. At this point, all of the other
> questions really speak to the fact about what should go into the
> label. So, I don\'t think we have to get into the nitty-gritty of
> exact wording for the label. It is helpful I think for the
> agency\--correct me if I am wrong\--to hear that there are differences
> of opinion on the committee. We were pretty uniform about not
> including monogamous and then there was a difference of opinion about
> stipulating heterosexual versus not. But I think we can probably leave
> it at that and keep going.
>
> MR. EBEL: I was just concerned that the monogamous piece was getting
> lumped in with the sexual orientation piece.
>
> DR. GULICK: No, I think we have separated those two issues.
>
> MR. EBEL: Thank you.
>
> DR. GULICK: Let\'s go on to the next question. In study 3009 over
> 4,000 couples were screened but only about 1,500 were enrolled. A
> large number of couples were excluded because susceptible partners
> were found to be HSV-2 positive without clinical symptoms. Please
> discuss the implications of screening susceptible partners for HSV
> prior to initiating therapy of the source partner with valacyclovir.
> Again, this is thinking about the label. Dr. Mathews?
>
> DR MATHEWS: Well, here the scenario changes quite a bit when you
> broaden the indication to non-monogamous couples because really the
> treatment in that setting is not a matter of a discussion between a
> source and a specific susceptible. It really is almost assuming that
> the source might have sexual contact with more than one or many
> people, in which case the education I think becomes very important for
> the clinician prescribing or contemplating prescribing the drug to
> talk with the patient about, you know, are you sexually active now, or
> are you going to be, are you going to discuss your serostatus with
> your partners. The question is, if they are casual partners, it is not
> really feasible to recommend, oh you know, you should go out and get
> tested before you have sex, if you are going to have sex on a casual
> basis.
>
> I am just thinking now. In the context of an established relationship
> it might be reasonable to recommend testing the partner. But if it is
> not a monogamous relationship I wouldn\'t necessarily put that in.
>
> DR. GULICK: Other thoughts on this? Dr. Kumar?
>
> DR. KUMAR: I am looking at this a little bit differently. If the
> susceptible partner is positive, then there is no reason for the
> source person to take the drug. Why would they have to take it for a
> prolonged period of time if the benefit is not going to be there?
>
> DR. MATHEWS: But they might have another indication for taking it to
> suppress their own reactivations, which is already an approved
> indication.
>
> DR. KUMAR: That is different but right now we are looking really for
> this indication of preventing transmission. In that, if the
> susceptible person is already positive, then there is no reason for
> the source person to take the drug. So, I would recommend that the
> susceptible partner needs to be tested.
>
> DR. GULICK: Would you require it or consider it?
>
> DR. KUMAR: I would strongly consider it. This is not a drug that you
> are going to take for a week, two weeks or three weeks. As long as
> that person is in that relationship you are going to take it every
> day.
>
> DR. GULICK: Dr. Englund?
>
> DR. ENGLUND: I think we should strongly recommend it for this
> indication because there is a great deal of money involved; there is
> potential safety and toxicity and if they are taking it you should
> know that it is for a reason. A serologic test costs under \$50 which
> is, whatever\--three weeks of pills. It really makes sense medically,
> socially and economically.
>
> DR. GULICK: Dr. Pazin?
>
> DR. PAZIN: I fully agree that we should strongly recommend getting
> tested.
>
> DR. MATHEWS: But how would that work in the casual partner setting or
> adolescents? What does that mean?
>
> DR. PAZIN: To be using the drug as a prophylactic if it is not going
> to accomplish anything is just a waste, as far as I am concerned. I
> just think that you ought to find out. There is a substantial
> possibility that the person already is infected. They may not think so
> but there is a good chance. So, it just would be I think very
> wasteful.
>
> DR. GULICK: Dr. Wald, did you have a comment?
