AHU.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> ANTIVIRAL DRUGS ADVISORY
>
> COMMITTEE MEETING
>
> Wednesday, August 20, 2003
>
> 8:05 a.m.
>
> Versailles Ballroom
>
> 8120 Wisconsin Avenue
>
> Bethesda, Maryland 20814
>
> [C O N T E N T S]{.underline}
>
> [AGENDA ITEM: PAGE]{.underline}
>
> 1\. Call to Order
>
> Roy M. Gulick, M.D. M.P.H., Chair 5
>
> 2\. Introduction of Committee 5
>
> 3\. Conflict of Interest Statement
>
> Tara P. Turner, Pharm.D.
>
> Executive Secretary 7
>
> 4\. Opening Remarks
>
> Debra B. Birnkrant, M.D.
>
> Director, Division of Antiviral Drug
>
> Products, FDA 9
>
> 5\. **HIV and STIs in Women: The Urgent Need for**
>
> **an Effective Microbicide**
>
> Salim S. Abdool Karim, M.D., Ph.D.
>
> Director, Center for AIDS Programme of
>
> Research in South Africa
>
> University of Natal
>
> Durban, South Africa 17
>
> 6\. **Lessons Learned from COL-1492, a**
>
> **Nonoxynol-9 Vagina Gel Trial**
>
> Lut Van Damme, M.D., M.Sc.
>
> International Clinical Research Manager
>
> Contraceptive Research and Development
>
> Program (CONRAD)
>
> Arlington, Virginia 32
>
> 7\. **Considerations for Topical Microbicide**
>
> **Phase 2 and 3 Trial Designs: A**
>
> **Regulatory Perspective**
>
> Teresa C. Wu, M.D., Ph.D.
>
> Medical Officer
>
> Division of Antiviral Drug Products
>
> FDA 47
>
> 8\. **Considerations for Topical Microbicide**
>
> **Phase 2 and 3 Trial Designs: An**
>
> **Investigator\'s Perspective**
>
> Andrew Nunn, M.Sc.
>
> Heard, Division Without Portfolio
>
> Medical Research Council
>
> Clinical Trials Unit
>
> London, United Kingdom 62
>
> [C O N T E N T S]{.underline} (Continued)
>
> [AGENDA ITEM: PAGE]{.underline}
>
> 9\. **Statistical Considerations for Topical**
>
> **Microbicide, Phase 2 and 3 Trial Designs:**
>
> **An Investigator\'s Perspective**
>
> Thomas R. Fleming, Ph.D.
>
> Professor and Chair
>
> Department of Biostatistics
>
> University of Washington
>
> Seattle, Washington 75
>
> 11\. **Statistical Considerations for Topical**
>
> **Microbicide Phase 2 and 3 Trial Designs:**
>
> **A Regulatory Perspective**
>
> Rafia Bhore, Ph.D.
>
> Mathematical Statistician
>
> Division of Biometrics, FDA 99
>
> 12\. Questions from the Committee 119
>
> **AFTERNOON SESSION:**
>
> 13\. Open Public Hearing
>
> \- Richard Bax, M.D.
>
> Vice President and Chief Scientific Officer
>
> Biosyn, Inc. 179
>
> \- Polly F. Harrison, Ph.D.
>
> Director, Alliance for Microbicide
>
> Development 183
>
> \- Ian McGowan, M.D., Ph.D.
>
> Associate Professor of Medicine
>
> Co-Director, Center for HIV and
>
> Digestive Diseases
>
> David Geffen School of Medicine, UCLA 189
>
> \- Don Waldron, Ph.D.
>
> Head, Clinical Research Unit
>
> Center for Biomedical Research
>
> Population Council,
>
> Rockefeller University 195
>
> \- Tim Farley, Ph.D.
>
> Coordinator
>
> Controlling Sexually-Transmitted and
>
> Reproductive Tract Infections
>
> Department of Reproductive Health and
>
> Research
>
> World Health Organization 200
>
> [C O N T E N T S]{.underline} (Continued)
>
> [AGENDA ITEM: PAGE]{.underline}
>
> \- Amy Allina
>
> National Women\'s Health Network 208
>
> \- Rosalie Dominik, Dr.Ph.
>
> Director of Biostatistics
>
> Family Health International 212
>
> \- Zena Stein, M.A., M.B., B.Ch.
>
> Professor of Epidemiology and
>
> Psychiatry Emerita
>
> Columbia University 219
>
> \- Malcolm Potts, M.B., Ph.D.
>
> Bixby Professor, School of Public Health
>
> University of California, Berkeley 224
>
> \- Laurie N. Sylla
>
> Director, Connecticut AIDS Education
>
> and Training Center
>
> Yale University School of Nursing WRITTEN
>
> \- Robert Munk, Ph.D.
>
> New Mexico AIDS InfoNet WRITTEN
>
> \- Anna Forbes
>
> Global North Programs Coordinator
>
> Global Campaign for Microbicides WRITTEN
>
> 14\. Charge to the Committee, Questions for
>
> Discussion
>
> Debra B. Birnkrant, M.D. 230
>
> 15\. Adjourn 357
>
> [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**
>
> DR. GULICK: Good morning. I\'d like to welcome everyone to today\'s
> meeting of the Antiviral Drugs Advisory Committee for the FDA.
>
> I am Trip Gulick from Cornell in Manhattan.
>
> We would like to start by introducing the members of the Committee, so
> if each member could state their name and their affiliation.
>
> We\'ll start with Dr. Brown.
>
> **Introduction of Committee**
>
> DR. BROWN: My name is Ken Brown. I am representing industry. I am on
> the faculty at the University of Pennsylvania.
>
> MS. HEISE: My name is Lori Heise, and I direct the Global Campaign for
> Microbicides, and I am the Consumer Advocate.
>
> DR. STEK: Alice Stek. I am an ob-gyn on the faculty of the University
> of Southern California.
>
> DR. HAUBRICH: Richard Haubrich from the University of California at
> San Diego. I mainly do HIV clinical trials.
>
> DR. PAXTON: Lynn Paxton. I\'m a medical epidemiologist at the Centers
> for Disease Control.
>
> DR. FLORES: I am Jorge Flores, of the Vaccine Clinical Research Branch
> at the Division of AIDS, NIH.
>
> DR. BARTLETT: I am John A. Barlett from Duke University Medical
> Center.
>
> DR. WASHBURN: Ron Washburn, Infectious Diseases, LSU, Shreveport.
>
> DR. MATHEWS: Chris Mathews, UC-San Diego.
>
> DR. FLETCHER: Courtney Fletcher, School of Pharmacy, University of
> Colorado Health Sciences Center.
>
> MS. TURNER: Tara Turner, Executive Secretary for the Committee.
>
> DR. STANLEY: Sharilyn Stanley, Associate Commissioner, Disease Control
> and Prevention, Texas Department of Health.
>
> DR. SHERMAN: Ken Sherman, University of Cincinnati, Division of
> Digestive Diseases.
>
> DR. WOOD: Lauren Wood, HIV and AIDS Malignancy Branch, NCI.
>
> DR. ENGLUND: Janet Englund, Children\'s Hospital, University of
> Washington Seattle.
>
> DR. DE GRUTTOLA: Victor De Gruttola, Department of Biostatistics,
> Harvard School of Public Health.
>
> DR. FLEMING: Thomas Fleming, Chair, Department of Biostatistics,
> University of Washington, and Co-Director of the Statistical Center
> for the HPTN.
>
> DR. BHORE: Rafia Bhore, Statistician, FDA.
>
> DR. WU: Teresa Wu, Medical Officer, FDA.
>
> DR. BIRNKRANT: Debra Birnkrant, Director, Division of Antiviral Drug
> Products, FDA.
>
> DR. COX: Edward Cox, Deputy Director, Office of Drug Evaluation IV.
>
> **Conflict of Interest Statement**
>
> DR. GULICK: Thanks.
>
> Tara Turner will now read the Conflict of Interest Statement.
>
> MS. TURNER: \"The following announcement addresses the issue of
> conflict of interest with regard to this meeting and is made a part of
> the record to preclude even the appearance of such at this meeting.\"
>
> \"The issues to be discussed at this meeting are issues of broad
> applicability. Unlike issues in which a particular sponsor\'s product
> is discussed, the matters at issue do not have a unique impact on any
> particular product or manufacturer but rather may have widespread
> implications with respect to all topical microbicides for the
> reduction of HIV transmission and their sponsors.\"
>
> \"To determine if any conflicts of interest exist, the participants
> have been screened for interests in topical microbicides for reduction
> of HIV transmission and their sponsors. As a result of this review, it
> has been determined that no reported interests present a conflict of
> interest or the appearance of such at this meeting.\"
>
> \"In the event that the discussions involve any other issues not
> already on the agenda for which an FDA participant has a financial
> interest, the participant\'s involvement and 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 that is developing or studying a topical
> microbicide for the reduction of HIV transmission.\"
>
> Thank you.
>
> DR. GULICK: Thank you.
>
> Now we\'ll turn to Dr. Birnkrant for some opening remarks.
>
> **Opening Remarks by Dr. Debra B. Birnkrant**
>
> DR. BIRNKRANT: Good morning. Before I get to my opening remarks, I
> would like to take this time and opportunity to thank some members of
> our Committee who will be rotating off.
>
> The first person the Division would like to thank is Dr. Courtney
> Fletcher, who has served on our Antiviral Drugs Advisory Committee
> through many complicated meetings, and he has served the term from
> March 2000 until October of this year. We want to thank him for his
> contributions to the Committee.
>
> Next, I\'d like to thank Dr. Sharilyn Stanley, who has also served
> from March 2000, and her term ends October 31, 2003. We want to thank
> her for her comments and help during many complicated Advisory
> Committee meetings.
>
> Thank you very much.
>
> And lastly, I\'d like to thank Dr. Chris Mathews, who has served also
> on the Committee since March 2000. We are happy to have him here today
> as he ends his term as of October 2003.
>
> Thank you.
>
> \[Applause.\]
>
> DR. BIRNKRANT: With that, I would like to welcome our Advisory
> Committee members, guests, and consultants to today\'s meeting on
> topical microbicides. This is a landmark meeting because this is the
> first time we are bringing this topic to the Committee in a public
> forum\--although actually, we have been working on this area for more
> than 10 years as an agency.
>
> This tells you how complicated the field is. Another example of how
> complicated the field is relates to the history of N-9. Nonoxynol-9 is
> the active ingredient in over-the-counter spermicides, and although it
> has shown activity against HIV in vitro and in animal models, we now
> know, many trials later, that it is not an appropriate candidate for a
> topical microbicide because of its nondiscriminating surfactant
> properties.
>
> So, why are we here today?
>
> One of the main reasons why we are here today to discuss topical
> microbicide drug development is because we are receiving Phase 3
> clinical trials from sponsors, and we want to be able to provide them
> with the best possible advice. So we convened this meeting of experts
> to help us help the sponsors.
>
> To have a productive discussion today, I would like to lay out a
> background of topical microbicides, beginning with the definition that
> we developed.
>
> \[SLIDE\]
>
> It is a drug or biologic product that is being developed for the
> reduction of transmission of HIV or other sexually-transmitted
> infections, and given its name, it is applied topically.
>
> It comes in various formulations that can be used with or without a
> device, such as a sponge or applicator. Formulations range from
> cremes, gels, et cetera.
>
> It may or may not have spermicidal activity.
>
> It is applied prior to intercourse, intravaginally or to the rectum.