>
> DR. WALD: Thank you. I guess my feeling is that people should be
> tested but not necessarily in the context of considering this added
> benefit of valacyclovir therapy. We know from other studies that
> clinical history of genital herpes is not always accurate. In fact, in
> the STD treatment guidelines laboratory confirmation of all genital
> herpes cases is currently recommended. So, it is certainly recommended
> for the source partner to have laboratory documentation that they
> really do have HSV-2 infection.
>
> In terms of the susceptible partner, given the experience in this
> population and finding that a substantial proportion of people who are
> concordant, not discordant, this is a situation which actually brings
> relief to a lot of couples, that the susceptible is already infected.
> Because of that, I think that testing should be encouraged, maybe not
> even specifically with the thought of initiating suppressive therapy
> but just because of the clinical discordant status.
>
> DR. GULICK: Can I just make sure I understand this, the current
> recommendations for someone who has clinical symptoms of genital
> herpes is to undergo serologic testing?
>
> DR. WALD: It is to undergo laboratory confirmation of the diagnosis
> and which test, whether it be a viral detection test or a serologic
> test, depends on the clinical presentation.
>
> DR. GULICK: Okay, but that is for symptomatic patients.
>
> DR. WALD: That is correct.
>
> DR. GULICK: And either Dr. Wald or Dr. Stone, other populations where
> it is routinely recommended to obtain an HSV serology currently?
>
> DR. WALD: It is routinely recommended to serologically test those
> people who present for evaluation of STDs and request to be also
> evaluated for HSV.
>
> DR. GULICK: Dr. Stone?
>
> DR. STONE: Also, in the current version of the STD guidelines we say
> that serologic testing is useful for partners. We don\'t make a
> distinction between casual or regular partners. The thinking is, like
> Dr. Wald said, that the partner may already be infected and they are
> not going to get infected again so they don\'t need to worry about
> becoming infected. Also, they can benefit from counseling and learning
> to recognize symptoms and, you know, they themselves may become
> candidates for treatment. That is sort of the clearest indication for
> serologic testing in our guidelines.
>
> DR. GULICK: Other comments? Dr. Guinan?
>
> DR. GUINAN: There is a small problem with serologic testing in that it
> is type specific and if you are looking for HSV-2, then there is a
> certain percentage of genital herpes that is HSV-1. In other words, it
> is not exactly that I know this person is susceptible because they are
> HSV-2 negative because if the source has HSV-1 and the partner is
> HSV-1 positive, then that person wouldn\'t need the drug. Do you see
> what I mean? Since a certain proportion of genital herpes is type 1,
> then doing type-specific antibody to determine a susceptible if you
> use only type 2, then you will have some degree of error in
> determining susceptibility.
>
> DR. GULICK: Dr. Pazin?
>
> DR. PAZIN: It is not nearly as traumatic to get HSV-1 genital herpes
> as it is to get HSV-2 genital herpes. So, I think that is not a major
> concern.
>
> DR. GUINAN: Maybe not for you.
>
> \[Laughter\]
>
> DR. PAZIN: No, I can assure you that you can reason with those people,
> with the other ones it is more difficult.
>
> DR. GULICK: Dr. Guinan, no comment? Your gestures say it all! Other
> thoughts on the serologic question? Dr. Fish?
>
> DR. FISH: I mean, for the patient, they are not going to know whether
> they have 1 or 2 and I am not sure I can follow that argument. What
> was my other comment? Oh, a total serology\--I believe there is
> available serology that can detect both 1 and 2 so that might be a
> strategy that could be employed if the susceptible partner were going
> to be serologically tested.
>
> DR. GULICK: Dr. Guinan, can you fill us in on that?
>
> DR. GUINAN: I think I am going to say something controversial.
>
> DR. GULICK: Good!
>
> DR. GUINAN: I feel that women are disproportionately affected by this
> for lots of reasons, being more susceptible and having the poor
> outcomes of risk of transmitting this to a newborn. The male condom is
> not under the control of women and the treatment of the source, the
> male source is not under the control of women. Do you see what I mean?
> So, women are still very susceptible and what I think should be done
> is women should know their serostatus. In other words, women should
> know whether they are HSV positive or negative, especially for type 1
> infection, and then let them know that they are susceptible and their
> partners, if they have known herpes infection, should be. But this is
> what I have done and I have recommended off-label, and I am sure I
> will be put in jail some day but what I have done is to give young
> women valacyclovir who are in a relationship with someone because
> their male partner won\'t take it. So, I give it to the women to
> protect them. In other words, there is no data but it gives them
> something because they have nothing. They are madly in love and they
> can\'t resist. It is expensive and that is a big part, but the
> safety\--so from my point of view, this is something that needs to be
> addressed in some way. In other words, women are susceptible and in
> trying to prevent perinatal herpes infection you need to prevent it in
> the woman. So, women\'s knowledge of their serostatus I think is
> extremely important and trying then to give them information about
> protecting themselves against acquisition of infection.
>
> DR. GULICK: I think you are making important points. I don\'t want us
> to get too far away from where we are, which is what should be
> required in the label for valacyclovir for this indication.
>
> DR. PAZIN: Clearly that is another study if you are going to be giving
> it to prevent acquisition.
>
> DR. GUINAN: It will never be done.
>
> DR. GULICK: So, that was my point. So, interesting and provocative but
> maybe we should steer clear of it now. Dr. Kumar?
>
> DR. KUMAR: Dr. Gulick, isn\'t the indication right now to prevent
> transmission to a susceptible person? Isn\'t that the indication for
> this drug?
>
> DR. GULICK: Or to reduce transmission.
>
> DR. KUMAR: To reduce transmission. So, that is why I am so confused.
> If the susceptible person is not susceptible, then the source person
> should not be taking the drug. So, I just find this whole question
> extremely unclear because that is the indication. It says we are
> giving it to prevent or reduce transmission. So, I think the
> susceptible person should be tested.
>
> DR. GULICK: What I am hearing is consensus on this point but the
> practical world that Dr. Mathews describes is that not everyone has
> one partner that we can bring in for testing, and that is the clinical
> reality of this situation. So, I think most people around the table
> agree that serologic testing, if there is an appropriate person to
> test, would be of great benefit and might actually exclude the need
> for this drug but there are many people in the real world where you
> will not be able to apply that. So, I guess that is our feeling on
> this issue. Okay?
>
> DR. MATHEWS: Let me just give one example to make it very concrete. If
> a commercial sex worker who is HSV-2 seropositive has to require that
> their partners be tested in order to get this drug, you know it is not
> going to happen. So, I think or I would hope the sense of the
> committee is that, yes, it should be recommended to be done when it
> can be done but certainly not required, otherwise the people at
> greatest risk of transmission will not get access to the treatment.
>
> DR. GULICK: I think that sums up the consensus very well. Let\'s move
> on, question number four, in your opinion\--in your opinion,
> underlined\--will marketing of valacyclovir for reduction of genital
> herpes transmission have an impact on the use of condoms and
> abstinence from sex during clinical HSV-2 outbreaks? Dr. Fletcher?
>
> DR. FLETCHER: Well, I don\'t know is the easy answer but\--
>
> DR. GULICK: Question number five!
>
> DR. FLETCHER: You said you wanted to get out early! But I do have two
> points. I guess one has to say I hope not, and I think that goes to
> Dr. Mathews\' point about the confidence interval in the effectiveness
> in the reduction of transmission which, if my math is right, is 24
> percent to 94 percent. So, the message needs to get out very strongly
> that, you know, yes, it works but the extent to which it works is
> really uncertain.
>
> I think the second point that I want to make is that the benefit is
> not immediate. It seems from the data that Dr. Wald mentioned, it
> seems that one dose really does not convey a benefit. So, being on
> therapy, staying on therapy and using additional methods to prevent
> transmission seems to be the message that needs to get out. I think,
> great, to the extent possible efforts, aggressive efforts need to be
> made to ensure that people understand that other forms of protection
> need to be taken.
>
> DR. GULICK: Dr. Sherman?