>
> And for the purposes of today\'s meeting, we will be focusing on
> female-controlled, intravaginally-applied topical microbicides for HIV
> reduction.
>
> \[SLIDE\]
>
> What are some of the ideal characteristics of a topical microbicide?
>
> It should be non-irritating in that the normal vaginal defenses should
> be maintained as well as the epithelium and the natural flora that
> reside there.
>
> It should be discreet in that it should be odorless, tasteless, and
> colorless.
>
> It should be stable in most environments, because the hope is that it
> will be used worldwide to reduce transmission of HIV.
>
> And, although the FDA does not get directly involved in pricing, it
> should be affordable to reach as many people as possible.
>
> These are the ideal characteristics, but we also need a topical
> microbicide to be safe and effective. Although this is the standard
> for the U.S. FDA, it should also be the standard for developing
> countries as well as developed countries.
>
> \[SLIDE\]
>
> There are a number of classes of drugs in the pipeline that are being
> considered as topical microbicides. Broadly, there are surfactants,
> buffering agents, chemical barriers, entry inhibitors, and nucleoside
> and non-nucleoside reverse transcriptase inhibitors.
>
> Why is there such an urgency today to discuss this pertinent topic?
>
> I can think of three main reasons why we should be discussing topical
> microbicides in a public forum at this point in time. One, there is no
> vaccine on the market for HIV prevention. The second reason why I
> think there is an urgency is that it is difficult for women to deal
> with the condom issue. And lastly, HIV/AIDS remains an infectious
> disease of epidemic proportions.
>
> \[SLIDE\]
>
> This is seen on this slide, which is taken from the UNAIDS WHO
> database and shows adults and children estimated to be living with
> HIV/AIDS as of December 2002. And what is remarkable here is that of
> the 42 million, almost 30 million are living in Sub-Saharan Africa.
> But Eastern Europe, the Pacific, Latin America, and North America are
> also significantly infected and affected.
>
> \[SLIDE\]
>
> We take this data from UNAIDS and WHO and look at it in a more tabular
> format. What is remarkable in this slide, in addition to the numbers
> of people living with AIDS and HIV\--and that is the main mode of
> transmission of HIV. So throughout the world, particularly in
> Sub-Saharan Africa, North Africa and the Middle East, North America,
> et cetera, heterosexual transmission remains one of the main modes of
> transmitting HIV/AIDS.
>
> \[SLIDE\]
>
> In this slide, we see highlighted the number of women infected by this
> infectious disease. This is a global summary as of the end of 2002,
> and looking at the three categories\--number of people living with
> AIDS; people newly infected with HIV in 2002; and AIDS deaths in
> 2002\--you can see that women, highlighted in yellow, make up almost
> 50 percent of this epidemic.
>
> So it is hoped that with rational drug development, we will be able to
> develop a marketed microbicide that will help to decrease the numbers
> of new infections.
>
> \[SLIDE\]
>
> The United States has not been spared. This is a CDC estimate of AIDS
> incidence in women and adolescent girls as of 2001. What you can see
> on this pie chart is that heterosexual transmission accounts for 66
> percent, made up of the two categories, sex with injection drug user,
> 16 percent, and sex with men of other or unspecified risk, 50 percent.
>
> \[SLIDE\]
>
> So what will we be discussing at today\'s meeting to help sponsors
> develop Phase 3 clinical trials that will be successful?
>
> We will be discussing trial design issues primarily, and our speakers
> today will be presenting information on different types of trial
> design, namely, Phase 2/3 run-in versus traditional types of trial
> designs. We will be discussing the virtues of a single trial versus
> two adequate and well-controlled trials. We will also be asking the
> Committee to comment on control arms in three-arm and two-arm clinical
> trials and discuss the criteria of FDA of a \"win\" in a clinical
> trial.
>
> In addition, we will be asking you for your opinion on trial duration,
> the goal of which is to capture not only efficacy endpoints but assess
> durability of treatment as well as long-term safety.
>
> \[SLIDE\]
>
> Today we have a number of outstanding speakers, some of whom have
> traveled great distances to be here today, and we greatly appreciate
> that.
>
> Our first speaker will be Dr. Salim Karim from South Africa. He will
> give the global perspective on the urgent need for an efficacious
> microbicide.
>
> He will be followed by Dr. Lut Van Damme, who is the principal
> investigator in the COL-1492 clinical trial of nonoxynol-9 vaginal
> gel.
>
> Then, Dr. Teresa Wu, a Medical Officer in the Division of Antiviral
> Drug Products, will be presenting a regulatory perspective on
> considerations for topical microbicide Phase 2 and 3 clinical trial
> designs.
>
> This will be balanced by an investigator\'s perspective from Dr.
> Andrew Nunn from the UK.
>
> Then, we will have a presentation on statistical considerations by Dr.
> Tom Fleming, and we will have the regulatory perspective by Dr. Rafia
> Bhore.
>
> Thank you very much.
>
> DR. GULICK: Thanks, Dr. Birnkrant.
>
> So we\'ll jump right in and start with our speaker presentations.
>
> Our first speaker is Dr. Salim Karim, from the University of Natal in
> Durban, South Africa.
>
> **HIV and STIs in Women:**
>
> **The Urgent Need for an Efficacious Microbicide**
>
> **Dr. Salim S. Karim**
>
> DR. KARIM: Thank you very much.
>
> I\'d like to start by thanking the organizers for inviting me. What I
> hope to do in the next 15 minutes is to give you a very personal
> perspective, but I also want to share with you data that come from one
> of the potential trial sites for some of the microbicides that are
> going to be tested in Phase 2 and 3 trials soon.
>
> So I am going to try to address the issue of capturing the main issues
> in the epidemic, particularly the epidemic as it affects Sub-Saharan
> Africa, and I want to make the case for an urgent need for a safe and
> efficacious microbicide.
>
> Dr. Birnkrant has already touched on the issues of the global epidemic
> and the way in which women are particular infected, so I am going to
> skip over the first two slides. Just to make the point that within the
> entire global epidemic, the epidemic is particularly affecting
> Sub-Saharan Africa, where we have close to 30 million of the 42
> million infected individuals.
>
> \[SLIDE\]
>
> Within that context, the country that is most affected is the one I
> come from\--South Africa\--where we have some 5 million infected
> individuals. So I want to share with you some of the data from this
> epidemic to show the way in which this epidemic is affecting women in
> particular.
>
> \[SLIDE\]
>
> Let me start by sharing some data from the national antenatal surveys.
> These are done by the Government of South Africa each year, and they
> plot out the way in which the epidemic has been steadily growing in
> South Africa.
>
> So if we look at the period prior to 1990, we had almost no HIV
> infection in the general heterosexual population, and it picked up, as
> you can see, the first period of the epidemic, where there was a slow
> and steady increase. And that was followed in about 1994 with a period
> of very rapid rise in infection, and over the last few years, we are
> seeing some degree of evening off within this epidemic curve.
>
> \[SLIDE\]
>
> Now let me go to one particular site, and this is a rural community in
> a part of the country just 3 hours north of the city of Durban. I want
> to share with you data that come from this particular community in
> Hlabisa and show you how the epidemic has grown in this particular
> community.
>
> In 1992, the prevalence of HIV infection was 4.2 percent. A year
> later, it had grown to 7.9 percent, and 2 years later to 14 percent,
> to 27 percent\--and you can see in the latest data we have from 2001,
> the prevalence of HIV infection in prenatal clinic attendees is 36.1
> percent.
>
> Data on incidence, which we have calculated through a mathematical
> model, show how incidence has also grown concomitantly, driving the
> increase in prevalence. The latter estimates of incidence have also
> been corroborated with estimates calculated through the D-2
> \[inaudible\].
>
> \[SLIDE\]
>
> But this epidemic is not affecting both men and women equally. HIV in
> South Africa is a highly discriminating virus. It has a certain gender
> distribution and age discrimination, and let me try to capture this.
>
> Although these data come from an early point in the epidemic, they are
> still applicable today. So if you follow with me the yellow line, you
> can see how the prevalence arises in men and achieves a peak in the
> age group 25 to 29.
>
> If you compare that to the situation in women, we have a situation
> where the prevalence starts rising in the young teenagers. So we even
> have close to the peak of the HIV prevalence in the age group 15 to
> 19.
>
> So what we have is a situation where young women are particularly
> affected by the HIV epidemic in this community in Hlabisa.
>
> \[SLIDE\]
>
> Let me for a moment look at the cohort effect, and what I want to do
> is present data to you that is AIDS-specific from Hlabisa. So let me
> start by just asking you to focus on 1992.
>
> If one looks at the data for 1992, the prevalence in 20 to 24-year-old
> women was 6.9 percent. And if you look as you go to the older age
> groups, the prevalence steadily declines.
>
> If one looks at how the epidemic has grown over the period 1992 to
> 2001\--that is the 10-year period involved\--we see that the
> prevalence has grown from 6.9 percent to 21.1 percent to 39.3 percent
> to 50.8 percent. This is nothing short of a catastrophe. And what we
> are seeing in these young women is an epidemic that is growing
> explosively in these three intervals.
>
> Let me now ask you to cast your eye to the diagonals. What we have is
> because we have three differences in these periods of measurement, the
> individuals in this particular cell, a large number of them, will be
> in this cell some 3 years later, and so on.
>
> So if we follow this particular birth cohort, if we think about it as
> the \"class of \'92,\" these women experienced this epidemic growing
> from 6.9 percent, some 3 years later to 18.8 percent, to 23.4 percent
> to 36.4 percent.
>
> So what we are seeing in this setting is a rapidly growing and
> explosive epidemic.
>
> \[SLIDE\]
>
> And if we look at the incidence rates that we have been able to
> measure\--and we have been able to measure them in 1998 and in
> 2001\--what we see is not only that we have a growing prevalence rate,
> but we are seeing that the incidence rates continue to remain high. So
> that from the period 1998 to 2001, we continue to see high incidence
> rates.
>
> \[SLIDE\]
>
> One of the studies that we have where we have long-term follow-up
> data\--not data where women have only been followed up for a
> year\--comes from the COL-1492 trial. I have just collapsed the data
> for both arms of the trial in this particular slide. And if you look
> in this particular population\--and these are sex workers who work at
> the truckstops in the midlands or the middle region of the province of
> Kozulu Natal \[phonetic\]\--you see that in the period 1996 to 1997,
> the incidence rate was 16.8 percent per annum. In 1998, a year later,
> it had gone up to 18.2 percent, and in 1999 had gone all the way up to
> 20 percent per annum.
>
> Some people ask me, how can you even get an incidence rate of 20
> percent. Well, these are data that come from the follow-up of these
> women, and what we are seeing is the way in which this epidemic
> continues to rise, not only being driven by high incidence rates but
> even growing incidence rates at this level.
>
> \[SLIDE\]
>
> In the same group of sex workers, let\'s for a moment look at the
> incidence rates of STIs. For trichomonas vaginalis, the baseline
> prevalence on enrollment in the study was 36.1 percent, and by the end
> of each year on average over the 3 years of follow-up, a woman was
> being infected with trichomonas more than once. So we have an
> incidence rate of 114 percent per annum. And you can see again here
> the HIV incidence rate of 18.2 percent.
>
> So what we are seeing in this particular population is incredibly high
> incidence rates of STIs and HIV.
>
> \[SLIDE\]
>
> If we go back for a moment to the rural community of Hlabisa and try
> to understand in a little bit more detail one of the key issues
> regarding the way in which STIs are distributed within this community,
> let me for a moment present data that come from a collection of
> various studies that we have undertaken.