>
> DR. SHERMAN: Does the sponsor have that slide that showed\--I mean, we
> have data on this and it looked like condom use did go down. Was that
> statistically meaningful?
>
> DR. GULICK: Or was that the agency that showed it? Dr. Smith?
>
> DR. SMITH: We have that in our presentation. I think the applicant
> also showed a slide with the transmission.
>
> DR. GULICK: Could we see that again? What slide? DR. SMITH: It was
> towards the middle, right at the end of efficacy. I think it is 26.
> Well, it is actually 27 and 28.
>
> DR. HAVERKOS: Also 54.
>
> \[Slide\]
>
> Is that the one?
>
> DR. GULICK: Can you walk us through this again, please?
>
> DR. HAVERKOS: Basically, if you look at the reports of condom use in
> the month before study or baseline, remember, there are three groups,
> there is \"never,\" \"sometimes\" and \"always.\" As you see, we only
> have data on 725 of the 743 valacyclovir patients. It probably
> reflects the fact that they didn\'t actually collect some of this data
> until amendment I which was a couple of months into the study. But 32
> percent said they nearly always used condoms and 51 percent said they
> never used condoms. That is 83 percent of the total. For the other 17
> percent, there was either no data or \"sometimes.\" This was just for
> vaginal sex, 90-100 percent for \"nearly always.\"
>
> During the study itself you can actually calculate number of sex acts
> per month, and then each month you can calculate the condom use. If it
> is \"nearly always\" it is 90-100 percent. If it is zero, if they
> never used condoms for vaginal sex, anal sex or oral sex, it is never.
> Then, there is a group that gives you some data in between.
>
> Then they take a median. So, in other words, there is eight months of
> data from many patients; there is five months of data for others if
> you take the middle month, so if it is all \"nearly always\" it is
> nearly always. If it is four \"never\" and two \"sometimes\" and one
> \"nearly always\" it is never. So you can actually go back and
> calculate these numbers. So, it doesn\'t actually translate into
> 90-100 percent across the whole study. It is a unique way of
> calculating condom use. But if you look at the baseline data and the
> vaginal use data from baseline through the study, you get a slight
> drop in \"nearly always\" and you get a slight increase in \"never.\"
>
> DR. GULICK: The denominator is changing.
>
> DR. HAVERKOS: The denominators change, right.
>
> DR. GULICK: Let\'s go to the sponsor on the same point and then I will
> take a couple more comments.
>
> DR. COCCHETTO: Just a methodology caution on this. As you recognize,
> at baseline the information that is reported is the individual
> participant\'s recollection of activity from the prior month, whereas
> during the study it is actually diary card data that is being captured
> on a sexual contact by contact basis.
>
> DR. GULICK: Thank you. Dr. Potter?
>
> DR. POTTER: My one question was wasn\'t this during clinical outbreaks
> as opposed to during the full cycle?
>
> DR. GULICK: It was assessed all throughout the study.
>
> DR. POTTER: This was assessed but I meant the question. Wasn\'t it
> have an impact on the use of condoms and abstinence from sex during
> clinical outbreaks?
>
> DR. GULICK: Oh, I am sorry, you are focusing on the question here.
>
> DR. POTTER: Yes.
>
> DR. GULICK: We have been a bit too broad, although that is also
> perhaps of interest. So, we have been considering generally in terms
> of looking at this data and the concern expressed here is currently
> during a clinical HSV-2 outbreak the recommendation is to be abstinent
> from sex, and will the marketing of valacyclovir actually impact that.
> So, let\'s focus on that specific question. Thanks for that. Dr.
> Englund?
>
> DR. ENGLUND: I would just like to say that in my relatively limited by
> intense work with adolescents the answer is clearly no because they
> don\'t use condoms. They are not going to use condoms very much. We
> are trying hard, we really are but it is not going to change.
>
> DR. GULICK: Dr. Stone?
>
> DR. STONE: I would like to reiterate Dr. Englund\'s comment, common
> use is very low. Maybe I am a dreamer but actually the marketing could
> have a beneficial effect. Who knows about condoms, but the part on
> abstinence from sex when lesions are present, it could be that people
> haven\'t gotten this message that it is very important to not have sex
> when lesions are present. In a study alluded to by Dr. Corey and Dr.
> Wald, in the vaccine study, during the course of that study people
> were counseled on condom use and also to avoid having sex when lesions
> were present and they actually reported that that declines over the
> course of the study, having sex with lesions. So, the effect could be,
> you know, in a good direction.
>
> DR. GULICK: That is interesting. Dr. Guinan?
>
> DR. GUINAN: I think it is really difficult to interpret these data
> without information on birth control practices of the women because
> some people do use condoms for birth control. In fact, the most
> committed users of condoms are those that don\'t want to get pregnant
> rather than for protection from disease. If these women changed their
> contraceptive us during the study they would maybe not do condoms. Do
> you see what I mean? So, it may have nothing to do with the study but
> something to do with the contraceptive practices. So, I think you
> can\'t interpret that data that Dr. Haverkos presented without knowing
> what the other contraceptive practice was.
>
> DR. GULICK: Mr. Ebel?
>
> MR. EBEL: Yes, I would like to comment on the communications aspect of
> it because I think one of the things we know about counseling patients
> with herpes is that one of the areas where it is hardest for
> clinicians to spend time and do the counseling is precisely on impact
> on patient\'s sex life, and on risk reduction, and those kinds of
> things. I think the marketing of this and the increased awareness
> about the need for prevention and the awareness of a new intervention
> potentially could really have a positive effect in giving clinicians a
> more positive way to discuss this, in turn enabling patients to be
> more able to discuss it with their partners, and we know that that is
> a problem. So, the whole prevention thing at some point revolves
> around communication and this might help with that.
>
> DR. GULICK: Dr. Pazin?
>
> DR. PAZIN: When I look at these data, it suggest to me that these
> people put all their eggs in the pill basket. Really, when they go on
> a study, you know, if they didn\'t use condoms before they don\'t use
> them when they are on the study. Conversely, if they did use them
> almost all the time, they continue to do that. I think that it really
> doesn\'t have that much impact but I think that having the
> availability of the pill will have the impact of making them disregard
> that other possibility of using the condom.
>
> DR. GULICK: Let me try to summarize what we said here in terms of
> valacyclovir for prevention decreasing the use of condoms and
> abstinence during outbreaks. The consensus was that it could but
> recognizing that condom use tends to be low among people in general.
> We all agree I think, and would like to emphasize, that education is
> essential as part of the prescribing of this drug, putting
> valacyclovir in the context of other ways of avoiding transmission of
> HSV-2 and also recognizing the limitations based on the wide
> confidence interval once again. The fact that we are uncertain about
> the amount of benefit, that reduction is anywhere from 24-94 percent.
> Then Dr. Stone\'s point that this added education could actually be a
> benefit to tell people that active lesions are a time when they should
> be abstinent or use condoms.
>
> Let\'s go on to the next question. Number five, although patients ion
> the registrational trial were treated for eight months, valacyclovir
> for suppression of transplantation of genital herpes will likely be
> used for significantly longer periods of time. What additional studies
> would you suggest to evaluate the potential for longer-term adverse
> events, including resistance to valacyclovir?
>
> We have touched on this several times over the course of the day. I
> think it was the consensus of the committee that this is a concern of
> ours, about the long-term safety, and the fact that duration, as was
> raised earlier in the day, is really not stipulated right now in terms
> of the indication.
>
> Let\'s take that point first, duration of use here. What would we
> suggest as appropriate? Dr. Pazin?
>
> DR. PAZIN: People are going to use it as long as they are at risk. I
> don\'t think that there should be that much of a duration emphasis\--I
> think till their money runs out.
>
> \[Laughter\]
>
> DR. GULICK: Well, we heard a couple of interesting scenarios earlier
> today. Change of relationship, should that prompt a change in drug
> here? Or, what if the susceptible partner does seroconvert for HSV-2?