>
> In this particular community, we estimated that there are about 56,000
> women age 15 to 49 years. So in the reproductive age, we expect that
> there are about 56,000 women. Right now as I am speaking to you, we
> estimate that about 25 percent of these women have at least one STI.
> And I am referring here to the five major STIs in this particular
> community.
>
> Of these women, of these one out of four women who have an STI, we
> estimate that only half of them have some kind of symptom. The
> symptoms would be pain or burning on mituration \[phonetic\]. And of
> these symptomatic individuals, only 2 percent of these women will
> recognize these symptoms and seek treatment. And of those who seek
> treatment only 65 percent, or 2 out of 3, will be adequately treated.
> The other one-third of the patients will either go for traditional
> healing or would be treated incorrectly in the private or public
> sector.
>
> So w hat we have is a huge burden of sexually-transmitted infections
> in a community like this.
>
> \[SLIDE\]
>
> You might ask have we not been able to make any dent on this epidemic.
> What of all the prevention programs? Let me present some data that
> show that within South Africa, we have had a growing use of condoms in
> both males and females.
>
> Let me start by presenting some data on the male condom. In 1994,
> before the Mandela Government took over, the Government of South
> Africa distributed approximately 8 million pieces of condoms each
> year. In the first year of our democracy, that went up to 97 million.
> And you can see in the year 2000 that we distributed 250 million, and
> that went up to 267 million in 2001. I don\'t have accurate data for
> 2002, but these are national government estimates, and they estimate
> that they will be distributing some 358 million pieces of condoms.
>
> \[SLIDE\]
>
> If one looks at the situation for female condoms, one can see here
> again\--and female condoms are made available publicly through the
> government clinics\--we distributed 600,000 pieces in 2000, and that
> has grown to about 1.3 million pieces, and they estimate that that
> will continue to grow to about 2.5 million pieces last year.
>
> So in the presence of this kind of epidemic, what we are seeing is an
> increasing use of condoms, both male and female.
>
> \[SLIDE\]
>
> Just to give you some idea that these condoms are not merely being
> taken from clinics and thrown in the bin or being used as balloons at
> children\'s parties, we did a study where we followed up 384 condom
> recipients, and these were at six clinics throughout South Africa.
> These 384 individuals had received 5,528 condoms. We then revisited
> these individuals at 5 weeks, and we undertook an assessment to look
> at how many of the condoms had been used, how had they been used, and
> what remained.
>
> What we found was that 43.7 percent of these condoms had been used,
> that 21 percent had been given away, 8.5 percent had been lost or
> discarded, and 26 percent were still available for use. That enabled
> us to get some estimate that our wastage in condoms at 5 weeks remains
> still below 10 percent. So if we extrapolate the use of condoms in
> South Africa based on this, we were talking about 87 million condoms.
>
> So there is o question that condom use is already increasing and we
> have high levels of condom use in certain parts of South Africa.
>
> \[SLIDE\]
>
> What I would like to show is that what we have in this particular
> epidemic as it affects a community like Hlabisa is that the condom is
> of little use to the particular women who are at highest risk in this
> community. Why am I saying that?
>
> If one looks at the women in Hlabisa, many of the young women have
> partners who are migrant workers. A woman of let\'s say 20 years will
> have a partner of around 30 to 35 years, and that man will be a
> migrant worker either in the mines or in the city of Durban. When he
> comes home, he is coming home to his girlfriend or to his wife. She is
> looking to have his children. There is no possibility that the condom
> would even feature in that kind of equation. But when he is in the
> city or when is at the mine, he has a town wife or he is using
> visiting sex workers, so we have a situation where the very person
> that she wants to have unprotected sex with is the person who is
> infecting her.
>
> We see this over and over again in this particular setting. When I was
> working in Hlabisa Hospital, I remember a young woman coming to me
> with her newborn baby\--the baby was about 8 months or so by
> then\--and the child had severe diarrhea and really looked emaciated.
> We did an HIV test, and the child came back positive.
>
> I was involved in counseling this young women and explaining to her
> that the child does have HIV and that she should also be tested. So
> when we tested her and the result came back, she was also
> HIV-positive. And I was trying to explain to her how one gets HIV, and
> she explained to me that she doesn\'t sleep around; she has been
> faithful to her husband.
>
> So it is not a question that she has any of these risk factors, and it
> is very hard to explain to her that in fact it is the very person that
> she is having sex with\--her husband\--who is the one who infected
> her.
>
> We are looking at a setting where young women are really powerless to
> use these condoms, so the condoms that are being used are not being
> used in those particular age groups of young women where they could
> have maximum benefit. What we need in this particular age group are
> methods that women can use and control.
>
> So, what happens when prevention fails, as we have in our setting?
>
> \[SLIDE\]
>
> Let me show you again from this community in Hlabisa the prevalence of
> tuberculosis\--or, actually, it is the incidence, the number of cases
> of tuberculosis in this particular community.
>
> By the year 1990-1991, we had TB very much under control in this
> community. We have a superb DOT program in Hlabisa District. And at
> that point, Hlabisa Hospital had one TB ward for women and two TB
> wards for men. And if we look at the way in which the numbers with TB
> have increased, we can see that it has moved up from about 400 in
> 1990-1991 to a situation where we have a four- to five-fold increase,
> with a peak in 2001 of over 2,500 case of TV. We have had one whole
> section of the hospital that has been converted to TB wards, and we
> now have four female TB wards and two male TB wards.
>
> It just shows you again how this epidemic is growing particular in
> women and particularly in young women.
>
> \[SLIDE\]
>
> If one looks at our teaching hospitals, this is a study done in 1998
> in medical inpatients. So these are patients admitted to the medical
> ward. Fifty-four percent of the patients were HIV-positive, and 84
> percent of them met the criteria to be regarded as AIDS cases.
>
> We have more women being admitted than men, and that 56 percent of the
> HIV co-infected had tuberculosis. What is striking is if you look at
> the case fatality rates, where we have 22 percent of HIV-positive
> patients admitted to medical wards leave the hospital in a hearse
> compared to 9 percent for HIV-negative patients.
>
> \[SLIDE\]
>
> Let me end by sharing with you some data on mortality since these data
> tell the real crux of the story of the epidemic in South Africa.
>
> I need to explain briefly how to read the data on this particular
> graph. This point, the reference point of 100 or 1, is the average
> mortality rate in men during the period 1985 to 1990. So we have used
> that as a reference point.
>
> If one looks at the period 1996 to 1998, we see that the mortality
> rate in young men around 25 to 29 and 30 to 34 is starting to rise,
> although much of this is simply noise.
>
> If one looks at the mortality rate in 1999 and 2000, one can see a
> clear upward rise. So what we have is an increase in the mortality
> rate in men about one-and-one-half-fold in the age group 30 to 34
> years.
>
> So what we are seeing is about half as many more men dying during this
> particular period.
>
> \[SLIDE\]
>
> Now let\'s look at the situation for women. What we see here\--again,
> remember this is the baseline of 100\--is in the year 1999 to 2000,
> what we are seeing is a three-and-one-half-fold increase in the
> mortality rate in young women. And this particular peak occurs in
> women 25 to 25 to 30 years of age.
>
> So what we are seeing is an epidemic that is growing particularly
> rapidly where incidence rates continue to remain high against a
> setting of a high prevalence of other STIs, and we are now starting to
> see morbidity and mortality taking its toll, particularly in young
> women.
>
> \[SLIDE\]
>
> In conclusion, the epidemic in Sub-Saharan Africa with South Africa
> gives us one picture. We are experiencing five parallel effects. First
> is the continuing large numbers of new infections, and with the high
> prevalence of HIV in young women, this is the group that is also most
> reproductively active, so we have a growing number of both orphans and
> infected young children.
>
> We have rapidly rising mobility, and we can see its impact on our
> health services. And with that is the rapid rise in the number of
> deaths and an increase in the number of orphans.
>
> What it highlights to us is that although we have been making this
> plea that we must have treatment, we have got to avert this crisis of
> the growing mortality. Treatment on its own is not going to be good
> enough. We have to be looking at prevention and treatment.
>
> And lastly just to say that women are more severely affected by this
> epidemic and that condom uptake and use continues to increase, but
> there is still within that context a clear need for a woman-controlled
> method and that within this epidemic which is affecting young women,
> microbicides have the real potential to influence the course of this
> epidemic.
>
> Thank you.
>
> \[Applause.\]
>
> DR. GULICK: Our next speaker is Dr. Lut Van Damme, who is from the
> Contraceptive Research and Development Program in Arlington, Virginia,
> and was the PI of the COL-1492 study.
>
> **Lessons Learned from COL-1492,**
>
> **A Nonoxynol-9 Vaginal Gel Trial**
>
> **Lut Van Damme, M.D., M.Sc.**
>
> DR. VAN DAMME: Good morning. I will present the lessons learned from
> the COL-1492 trial for the design of future microbicide Phase 3
> trials.
>
> \[SLIDE\]
>
> UNAIDS was the main sponsor of this study. COL-1492 is marketed in the
> United States as Advantage S and is a vaginal gel containing 52.5 mg
> of nonoxynol-9 in a bio-adhesive carrier.
>
> The placebo that we used in all the trials is a vaginal moisturizer
> also on the market under the name of Replens. This is very similar to
> COL-1492, although a little bit more viscous and a slightly lower pH.
>
> The study was two-arm, randomized, blinded, placebo-controlled study.
> And I want to draw your attention to the fact that we did a Phase 2/3
> trial. Women who were enrolled in the Phase 2 in which we performed
> colposcopy could stay in follow-up while we awaited on our DSMB
> decision to continue with the Phase 3, and those women were all
> contributing to the main analysis of the study.
>
> \[SLIDE\]
>
> Before starting on a Phase 3 study, we decided to test the product for
> its safety. First, we tested it on low-risk women who used the product
> once a day for 14 days. In this safety study, we did include a
> no-treatment arm, and there was no difference with regard to the
> incidence of lesions with an epithelial breach in the three arms, and
> this incidence was also very low.
>
> Based on these results, we started our Phase 2/3 trial and started
> enrolling women in the Phase 2 part of the study. This is a study
> population at high risk of infection, using the product as much as
> they wanted because there was no set maximum, and also here, the
> incidence of lesions with an epithelial breach was low, and it did not
> differ between the two treatment arms.
>
> \[SLIDE\]
>
> Back to our Phase 3 trial and the main results. The main analysis was
> done under intent-to-treat principle. There were a total of 104
> seroconversions, 59 of which occurred in the COL-1492 arm, giving a 15
> percent incidence of HIV, compared to 10 percent in the placebo, and
> this difference was significant.
>
> \[SLIDE\]
>
> These are the issues I would like to briefly discuss with you during
> my talk. Some of them are a direct consequence of the COL-1492 trial
> results as the placebo and the no-treatment arm. Others are more
> generally linked to Phase 3 microbicide trials.
>
> \[SLIDE\]
>
> When the COL-1492 results became available, the placebo that we used
> was questioned as to its ability of protecting women from HIV
> infection. We cannot completely answer this question since we did not
> design a trial for measuring the placebo effect. However, our
> explanatory analyses do point toward a toxicity of COL-1492 use.
>
> But it is indeed correct that an ideal placebo should have no impact
> at all on HIV infection, be it by lowering the vaginal pH or coating
> the vaginal walls or having an impact on the flora. And it should also
> be indistinguishable from the experimental product to allow blinding
> of the trial. However, if we cannot completely blind, it\'s better to
> partially mask than to have no masking at all.
>
> Based on discussions with colleagues from CONRAD and Vita H. Petty
> \[phonetic\] and Tom Lynch from Reprotect \[phonetic\] have now
> developed the ideal placebo which is a HEC-based gel and which should
> have no effect at all on HIV.
>
> Currently, this product is being tested for safety in the clinical
> facilities of CONRAD in Norfolk.
>
> \[SLIDE\]
>
> Another often-made argument is that if we had included a no-treatment
> arm in our trial, our data interpretation would have been much more
> simple. That is correct on first glance, but when you look more
> closely at the issue, it definitely is not.
>
> Suppose that we have a no-treatment arm which has an equal HIV
> incidence with the placebo arm. What does this mean? Is it indeed that
> we have found the ideal placebo which has no effect at all on HIV, or
> are we looking at the differential behavior change between the two
> groups?
>
> This differential behavior change may go in two directions. We could
> imagine that the women who are assigned to no treatment are adhering
> much more to the safe sex counseling guidelines than the women in the
> treatment arms, and thus they increase their condom use, and thus, the
> equal HIV incidence that we see is in fact women in the no-gel arm
> using more condoms and thus masking the protective placebo effect.
>
> However, we cannot predict if this change will go in the direction I
> just pointed out. It could also go in the opposite direction, and that
> is that women who are assigned to a gel are much more motivated to
> keep to the trial procedures, and trial procedures do include safe sex
> counseling, and thus women increase their condom use more so than
> women in the no-gel arm.
>
> So we cannot exclude that with a no-gel arm treatment there will be a
> differential behavior change. That\'s one thing. Two, we cannot
> predict in which way this behavior change will go. And three, if it
> happens, we cannot predict the magnitude.
>
> The randomization takes care of baseline characteristics but does not
> correct for prospective bias happening because of differential
> behavior change after randomization. This prospective bias is a very
> big threat to our data interpretation.
>
> There also would be an impact on the loss-to-follow-up. It may well be
> that women who are not assigned to the gel arm are not so motivated to
> stay in the trial for the period of length that we are testing and
> come to the clinic on a regular basis, and thus, you are introducing a
> differential loss-to-follow-up among the gel arms compared to the
> no-gel arm\--again, making our data interpretation much more
> difficult.
>
> Some investigators feel that there may be an impact on recruitment
> potential, since for many people, if you are part of a study, it means
> you will have to use a study product, so when they hear they can be
> assigned a no-gel arm, this may make them lose interest in trial
> participation.
>
> And we should not forget that there may be a tendency that women who
> are assigned to a gel arm would be inclined to share their product
> with women, often their friends, who are assigned to a no-gel arm.
>
> Besides those factors, there is also the impact on the real conduct of
> the trial. If we have to implement a three-arm study with two control
> arms, are sample sizes per definition increased? I am sorry\--I don\'t
> know why that sign is there; it should be a double arrow. This makes
> the sample size bigger, much more difficult to recruit, a much more
> expensive trial, logistics more difficult to handle, and it will take
> much longer to finalize a trial.
>
> \[SLIDE\]
>
> We should also not forget that any experimental product which has less
> effect than a placebo, even if this has a low effect, will not have a
> tremendous effect on HIV prevention on a worldwide scale. Some of
> those products are already there, and this might just reduce the
> looming HIV epidemic.
>
> Another challenging thing is what about the behavioral data
> collection. One could argue that since we do all the Phase 3 main
> analyses under the Intent to Treat principle, we do not really need to
> collect those data since we do not use them for doing our main
> analysis.
>
> However, they may prove very useful if we want to better understand
> trial results and do exploratory analysis as we find out with the
> COL-1492 trial. Only these data allow us to better understand what was
> happening in the trial.
>
> We assume that the \[inaudible\] would be equal in the two arms since
> both were assigned to a gel, and the trial was blinded.
>
> How best to collect those data is not known today. We started with a
> simple coital log chart which we then changed to a more detailed
> coital log chart. This had been piloted before, with success. However,
> in the big trial, it was not all that good. Also, the counting of all
> those different sexual acts, with or without gel and with or without
> condom, was a huge burden to the staff. So we changed the procedure
> and asked them direct questions on their most recent sexual acts.
>
> Some say\--and this may indeed be true\--that women are inclined to
> report behavior that they think the researchers would like to hear and
> thus over-report safe sex behavior. This may be correct. Therefore,
> some researchers \[inaudible\] the older, computer-assisted
> self-interview. This would decrease the desirable behavior tendency,
> and it would also decrease the intensity that goes together when you
> talk directly with women on sexual behavior issues which are still
> sensitive and sometimes a tabu issue.
>
> \[SLIDE\]
>
> And then, what to do with the safety trials. In our safety trials with
> COL-1492, we did not detect any toxicity that worried us despite that
> in the second safety trial among high-risk women, they could use the
> product as much as they wanted. In the Phase 3 data, however, we saw a
> strong association between having a lesion with an epithelial breach
> and the HIV seroconversion. This risk was twice the risk among women
> who had never had such a lesion.
>
> Should we disregard all the safety trials because probably what we see
> is that the sample size in a safety trial is too small to detect any
> significant effect? I would say no. One, if there were a major
> toxicity, we would detect it. Two, the COL-1492 trials show indeed
> what we thought\--a lesion with a breach increases a woman\'s risk of
> HIV infection. We can detect those lesions.
>
> The problem, however, today is that we do not know the threshold of an
> acceptable incidence of lesions, and this today can only be assessed
> in a Phase 3 trial where the sample size is big enough to detect any
> significant effect because a product which has limited toxicity may
> prove to be protective against HIV.
>
> A third reason for doing the safety trials is to detect any systemic
> toxicity that the product may have.
>
> Currently, investigators are looking at different ways of addressing
> and assessing the safety of a product beyond colposcopy. Today, it
> would probably be best if you could put all the data together of
> cytokines, neutral fields \[phonetic\], and so on, but today again,
> you cannot link the results of this extra testing to the risk of a
> woman becoming HIV-infected.
>
> \[SLIDE\]
>
> Enrolling sex workers has also often been criticized by saying that a
> sex worker is not representative of women in the general population,
> and thus we cannot generalize study results to a general population
> setting.
>
> But what is a general population? If we go to women in stable
> relationships who have an average of two acts per week, can we say she
> is representative for a young girl in her early sexual debut and who
> goes out on the weekend and has multiple acts?
>
> We should also not forget that by generalizing results from a trial,
> we always have to be careful, because once a product is on the market,
> it will be used in a different way than when it was in the trial,
> since the pressure of being in a trial and regular contacts with study
> staff will be gone.
>
> We should also keep in mind that women who enroll in a trial do show
> an interest in that product, or else they would not volunteer to
> participate in the trial. Today we do not know, since there is no
> effective microbicide, if that interest in using a product is really
> generalizable to the general population.
>
> Another argument against sex workers has been that we may be
> withholding a potential beneficial product because those women are
> using the product multiple times a day, thus triggering its toxicity,
> and this may be correct.
>
> However, we should not forget that most women will use a product at
> one time or another multiple times a day. The COL-1492 results show
> clearly that it is very important to know what happens if women are
> using this product multiple times in a short period of time\--and this
> can happen not only in sex worker populations but in every general
> population, especially among the young women, who are very vulnerable
> to HIV.
>
> \[SLIDE\]
>
> And then, the p-value. This is not directly linked to the COL-1492
> trial results. However, it is very high on the current agenda since
> the FDA requires a p-value of .001.
>
> On this side, you can see the impact that the p-value has on the
> sample size, and thus, you may see that the p-value of .001 doubles
> the required sample size compared to a p-value of .05.
>
> We do indeed not want to erroneously decide that a product is
> effective when it is not. However, the .001 value is, I think, too
> high a threshold. There is an urgent need to find a method that women
> can use to protect themselves, so it is very important that we can do
> the trials in a timely fashion. By using a .05 p-value, we do not do
> any harm to the quality of the science.
>
> \[SLIDE\]
>
> So, based on the COL-1492 experience, based on discussions with
> colleagues in the field and choosing to do high-quality science which
> can be done in a timely fashion due to the urgent need for a
> female-controlled method, CONRAD has assigned on its Phase 3 design as
> shown on this slide.
>
> It will be a 2-arm trial, randomized placebo control with an 80
> percent power and a two-sided .05 significance level. We assume a 50
> percent effectiveness of the product, a one-year retention of 80
> percent, and we will ask women to stay one year in the trial.
>
> The one-year retention rate is based on real life data, and the
> one-year follow-up is based on what we think is feasible to implement
> in the field.
>
> \[SLIDE\]
>
> I will now briefly discuss some ethical issues and can go quickly over
> this slide, because for once, there is consensus in the field.
>
> We are all aware that obtaining informed consent is not a \"once and
> for all\" event and that we have to repeat our information to trial
> participants, since women tend to forget what has been told them.
>
> At the end of the session, when we obtain a woman\'s consent, we ask
> her a set of questions on the basic principles of the trial\--for
> instance, randomization and blinding. We repeat this set of questions
> throughout the trial, and whenever she does not remember certain
> aspects, we repeat the information.
>
> No matter how long and how often we repeat some information, there are
> beliefs which are very difficult to change\--for instance, \"What
> every doctor tells me is good for me.\"
>
> \[SLIDE\]
>
> And then, last but not least, there is the issue of providing
> treatment. There is no discussion at all on providing STI treatment
> for all women in the trial at screening and during trial
> participation. However, providing antiretrovirus \[phonetic\] is a
> different issue. Some say that we should continue to refer to the
> local standard of care, whatever that is; others feel that we should
> make ART available to women who seroconvert while they are
> participating in the trial.
>
> CONRAD has not made a final decision yet, and we will discuss it with
> AID, one of our main sponsors, and with investigators in the field.
> In-house discussions pointed toward that we would try to make a fund
> available for investigators so that they can use this fund whenever
> women who seroconvert during the trial need to go on ART. We probably
> would set a pre-set limit on the period of time that this ART would be
> sponsored, and of course, we would also sponsor and pay for the
> prevention of opportunistic infections.
>
> These are the things I wanted to discuss.
>
> Thank you.
>
> \[Applause.\]
>
> DR. GULICK: Thanks, Dr. Van Damme.
>
> The next speaker is Dr. Teresa Wu, from the agency.
>
> **Considerations for Topical Microbicide Phase**
>
> **2 and 3 Trial Designs: A Regulatory Perspective**
>
> **Teresa C. Wu, M.D., Ph.D.**
>
> DR. WU: I would like to firstly thank the two previous speakers for
> nicely explaining why there is a real need, a real global and urgent
> need, for developing a safe and efficacious microbicide.
>
> My name is Teresa Wu, and my charge this morning is to present
> considerations for topical microbicide Phase 2 and 3 trial design from
> a regulatory perspective.
>
> \[SLIDE\]
>
> What I plan to accomplish in my presentation is to firstly summarize
> for you the types of microbicide in the pipeline or in clinical
> development. Then, I will describe the regulatory tools in existence
> provided by the U.S. FDA that may facilitate and expedite review of a
> microbicide application.
>
> I will then describe the Divisions current recommendation on how to
> develop a microbicide from non-clinical to Phase 1, 2, and 3 trials.
>
> For Phase 2 and 3 trials, which are the focus of today\'s meeting, my
> colleague, Dr. Bhore and I have selected the following
> topics\--design, populations, endpoints, controls, effect size. And
> Dr. Bhore will later discuss the statistical issues such as study
> duration, single trial, sample size.