>
> DR. PAZIN: Then you don\'t take it anymore.
>
> DR. GULICK: There you go! Maybe this is painfully obvious here.
>
> Specific studies to look at long-term adverse events? Dr. Englund?
>
> DR. ENGLUND: I really think we need a pregnancy registration. We are
> used to using acyclovir in pregnant women. I personally don\'t know
> how much Valtrex is being used in pregnant women but I think that
> needs to be followed up because although I think there is no good data
> about immunocompetent adults ever getting resistant virus, I would be
> concerned potentially about a baby being infected with resistant
> virus, on a theoretical basis not based on what I see. I think that
> there is an obligation to follow the use of this through registration
> as opposed to a study.
>
> DR. GULICK: Does the sponsor have data on valacyclovir in pregnancy?
>
> DR. COCCHETTO: We do have some information. In concert with CDC and
> others we had a pregnancy registry that was initiated in 1984 with
> acyclovir and then subsequently expanded to include valacyclovir once
> that product was initially approved within the United States. Dr.
> Alice White is the head of our epidemiology group who collaborated
> with Dr. Stone and others on that effort. I would be happy to ask her
> to comment on that briefly if you like.
>
> DR. GULICK: Sure, that would be great.
>
> DR. WHITE: Hi, I am Dr. Alice White, vice president of the
> epidemiology department at GlaxoSmithKline. As Dr. Cocchetto
> mentioned, we did initiate the pregnancy registry in 1984. It was
> really designed to look at major birth defects and compare the risk
> that might be observed with acyclovir used prenatally with risk of
> birth defects observed in the general population, through the CDC\'s
> birth defects surveillance system. As the first one approved that
> would be used widely in women of childbearing age, we felt it was
> important to look at major malformations. It was a short-term
> registry. Generally by the six-week visit we followed up to get birth
> outcome information. We have some results from that study on slides if
> you would like to see them. We terminated the registry in 1999 on the
> advice of our independent advisory committee because it was felt that
> the body of evidence about safety with respect to major malformations
> was sufficient. Our enrollments had dropped off as clinicians and
> patients became more comfortable with use of the drug in pregnancy.
> So, we stopped it. Of course, at that point we weren\'t looking for
> things like resistance..
>
> DR. GULICK: Would we be interested in seeing the data?
>
> DR. ENGLUND: It is the acyclovir data, I don\'t need to see it; I have
> seen some of it. No.
>
> DR. GULICK: Okay. Then, your other point I guess was about resistance
> in newborns as well.
>
> DR. ENGLUND: Right. As we have said, I am not concerned about the
> transmission of resistant virus in the patients that we specify for
> use. I am concerned about the development of resistance in patients
> for whom this relatively low dose of drug is being used for a long
> period of time and who may have partners who are not who we want to
> give the drug to or who are themselves unrecognized as being
> immunocompromised. So, I would have some concerns about resistance for
> follow-up, not necessarily to change what we are doing today.
>
> DR. GULICK: Is it fair to say\--and this came up earlier too\--that
> follow-up of susceptible partners who seroconvert is pretty key, and
> it would have been helpful to see that in the study that was presented
> to know the clinical outcomes? We heard the resistance data I guess
> for ten of them, but also the clinical outcomes because of this
> concern that resistance could be a problem long-term, particularly as
> this gets into the population with widespread use. Dr. Wald, a comment
> on that?
>
> DR. WALD: When we were designing the study we actually did not feel
> that that information to be very important because immunocompetent
> people heal their primary herpes whether or not they are given
> antiviral therapy. So, following somebody for a single episode and
> seeing it heal or not heal without any comparison really would not
> have, I believe, have provided us with any additional useful
> information to this point.
>
> DR. GULICK: May I suggest that it would have been quite easy to put
> together and quite reassuring to know that the partners all had a
> normal course after receiving valacyclovir?