>
> \[SLIDE\]
>
> To reiterate what Dr. Birnkrant showed in her introduction, the types
> of microbicides are grouped by mode of action. One group is
> detergent-like chemicals which are capable of destroying pathogens
> nonspecifically. The second group of chemicals provide natural acidity
> of a normal vaginal environment and therefore maintain vaginal
> defenses against infection. The third group is based on mechanisms
> targeting attachment of pathogens to target cells. The fourth group is
> based on specific mechanisms targeting HIV at either entry or
> replication steps.
>
> There are still potential microbicides with mechanisms of action
> unknown, such as herbal agents.
>
> \[SLIDE\]
>
> In a survey conducted by Alliance for Microbicide Development,
> approximately 60 products are currently in the pipeline. About 20 of
> these are either planned for or are entering human testing. There have
> been 9 applications filed with FDA, and four of them are presently
> planned for Phase 2 or 3 human trials.
>
> \[SLIDE\]
>
> What are the regulatory tools? Given the urgent need for an
> efficacious and safe microbicide, our present goal is to guide
> promising candidate microbicides to quickly move into Phase 2/3
> trials.
>
> \[SLIDE\]
>
> Under the regulation, topical microbicides are eligible for the
> so-called Fast-Track Drug Development Program because they are
> intended to prevent a serious or life-threatening condition, and
> development of a microbicide will have the potential to address unmet
> medical needs.
>
> \[SLIDE\]
>
> Sponsors can apply for a Fast-Track application any time after the IND
> submission. Under the Fast-Track Drug Development Program, there are
> several regulatory tools that can expedite the review process. Before
> an IND submission, sponsors are highly recommended to have early
> contact with FDA through pre-IND consultation. After IND submission,
> sponsors are entitled to request regular meetings with the Division,
> such as Phase 1, end of Phase 1, end of Phase 2, pre-NDA meetings, to
> discuss and achieve agreement on critical issues.
>
> When the NDA is submitted, FDA may consider to review portions of a
> marketing application before the complete NDA is submitted. This is
> the so-called rolling submission.
>
> The review clock will not begin until the applicant informs the agency
> that a complete NDA has been submitted. A priority review will be
> granted after FDA determines the fileability of the application. The
> review time for a priority review product is 6 months as compared to a
> standard review time of 10 months.
>
> \[SLIDE\]
>
> There are two recently-published guidelines which summarize a
> consensus developed by participants from academic, pharmaceutical, and
> regulatory organizations including FDA at two separate workshops. One
> was sponsored and then issued by the International Working Group on
> Microbicides, or IWGM, in 2001, and the other was sponsored by the
> Rockfeller Foundation in the year 2002. Both publications are
> complementary to each other.
>
> Despite these two published guidelines, there are still issues
> unresolved on the development of topical microbicides. This is why we
> are having today\'s meeting.
>
> As a regulatory agency, our recommendations on how to develop topical
> microbicides are in large part consistent with these two published
> guidelines.
>
> In the remaining slides, I am going to summarize FDA\'s current
> recommendations.
>
> \[SLIDE\]
>
> Before a microbicide product can be administered to humans, vigorous
> nonclinical studies are required. These include in vitro antiviral
> activity, cytotoxicity, mode of action, resistance and
> cross-resistance activities, impact on pathogens causing
> sexually-transmitted infections.
>
> Today, the animal models used for demonstrating microbicide antiviral
> activity have had limited utility in helping to decide which compounds
> should go forward into clinical trials.
>
> Nonclinical studies to assess local and systemic, general and
> reproductive toxicity and pH should be conducted.
>
> Microbicide products should meet the standard chemistry and
> manufacturing control expectations in terms of their proper
> identification, stability, purity, and strength.
>
> \[SLIDE\]
>
> Phase 1 trials of topical microbicide typically are conducted in about
> 200 subjects. The primary objectives are to assess local and systemic
> safety; selection of dose, formulation and initial product
> acceptability; usually, the microbicide is given once or twice daily
> for 7 to 14 days; in HIV-negative women, first including women to be
> abstinent during the study, followed by enrolling sexually active
> women.
>
> \[SLIDE\]
>
> Conventional Phase 2 trials commonly enroll several hundred women, are
> designed to collect local and systemic safety data and acceptability
> than a larger group of women, and also to evaluate microbicide
> activity as proof of concept study.
>
> \[SLIDE\]
>
> However, in microbicide trials, since there are no known clinical
> correlates available, proof of concept for HIV prevention can only be
> measured in studies with very large numbers of participants.
>
> \[SLIDE\]
>
> This is because of two factors. Number one, low HIV incidence rate in
> high HIV-prevalent regions\--for example, one study showed that in
> India, Zaire, and Rwanda, among commercial sex workers receiving
> condom counseling, the instances were three to five per 100
> person-years. In another study in Cameroon, where the HIV prevalence
> rate was very high, the rate was reported to be seven per 100
> person-years.
>
> These numbers are lower than those presented by Dr. Karim due to the
> considerable variation in HIV prevalence between different regions in
> Africa. A 5-per-100 person-year rate has been commonly used by
> sponsors for calculating trial sample size.
>
> \[SLIDE\]
>
> The second reason is that HIV is a fatal and incurable disease. It is
> ethically necessary to promote condom use and provide safe sex
> counseling to all participants. Here, I am referring to male condom
> use only. Therefore, high levels of condom use will likely further
> reduce HIV incidence rates.
>
> \[SLIDE\]
>
> Both the IWGM and Rockefeller Foundation initiatives have suggested a
> hybrid design for combining Phase 2 into Phase 3 design. A subgroup of
> participants will enroll in the Phase 2 component and undergo monthly
> visit evaluations, more intense safety evaluations, including expanded
> local safety testing. Moreover, a subset of this group will undergo
> colposcopy examination for vaginal epithelial abnormality.
>
> Phase 2 participants will continue follow-up and the first 3 months
> Phase 2 data will be reviewed by DSMB.
>
> Concurrent with the follow-up portion of the Phase 2 component and the
> time required to complete the Phase 2 data review, accrual of Phase 3
> participants will begin, and the earlier Phase 2 participants will
> uninterruptedly be phased into Phase 3. Examination will be quarterly.
> HIV seroconversion will be tested quarterly as well.
>
> This design allows for a more intense safety evaluation in the Phase 2
> component before a large number of women exposed to the candidate
> microbicide. I should point out that the Phase 2 component is not
> designed to address the proof of concept.
>
> \[SLIDE\]
>
> Who should be studied?
>
> It is generally accepted that the ultimate goal is to make a
> microbicide product available to women at risk at all levels. The
> study population will be women in regions with high HIV prevalence;
> they are HIV-negative, sexually active, and non-pregnant and at risk
> for sexually-transmitted infections.
>
> Such high HIV prevalence rates occur predominantly in developing
> countries such as Sub-Saharan African countries.
>
> Some sponsors have proposed a study exclusively in commercial sex
> workers because of higher instance of HIV infection. Given their
> potentially high rate of product application, which might enhance the
> rate of vaginal irritation, results obtained from commercial sex
> workers may not be fully representative of a product\'s safety and
> efficacy among other groups of women.
>
> Therefore, we generally recommend that women at varying degrees of
> risk for STI infections be included.
>
> One important group which should be particularly mentioned is
> adolescents. Adolescents represent a very high-risk population for
> acquisition and spread of STIs. A safe product in adults is not
> necessarily safe in adolescents given adolescents\' maturing anatomy
> and physiology and risk behavior.
>
> However, due to legal and cultural constraints, including adolescents
> in clinical trials may be logistically difficult.
>
> \[SLIDE\]
>
> Because most topical microbicide trials will be conducted in
> developing countries, and sponsors have expressed an interest to seek
> marketing approval for their product in the U.S., studies conducted in
> foreign countries will likely become the major if not the only basis
> for most microbicide applications.
>
> When foreign data as the sole basis for marketing approval is sought,
> one of the requirements is that \"data are applicable to the U.S.
> population and U.S. medical practice.\"
>
> \[SLIDE\]
>
> Since most microbicide trials will be conducted in developing
> countries, we think the easiest way to meet this requirement is to
> have a U.S. bridging population as part of the package for a candidate
> microbicide application.
>
> U.S. population is primarily for determining the safety profile and
> acceptability under the condition that the duration of microbicide
> usage will be comparable to that of non-U.S. participants.
>
> There are a number of options the sponsors could choose from by
> including a subset of U.S. participants in Phase 2 run-in Phase 3
> trial, or by using data from a separate contraceptive trial if the
> microbicide is also a spermicide, or by using data from STI prevention
> trials other than HIV, such as chlamydia prevention in U.S. women.
>
> \[SLIDE\]
>
> The primary goal is to measure the rate of HIV acquisition and safety
> of the product, depending on the adequacy of the diagnostic facility
> available at the study site and the prevalence rate at the site. The
> study should include but not be limited to STIs such as chlamydia,
> gonorrhea, syphilis, trichomoniasis, and reproductive tract infections
> such as BV, vulvovaginal candidiasis as a secondary endpoint.
>
> To include STIs as secondary endpoint is based on the fact that STIs
> have been considered cofactors in HIV acquisition. In particular,
> ulcerative STIs have been shown to promote HIV acquisition and
> transmission.
>
> The potential to increase susceptibility to one or more STIs should be
> assessed.
>
> \[SLIDE\]
>
> The selection of controls is a complicated issue for the topical
> microbicide. As I mentioned earlier, a microbicide trial, all
> participants should receive condom promotion counseling. We have
> recommended some sponsors to consider using two parallel controls\--a
> placebo and a no-treatment arm. We prefer the term \"no-treatment
> arm\" over \"condom-only arm\" because in developing countries, condom
> use rate are very low despite condom counseling.
>
> \[SLIDE\]
>
> Placebo is the logical comparator at a time when there is no approved
> microbicide. Placebo remains the gold standard for providing blinding,
> maximizing unbiased estimate of efficacy and safety of the candidate
> microbicide.
>
> \[SLIDE\]
>
> In the case of microbicides, some components of the vehicle of the
> candidate microbicide, for instance, carbomer, have shown anti-HIV and
> anti-bacteria activity. Thus, more and more sponsors have turned to
> using a totally unrelated gelling compound as a placebo for the
> microbicide trial\--the so-called \"universal placebo.\" This term has
> gained popularity recently.
>
> Because this universal placebo is not a vehicle, we have required
> sponsor to conduct limited nonclinical and Phase 1 studies prior to
> being used in Phase 2/3 trials. The universal placebo has been shown
> to have no in vitro activity against HIV and bacteria. However, some
> uncertainties still remain.
>
> \[SLIDE\]
>
> What are the uncertainties? The universal placebo gel itself is a
> physical barrier while intravaginally applied. Thus, placebo may have
> an unknown level of efficacy. Equally unknown, a placebo may
> contribute to some level of local toxicity. Even if the placebo shows
> no vaginal toxicity in a small number of participants in Phase 1
> studies, the safety profile in a large number of women still has to be
> established in a Phase 2/3 trial.
>
> \[SLIDE\]
>
> Thus, the advantages of having two parallel control groups are:
> blinding; validate the interpretation of efficacy and safety data
> obtained from the candidate microbicide arm; since the placebo may
> have some level of efficacy and/or toxicity, the inclusion of a
> no-treatment arm is to validate interpretation of the efficacy and
> safety data obtained from the placebo arm.
>
> However, we are mindful of the disadvantages associated with the
> inclusion of a no-treatment arm. The no-treatment arm cannot be
> blinded, and as a result, participants may drop out of the study,
> resulting in differential dropout rates. Participants\' risk behavior
> may change, either more or less motivated to use condoms. This would
> likely create a bias between groups.
>
> Another potential effect could be gel-sharing, which will be very
> difficult to document. And regarding the control arms, my colleague
> Dr. Bhore will discuss further this issue in her presentation.
>
> \[SLIDE\]
>
> In a setting where condoms would be used consistently and correctly,
> condom alone can offer 85 percent protection against HIV transmission.
> However, low rate and incorrect condom use have been the norms in most
> developing countries. The microbicide community has generally accepted
> that even if the first product approved is shown to be only modestly
> protective, that is, relative to the consistent and correct use of
> condoms, one can still expect a significant public health impact on
> the reduction of HIV transmission.
>
> Measuring the level of efficacy of microbicide in the present design
> is to measure incremental benefit offered over imperfect or actual use
> of condom use alone. The range of effect size expected for the first
> generation of microbicides in conjunction with imperfect or actual use
> of condoms is between 30 to 50 percent, as most experts in the field
> have agreed.
>
> We acknowledge that this range is arbitrary; nevertheless, it was
> based on clinical judgment.
>
> \[SLIDE\]
>
> In summary, we recommend a Phase 2 run-in Phase 3 trial design;
> population enrolled should be generalizable, and data should be
> applicable to the U.S. population. Endpoints include HIV incidence,
> safety, STI incidences. We prefer two parallel controls, and effect
> size would be 30 to 50 percent in the context of condom promotion.
>
> Thank you for your attention.
>
> \[Applause.\]
>
> DR. GULICK: Thanks, Dr. Wu.
>
> Our next speaker is Andrew Nunn, from the Medical Research Council,
> London, UK.
>
> MR. NUNN: Mr. Chairman, ladies and gentlemen, I would like to begin
> with a couple of introductory remarks, first of all to thank you very
> much for the invitation to speak today; secondly, to indicate that
> although what I\'m saying is very much a personal perspective, it does
> reflect the views of those of us involved in the UK-based Microbicide
> Development Program, which is actually involved right now in the
> development of a protocol for a large Phase 3 trial which we hope will
> begin next year.
>
> \[SLIDE\]
>
> I have been given 20 minutes, and in 20 minutes, it is likely that 100
> women will have been infected with HIV. Most of those women are in the
> developing world, and most of the women will probably have had little
> opportunity to prevent that infection to protect themselves.
>
> How many of those infections could have been prevented by the use of
> an effective vaginal microbicide?
>
> \[SLIDE\]
>
> We may differ in respect to a number of points that we are discussing
> here today, but I think we have a common goal that we will all agree
> on: We need a microbicide which is effective, safe, acceptable, and
> affordable.
>
> \[SLIDE\]
>
> There is a particular link between safety and efficacy which is almost
> unique in this situation, because local adverse events, some of which
> may actually be very minor in effect and may not even get reported,
> such as minor inflammation, may be closely linked to an increased risk
> of infection and thus reduce the effectiveness of a product.
>
> Clearly, the experience gained in the COL-1492 study which we heard
> about briefly earlier has alerted us to the need for a new level of
> vigilance concerning possible adverse effects from products under
> study.
>
> \[SLIDE\]
>
> What is the most urgent priority today? These are al priorities, but
> what is the most urgent\--a highly effective product, a licensed
> product, or proof of efficacy?
>
> \[SLIDE\]
>
> I would suggest that in fact proof of efficacy is particularly
> important, because funders will only go on funding for so long, and if
> we reach a point in time at which they say, \"We don\'t have much
> evidence of efficacy,\" they may lose interest and not be willing to
> continue funding.
>
> Now, effectiveness of a microbicide will depend on the extent to which
> that microbicide is used. Use will depend on acceptability. And
> acceptability is likely to vary considerably between populations.
>
> Heterogeneity of populations may provide us with the best chance of
> demonstrating proof of efficacy. I shall return to this point a little
> bit later on.
>
> \[SLIDE\]
>
> In an ideal world, our trial design would be something like this. We
> would have several promising products to look at, and we would test
> them in one trial. The products would be outwardly indistinguishable
> from each other and from the placebo. The placebo would be completely
> ineffective, and behavior would be unaffected by participants taking
> part in a trial.
>
> \[SLIDE\]
>
> In reality, things are often different from that. Products may not be
> indistinguishable from each other\--it may be necessary to have a
> placebo for each product. And sometimes one has to have dummy placebos
> in certain contexts, two placebos to each individual\--but not in this
> particular context.
>
> Placebos may have some protective effect, as has already been alluded
> to, and behavior will change. In fact, I would suggest that in a
> trial, behavior almost always does change, because of course, it\'s
> not a very real situation.
>
> So, as a consequence of points 2 and 3, any such trial would not
> mirror what happens if microbicides were to be introduced into a real
> life situation.
>
> \[SLIDE\]
>
> So the question has been raised, would a second control arm help. Two
> control arms have been proposed\--a conventional matched placebo
> control an a condom-only, or what I prefer to call a no-gel arm.
>
> \[SLIDE\]
>
> The no-gel arm has, it would appear, certain advantages. It would
> eliminate problems associated with a placebo which might have a
> protective effect, and it would reflect real life. But I would ask the
> question: Are these advantages real? Would it really reflect real
> life?
>
> \[SLIDE\]
>
> What are the disadvantages of a no-gel arm? I believe they come under
> two headings. First of all, differential behavior change within the
> population,a nd secondly, difficulty in achieving a uniformly high
> follow-up.
>
> \[SLIDE\]
>
> What are the behavior change issues, first of all? In a randomized
> clinical trial, participants usually behave differently to how they
> would outside the trial. They are being seen much more frequently,
> they are being counseled regularly. In a microbicide trial, they will
> receive regular counseling about safer sex.
>
> Within the trial, behavior changes are not so important when comparing
> indistinguishable treatments if we want to look at the relative
> effects of two treatments. However, as we have already heard, a no-gel
> arm clearly unblinds participants and almost certainly results in
> differences in behavior change. Women allocated to receive no gel may
> choose to share the gel with those allocated no-gel. I mean, many
> women are actually going to help recruit others to the trial. Women
> will recruit their sisters, their cousins, their friends\--and the
> reality is that most women will hope to be receiving gel. They will be
> very disappointed when they don\'t get it, however well we try to
> counsel people otherwise.
>
> Consequently, what may well happen is that one woman will say,
> \"Don\'t worry, I\'ll get a bit more gel, and you can have some of
> mine.\" And that may be very difficult to measure, but the reality is
> it is likely to happen.
>
> \[SLIDE\]
>
> Could we allow for these problems, these issues, behavioral issues, in
> our analysis?
>
> Sexual behavior data such as partner change, frequency and type of
> sexual intercourse, use of condoms are inherently very difficult to
> ascertain accurately. We could never be sure of the true differences
> between the distinguishable treatment arms. Consequently,
> interpretation of differences, I believe, would be impossible.
>
> There are also, as I said, follow-up issues. However good our consent
> process, it\'s almost certain that many women will enroll into a
> trial, as I have already said, in expectation of receiving gel.
>
> Women requested to attend for regular follow-up who receive no gel are
> likely to be less adherent\--unless they manage to get it from another
> source\--than those who receive the gel.
>
> Without coercive incentives, women allocated no gel are more likely to
> default from the study than those receiving gel. And of course, the
> longer the study, the more likely that is to be the case.
>
> \[SLIDE\]
>
> So I would say that at this point, we could conclude that the no-gel
> control arm would make the study impossible to interpret. Results from
> a study including a no-gel arm are likely to be, at best, of interest
> but at worse will be seriously misleading.
>
> \[SLIDE\]
>
> I want to return to the issue of collecting accurate sexual behavior
> data. Although, as I have already alluded, it is very difficult to
> collect, I believe it is very important to attempt to obtain accurate
> data\--as accurate as we can obtain\--in order to be able to better
> understand the results of our study.
>
> For example, if we see no effect in one particular site, but we see
> effects in other sites, could that be explained by what we term
> \"condom migration\"\--that is, women who are receiving gel, who have
> been using condoms, actually using condoms less because they don\'t
> think they need them.
>
> \[SLIDE\]
>
> How do we use the sexual behavior data? I believe that if a gel shows
> evidence of effectiveness in most but not all of the sites in a trial,
> this may be due to differences, for example, in acceptability,
> difference in adherence and/or sensitive behavioral factors such as
> the frequency of anal sex\--which we may have little evidence on as to
> whether it is being practiced unless we have good behavior data for
> our populations.
>
> We need to know why we are getting different results from different
> sites, and I think it is extremely likely that there will be variation
> in results from sites if we have different sites from different parts
> of Africa, different populations, urban and rural.
>
> \[SLIDE\]
>
> So I come back to a point I alluded to a little bit earlier, and that
> relates to heterogeneity of sites. Is it a good thing or is it a bad
> thing?
>
> You could regard it as bad insofar as it could reduce your change of
> demonstrating overall effectiveness. That would be true, of course, if
> you had actually been fortunate in identifying a site where you
> expected to actually be able to demonstrate an effect\--but I don\'t
> think we are in such a fortunate position.
>
> Alternatively, since a product may not be universally acceptable or
> effective, variation between sites could increase the chance of
> demonstrating an effect on the primary endpoint or at least explaining
> reasons for lack of an overall effect if we see variation in effect
> between sites.
>
> And again here, this is where the sexual behavior data becomes
> important, too.
>
> \[SLIDE\]
>
> There has been some discussion, too, and it has been referred to by
> earlier speakers, about how long the Phase 3 trial should be. Both
> adherence to gel use and regularity of follow-up are likely to be
> influenced by the duration of the trial design.
>
> Even persons who are under treatment for active disease, in such
> populations, we know that maintaining adherence is very difficult. I
> have a background in tuberculosis, and in fact in the days before
> short-course chemotherapy, there were very dramatic findings of how
> populations dropped off with time in terms of collecting their drug.
> Even though they were populations where the patients knew the
> seriousness of their disease and the importance of actually receiving
> it, by the time you got to 12 months, the proportion of men and women
> who got TB who were picking up their drug could be as little as 25
> percent of those who had been originally enrolled.
>
> The problems have also been demonstrated, I think, in some of the HIV
> therapy trials in recent days as well.
>
> Maintaining good adherence with preventive therapy can be even more
> difficult, and it can become increasingly difficult with time.
>
> \[SLIDE\]
>
> So we could ask the question, well, how short could the Phase 3 trial
> be.
>
> Shorter designs of maybe six or nine months are more likely, I
> believe, to demonstrate proof of efficacy than studies requiring
> participants to be adherent, shall we say, for periods up to 24
> months.
>
> Long-term safety data could be obtained from such studies by following
> a subgroup of women for longer periods of time. Not all women would
> actually just stop being followed at six or nine months. We could go
> on following women beyond that time to collect long-term safety data.
>
> Long-term effectiveness, because it will be dependent on adherence, is
> likely to improve once proof of efficacy has been demonstrated, and we
> can say to women that we have good reason to believe that these
> products are going to be beneficial. We cannot say that at this point
> in time.
>
> \[SLIDE\]
>
> One of my final points relates to population selection. Proof of
> efficacy will be more difficult to achieve in certain
> circumstances\--such as, if we include participants who are unlikely
> to benefit from microbicides\--for example, those who are regular
> condom users or those frequently practicing anal sex. We would clearly
> make our work more difficult to actually identify an effect in a
> population.