>
> DR. WALD: That is correct but they didn\'t have susceptible isolates.
>
> DR. GULICK: That is helpful. Dr. Fish?
>
> DR. FISH: I think that the package insert could just relate the fact
> of how long the trial lasted; that the experience was eight months, or
> whatever it is; and leave it to the provider and the patient to make
> the decision beyond that. I think it also adds to Dr. Mathews\' point
> earlier about a recommendation for HIV testing because that is where
> we do see a not infrequent occurrence of resistance to acyclovir or
> the other agents that we have used historically. So, in that patient
> population we wouldn\'t necessarily want to be inadvertently treating
> them for suppression or otherwise and have the resistance issue come
> up.
>
> DR. GULICK: Okay. I think we have covered that. Let\'s move to our
> last question. The primary endpoint in 3009 was the proportion of
> couples with clinical evidence of a first episode of genital HSV-2 in
> the susceptible partner. Would you recommend that primary endpoint in
> future studies? If not, what primary endpoint would you recommend?
>
> We have really already considered this, haven\'t we? I guess the
> feeling was that because of asymptomatic shedding and transmission
> seroconversion is a valuable endpoint, or the composite endpoint of
> both serological and clinical would be\--I am trying to speak for
> everyone\--it would be our consensus that that would be even a better
> endpoint than clinical alone. Comments? Dr. Pazin?
>
> DR. PAZIN: I think they should be sort of co-equal endpoints in the
> sense that I am interested in how many people develop clinical
> disease, recognizable and documented, confirmed. I am also interested
> in serologic conversions. I think, you know, pretty much the way this
> study did it, should be sort of co-equal endpoints, that they should
> both be incorporated.
>
> DR. GULICK: Well, co-endpoints is tough. You could have a composite
> including both or you could make one your primary and one your
> secondary. But you are saying that they both tell you important
> information.
>
> DR. PAZIN: Yes, important information.
>
> DR. GULICK: Any other thoughts about that? Yes, Dr. Englund?
>
> DR. ENGLUND: I would just say I think the primary should be serologic
> and the secondary could be the clinical.
>
> DR. GULICK: It certainly would make studies easier to do.
>
> DR. ENGLUND: Well, it would also give uniformity. You know, with
> frequent serology it would give uniformity to Australia and eastern
> Europe, things like that.
>
> DR. GULICK: We are all for uniformity in Australia and eastern Europe.
> Dr. Mathews?
>
> DR. MATHEWS: I had a comment on a different matter.
>
> DR. GULICK: Okay. Any other comments on endpoints? We have pretty much
> covered that I think. So, last couple of matters to think about.
>
> DR. MATHEWS: I have a concern about the dose appropriateness for this
> indication. Because the risk reduction, depending upon what the
> endpoint was, varied from 0.5 to 0.75, it is clearly not zero. If you
> were to restrict this analysis to people who are at high risk of
> transmission, namely, some of those characteristics would be recently
> acquired infection, relationships of short duration, very frequent
> intercourse and other factors, a lack of use of condoms, all of these,
> what do we know about how well the drug at this dose works in the high
> risk setting? That is to say nothing about other populations, for
> example the dose in immunocompromised or where the predominant form of
> contact is not vaginal intercourse, and so on. So, I think this is an
> area for additional study to examine the dose and to try and identify
> settings in which people at high risk for transmission can be studied
> because, this population, really the way it was constructed to make
> the study feasible was skewed towards relatively lower risks of
> transmission I think.
>
> DR. GULICK: Other comments on other issues that people would like to
> make? Dr. Birnkrant, how did we do?
>
> DR. BIRNKRANT: Very well today. We got a lot of useful information.
>
> DR. GULICK: Great! So that brings us to the end of the meeting. I
> would like to thank the sponsor and the agency for their presentations
> today, the committee for a lively, provocative and far-ranging
> discussion, and we will close the meeting now. Thanks.
>
> \[Whereupon, at 3:15 p.m.., the proceedings were adjourned.\]
>
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