>
> However, restrictive inclusion criteria prevents subsequent
> generalization of our findings, and we must always bear that in mind
> as well.
>
> The reality is that site selection and to a lesser extent, the study
> personnel that are conducting our studies are likely to be important
> in determining the outcome of our studies. You could even say it
> depends on who your friends are, which sites you have actually chosen,
> the ones that you have experience with, which will have quite a major
> determinant on what the results of the study may actually turn out to
> be.
>
> \[SLIDE\]
>
> So in conclusion, if we are to reduce the number of new infections, we
> need a flexible approach to study design which will maximize our
> chance of achieving proof of efficacy and reducing the number of women
> likely to be infected in the next 20 minutes.
>
> Thank you very much.
>
> \[Applause.\]
>
> DR. GULICK: Thank you.
>
> What I would like to do is hold questions until we hear the two
> statistical presentations.
>
> Let\'s now take a 20-minute break. We\'ll reconvene at 9:55.
>
> \[Break.\]
>
> DR. GULICK: Welcome back. We are ready to resume the meeting.
>
> Our next speaker is Dr. Tom Fleming from the University of Washington.
>
> **Statistical Considerations for Topical Microbicide**
>
> **Phase 2 and 3 Trial Designs:**
>
> **An Investigator\'s Perspective**
>
> **Thomas R. Fleming, Ph.D.**
>
> DR. FLEMING: Thank you, Dr. Gulick.
>
> \[SLIDE\]
>
> I am pleased to be here. The discussions that we have already heard
> have certainly pointed out that there are many challenging issues that
> we face with the design of topical microbicide studies.
>
> What I would like to do is try to touch on a few of these key issues,
> and I will be talking about choice of controls, required strength of
> evidence, and what to do after Phase 1.
>
> \[SLIDE\]
>
> So let me begin by addressing further issues we have already discussed
> a fair amount today, that is, the role of blinding.
>
> It has long been understood in clinical trials, particularly when you
> would have, let\'s say, a subjective endpoint such as pain that bias
> can occur if the treatment that the participant is taking is known to
> the evaluators\--for example, where their judgment could be influenced
> by their being unblinded\--it is known that if it is known to the
> participant or patient, there could be placebo effects. And if
> caregivers are unblinded, in those settings where the endpoint, such
> as hospitalization, is one actually influenced by the caregiver, then
> the unblinding could introduce some bias.
>
> \[SLIDE\]
>
> If we look at the potential mechanisms of action of an intervention,
> using a placebo control as a comparator to the active microbicide
> would be an ideal approach to be able to estimate the antimicrobial
> effects of that intervention.
>
> It has also, though, been recognized for a long time that there are
> controversial issues in some settings with the use of blinding. Pocock
> has addressed a number of these many years ago.
>
> We look first of all at the practicality issues. Treatments or
> interventions need to be of a similar nature and cannot induce obvious
> side effects, so for this reason, a large fraction historically of
> comparative trials in the oncology setting, for example, have been
> unblinded trials.
>
> Ethical issues are also important. Blinding should not result in harm
> or risk. So it wouldn\'t be ethical to try to induce within a blinded
> control in an oncology setting an intervention that would induce
> nausea, vomiting, stomatitis, alopecia, et cetera, in order to achieve
> the blind.
>
> There are a number of other important issues that really are key to
> consider when you are thinking about blinding in a microbicide trial.
> One of the issues is how serious is the risk of bias without blinding,
> as Pocock mentions. These risks are more serious with subjective
> endpoints. Fortunately, dealing with an HIV infection endpoint, it is
> a more objective endpoint such as survival would be in an oncology
> setting, and that reduces some of the risk of bias that would occur in
> an unblinded setting.
>
> The importance of understanding efficacy and effectiveness is also
> critical. A microbicide intervention is by its nature not only made up
> of its antimicrobial components but also involves behavioral
> components, and understanding the global aspect of the effect of the
> intervention is critical, so understanding efficacy and effectiveness
> is important.
>
> \[SLIDE\]
>
> And it is also key to have adequate evidence to establish that the
> placebo is truly inert. So if we return to this consideration of the
> potential mechanisms of action of a microbicide intervention, not only
> are those mechanisms antimicrobial effects, but the microbicide might
> also provide protection through physical barrier effects, lubrication
> effects, and other effects.
>
> These components may in fact also be carried by the placebo. So a
> simple comparison against the placebo may actually be even
> underestimating efficacy.
>
> In contrast, a comparison of the active microbicide against the
> unblinded control would incorporate not only the antimicrobial effects
> but also all of these other effects and would also be able to
> incorporate effects on risk behavior, being able to look, then, at a
> global estimate of effects or in essence on effectiveness.
>
> \[SLIDE\]
>
> Let me consider half a dozen specific circumstances to get a little
> bit more insight into what we might learn in a trial that would in
> fact have both a placebo control and an unblinded control.
>
> To explore this, in each of these six settings what I am presenting on
> this slide is the annual risk in the active arm as well as the placebo
> arm as well as the unblinded control arm.
>
> In the lower left-hand side, we would have a situation where the
> annual risk is 3 percent in each of these groups, and we would clearly
> have a setting in which we would have established a microbicide with
> this particular mode of delivery in this population as being
> ineffective.
>
> A more ideal circumstance would be where we would have a one-third
> reduction in transmission rate relative to both the placebo comparator
> group and the unblinded control group; and clearly we would have a
> positive circumstance there.
>
> What I have presented in the upper portions in the right-hand column
> are settings where we still have a one-third reduction relative to the
> placebo control, but in this setting, we have about a 20 percent
> relative increase in risk-taking behavior in the blinded arms; here, a
> 50 percent increase in risk-taking behavior in the blinded arms.
>
> When we would then look at the comparison not only against the placebo
> but against the open-label control, we would see that we still have
> evidence of effectiveness here, although there would not be net
> effectiveness in this setting.
>
> In the left-hand column, we have two circumstances where we still have
> a one-third reduction relative to the open-label unblinded control. In
> this setting, we have a situation where we have about a 20 percent
> relative efficacy as estimated against the placebo, but by having the
> open label, we see a more complete sense of the true treatment effect,
> which is in fact potentially somewhat missed by a placebo that in fact
> is itself carrying some of the benefit.
>
> This is a circumstance where we in fact have a one-third reduction
> carried by the placebo, but there is no additional antimicrobial
> effect. And in fact this is not hypothetical. In the past year, in
> another setting studying an antimicrobial where the FDA had urged the
> sponsor to have both a no-treatment open-label as well as a placebo,
> this is exactly the circumstance that arose in that setting.
>
> How would we interpret results? What conclusions would we draw in each
> of theses settings?
>
> What I would like to do is come back to that question after taking a
> moment to consider the issue about required strength of evidence.
>
> \[SLIDE\]
>
> A standard that has long existed within FDA for regulatory approval is
> to have two adequate and well-controlled trials. Essentially,
> statistical significance for each trial would be based on the strength
> of evidence by obtaining a one-side p-value less than .025\--or in
> essence, if we have evidence where the result is sufficiently
> favorable that this result would occur by chance alone if there were
> no true treatment effect would only be 2.5 percent, that\'s the
> standard for strength of evidence of a single positive study.
>
> When we have had major clinical endpoints, the FDA has been flexible
> to consider a single trial situation, a single pivotal study. These
> could be situations where the endpoint is death, stroke, loss of
> vision, or HIV infection. And in particular in these settings that are
> also involving resource-intensive trials, the FDA has considered
> applications based on single pivotal studies, and what I have noticed,
> a fairly consistent terminology that they use is that the strength of
> evidence for that single pivotal trial needs to be \"robust and
> compelling.\"
>
> When sponsors have asked, \"What does that exactly mean in terms of a
> p-value?\" the FDA has correctly said, it\'s not so simple as a single
> p-value. The ultimate judgment about approvability of an intervention
> needs to take into account not just the primary endpoint, which is
> critical, but all relevant data\--data on secondary endpoints, data on
> safety, external data and, importantly, data on quality of trial
> conduct.
>
> My sense is that a proposed guideline for strength of evidence, then,
> when you are planning such a study might be to target a strength of
> evidence that might be midway between the strength of evidence of a
> single positive study and the square of this, which would be two
> positive studies\--essentially, to be in a position that one would
> have sufficiently robust and compelling results even in the event that
> there may be certain irregularities that show up in the trial.
>
> \[SLIDE\]
>
> One study that is under design right now is the HPTN 035 trial, and
> I\'ll use this briefly to illustrate some of these concepts.
>
> This is a study that is in fact planning to look at both the placebo
> control and an unblinded control, and we will be looking at two active
> microbicide interventions.
>
> It is targeting 33 percent effectiveness with 24 months of follow-up.
>
> The question is with this particular design, for any of these
> pair-wise comparisons that may be made of active against control, how
> big does the study have to be; what does this actually mean in terms
> of events.
>
> \[SLIDE\]
>
> In Scenario 1, if we were looking at building a study to have strength
> of evidence, that is, the traditional 2.5 percent false-positive error
> rate, if we were trying to detect 90 percent power to detect a 33
> percent effectiveness, that would take 256 endpoints. And essentially,
> in a setting that we are looking, about 4,000 participants per
> pair-wise comparison, or 2,000 participants per arm.
>
> In Scenario 2, where we might be building for essentially a strength
> of evidence midway between that of strength of evidence of a single or
> two trials, again, if we are looking at 90 percent power to detect 33
> percent effectiveness, essentially, it would take\--as you might
> expect\--about one-and-a-half-fold, or about 405 events, or about
> 3,000 participants per arm.
>
> \[SLIDE\]
>
> Essentially, what would the estimated effect have to be in these two
> settings? So, in Scenario 1, where we are essentially targeting a
> traditional 2.5 percent false-positive error rate, what I have plotted
> here in yellow is what the percent reduction in HIV risk may be in
> these trials, and essentially in this setting to achieve the strength
> of evidence of a single positive trial, your estimate would have to be
> about a 21 percent relative reduction. Strength of evidence of
> one-and-a-half trials, if you in fact achieve the 29.5 percent
> estimate reduction and a 33 percent would be the strength of evidence
> of two trials.
>
> Not surprisingly, in Scenario 2, where we are actually looking at 405
> events per pair-wise comparison, powering it in essence to the
> strength of evidence of one-and-a-half trials, it would take a less
> impressive estimate to achieve the strength of evidence of a single
> study\--17 percent\--and roughly 24 percent estimated reduction for a
> strength of evidence of one-and-a-half studies.
>
> \[SLIDE\]
>
> Now, in a setting where you have dual controls, what might in fact be
> a general guideline for strength of evidence against these two arms?
>
> My proposal for illustration would be a setting where essentially, we
> require the .0025 for one of the comparisons, where the other one
> would just need to be at the traditional .025 level.
>
> So specifically, then, if we obtained a compelling result against
> placebo, the strength of evidence against the unblinded control might
> only need to be supportive; or if the result against the unblinded
> control is in fact compelling, the result against the placebo may only
> have to be supportive.
>
> \[SLIDE\]
>
> With this as an illustration for targeted strength of evidence, then,
> what might the conclusions be in a trial where you had a comparison to
> the placebo and the unblinded control?
>
> Let\'s return to these six circumstances here. Clearly, in the lower
> left-hand circumstance, we would conclude that it is a negative trial,
> a trial that has ruled out benefit. In the lower right-hand side, we
> would have clear evidence of efficacy as represented by both the
> comparisons against the placebo and the open label.
>
> In these middle scenarios, on the right-hand side, we would have
> compelling evidence against the placebo control and supportive
> evidence against the open label, which I would argue would also be a
> positive circumstance. Or, on the left, we would have compelling
> evidence of effectiveness and supportive evidence in the comparison
> against the placebo.
>
> The illustrations up here on the top are illustrations where, on the
> left, we have essentially evidence of minimal effect of the
> antimicrobial components of the microbicide; and on the right, we have
> minimal evidence of effectiveness.
>
> It has been argued by some that when you add the unblinded control,
> the end result is simply to make it more difficult to conclude
> benefit\--and in fact, I would argue that that is not true. There is
> really symmetry here. I have underlined here the two situations where
> the unblinded control would give you a different conclusion than you
> would have had if it didn\'t exist in the trial.
>
> And certainly in this setting where you have evidence of no
> effectiveness, it does lead you to have concerns about approval of
> this intervention. But in this particular circumstance, if you would
> just look against the placebo control, you would have had an estimate
> of only a 20 percent reduction in transmission rate, whereas when you
> have added this additional insight from the open label, you are
> getting a clear indication that you may have in fact underestimated
> the efficacy by missing components of benefit that in fact were also
> carried by the placebo.
>
> \[SLIDE\]
>
> I\'d like to spend a little bit of time talking about issues that
> relate to where do we go after Phase 1.
>
> If you have in fact completed a Phase 1 trial with on the order of 100
> participants, what would be the next proper step? Traditionally in
> clinical trials, we have gone to Phase 2 studies, and Phase 2 studies
> provide many important benefits.
>
> \[SLIDE\]
>
> One of the key areas of benefits of a Phase 2 study is it provides
> invaluable insights to allow us to design an improved Phase 3 trial.
> For example, by conducting a Phase 2 study, we are able to learn a
> great deal about how to achieve timely enrollment of participants,
> high-quality study implementation, and high-quality data including
> retention. To achieve interpretable unbiased results, it is going to
> be extremely important to keep loss-to-follow-up rates low. We really
> should be targeting for 12-month follow-up 95 percent retention.
>
> Phase 2 studies are going to give us important insights about how to
> improve our ability to retain patient participants in trials.
>
> Adherence will also be critical, and Phase 2 studies can also provide
> important insights. We are not dealing with a vaccine that may require
> a one-time implementation. To achieve the full benefit of microbicide,
> we are going to need to have consistent adherence. How can we in fact
> improve the behavioral element of this intervention to maximize the
> adherence to the active microbicide, and also to maximize the
> adherence to condom use and other approaches to reduce risk of
> transmission.
>
> So these are all insights that will be invaluable to the design and
> conduct of a Phase 3 trial that comes out of a Phase 2.
>
> Traditionally, of course, as well, Phase 2 trials give us important
> additional clues about safety that will be important to have in hand
> before doing Phase 3 trials and, in addition to that, plausibility of
> efficacy by using biological markers and establishing effects on those
> markers.
>
> Unfortunately, in settings such as topical microbicides, there aren\'t
> in fact biological activity measures that we can use to assess
> plausibility of efficacy. So what might be an approach to take rather
> than launching immediately into a full-scale Phase 3?
>
> \[SLIDE\]
>
> One additional approach to consider that I\'ll talk a little bit about
> would be a Phase 2B trial, or we might call it an intermediate trial.
> So in the setting of the 035 trial, if it is in fact conducted as an
> intermediate trial, the primary endpoint would in fact be the HIV
> infection rate itself, but essentially, we might be looking at a much
> smaller version of the study; rather than the 400 events per pair-wise
> comparison, we might be looking at a third to one-quarter that
> size\--for example, 100 endpoints per pair-wise comparison.
>
> The goal, of course, would be to estimate the true percent reduction
> in HIV infection risk, and the estimate of that, I will denote by
> delta hat.
>
> \[SLIDE\]
>
> So what we see on this slide is the nature of the evidence that we
> would obtain in an intermediate trial versus the full-scale Phase 3.
> So let me start with the full-scale Phase 3 trial.
>
> \[SLIDE\]
>
> In this particular setting, with 400 events per pair-wise comparison,
> we would have considerable precision\--basically, our two standard
> errors would be plus or minus 17 percent\--and recollect that we said
> earlier that when there were 405 events, a p-value of .025 would be
> obtained if you had essentially a 17 percent estimated efficacy; a
> strength of evidence of 1-1/2 trials, if you had an estimated 24
> percent.
>
> So what we see down here is that if in fact there truly is a one-third
> reduction, then you would have high probability, about 97.5 percent,
> of achieving strength of evidence of at least a single trial and about
> 90 percent chance of obtaining an estimate of 24 percent or higher.
>
> \[SLIDE\]
>
> Now, if instead you embarked on the intermediate trial, which would be
> about one-quarter the size, it would have roughly twice the
> variability. So that essentially you would have to observe now a 33
> percent efficacy to be able to have the strength of evidence of a
> single trial.
>
> Suppose we took the following approach, basically, a multiple-decision
> outcome. If you see 15 percent estimate of efficacy or less, you
> abandon the intervention. If you see 15 to 33 percent, you have
> encouraging evidence that would require confirmation in a Phase 3
> trial. If you have basically 33 to 44 percent, you have at least the
> strength of evidence of a single trial, and 44 or better would in fact
> be conclusive evidence of benefit.
>
> If in fact there truly is 33 percent efficacy, this is a strategy that
> has the desirable properties that you have only one chance in eight of
> abandoning the regime; you have three chances in eight, basically, of
> having evidence that would require additional confirmation; and you
> would have about a 50 percent chance of actually in this trial
> achieving evidence that would be at least the strength of evidence of
> a single positive trial.
>
> Another benefit of this approach is for an intervention that doesn\'t
> provide benefit. You have about an 80 percent chance of getting a more
> efficiency answer to that question without having to spend as much in
> resources.
>
> One of the benefits of this is that if you do obtain evidence that is
> encouraging but not conclusive, a follow-up trial could in fact be
> smaller. It would only have to be a study that would provide the
> traditional strength of evidence of a single positive study.
>
> An appropriate question, though, is if you get encouraging but not
> conclusive evidence, can you in fact validate that result; is it
> practical to do so?
>
> \[SLIDE\]
>
> To illustrate this issue, I would like to move to another setting that
> in fact in certain circumstances is very similar to what we are
> confronting today with microbicides. It is the surgical adjuvant
> therapy setting for colorectal cancer.
>
> This is a setting where a surgeon can make a complete clinical en bloc
> resection of the disease, but minimal microscopic undetected residual
> disease exists. It leads to the very significance risk of a 50 percent
> mortality within 5 years. For 20 years up to 1980, there had been
> repeated efforts of looking at adjuvant chemotherapy to try to reduce
> this risk, without success. So there was a very serious unmet need for
> survival hazards of 50 percent in this population.
>
> The particular trial in hand was looking at 5-FU levamisole and
> levamisole, and this study, the North Central Cancer Treatment Group
> study, was basically a 2B trial looking at about 100 events per
> pair-wise comparison. This study showed very encouraging evidence\--a
> 33 percent reduction in death rate\--from both 5-FU levamisole and
> levamisole alone.
>
> \[SLIDE\]
>
> In spite of the fact that there was a serious unmet need for survival
> in this setting, it was recognized that confirmation was necessary. A
> cancer intergroup study was done of approximately four times the size.
>
> \[SLIDE\]
>
> So this is at least an illustration that confirmatory trials of
> promising but not conclusive intermediate trials can be performed
> successfully. It also illustrates the value of confirmatory trials
> because they can reveal both true positives and true negatives, and to
> look at this more closely, 5-FU-levamisole had a 33 percent reduction
> in death rate. That was exactly confirmed by the cancer intergroup
> trial. However, levamisole alone also had had an estimated 33 percent
> reduction in death rate, but the much larger, more reliable trial
> showed that in fact that was a false-positive conclusion.
>
> So with this suggestive evidence of benefit of levamisole, it was
> actually proven to be an unreliable lead.
>
> This confirmatory trial was extremely important because it provided
> much more reliable evidence so that people in fact were able to be
> treated with a regimen that in fact was beneficial rather than a
> potentially somewhat less toxic regimen but in fact one that was
> established to not be beneficial.
>
> \[SLIDE\]
>
> The question is could an intermediate trial itself provide compelling
> results. An illustration of this could be provided by the HIVNET 012
> trial that was looking at mother-to-child transmission of HIV, looking
> at two short-course regimens. And again, this was a study that had
> approximately 100 events per pair-wise comparison.
>
> This study showed results that were in fact statistically very
> compelling, on the order of the strength of evidence essentially of
> two positive trials.
>
> Well, this in fact arose by essentially having an estimate of a 47
> percent reduction in transmission. So in this trial, we were right
> here at a 47 percent reduction that does in fact translate into
> compelling evidence of benefit.
>
> \[SLIDE\]
>
> In conclusion, just returning to the three points, for blinding,
> certainly a blinded control often is the gold standard. But we need to
> have reliable evidence that the placebo itself is inert, and might the
> physical barrier or lubricant or other effects that the placebo itself
> carries lead us truly to underestimating efficacy if we simply look at
> a placebo control.
>
> Furthermore, in this setting, efficacy and effectiveness are relevant.
> Microbicide regimens in fact have both an antimicrobial component as
> well as a behavioral component. Understanding the global effect that
> this intervention would have in the real world setting is important.
>
> There could be flexibility here, though. That is, certain trials such
> as the HPTN 035 trial could be studies designed to look at dual
> controls. It doesn\'t mean necessarily that all studies would have to
> have dual controls. If certain studies provide a foundation to
> understand more globally both the comparisons against placebo and
> against the open label, it is entirely possible that other studies
> could be designed by other sponsors that would simply have the placebo
> control.
>
> Secondly, relating to standard of care, FDA has shown flexibility in
> allowing single trials in some settings. When they have allowed single
> trials, they have consistently asked that data be \"robust and
> compelling.\" I believe sponsors would be well-advised, then, when
> planning single-study applications, to target strength of evidence
> that would be between that of one and two trials.
>
> And just as a simple example of these irregularities that can arise,
> in 2001, the Anti-Infective Drugs Advisory Committee was considering
> Zigris \[phonetic\] for another compelling unmet need setting, which
> is improvement of survival in severe sepsis patients. And in that
> particular trial, the results were in fact somewhat stronger than the
> strength of evidence of a single trial, one-sided .025. But there
> were, as is often the case in trials, irregularities. There were
> concerns in interpreting the data about inconsistencies in subgroups,
> about changes in the regimen, et cetera, and ultimately, that
> committee was left with a 10-10 vote, a split vote of uncertainty as
> to how to proceed.
>
> In fact when we are dealing with a single trial, it is advisable to be
> targeting stronger evidence to provide results that are robust and
> compelling.
>
> And finally, after Phase 1, particularly in settings where there is no
> biomarker for Phase 2 plausibility of efficacy, what is the right
> step? And I grant this is a very difficult issue. The HPTN in thinking
> about this issue had major jumps in jumping from roughly 100-person
> Phase 1 studies to a \$100 million, 8,000 to 12,000-participant
> four-arm Phase 3 trial. And in looking at this, those concerns were in
> part based on the fact that we don\'t have Phase 2 proof-of-principle
> biological markers to establish plausibility of efficacy and because,
> even though there had been extensive preparedness studies done to
> provide assurances that we could provide timely enrollment, high
> levels of retention, high levels of appearance, to be able to do so in
> the context of a 10,000-person study was something that the group was
> very uncertain about and much more comfortable moving into a
> 3,000-person study.
>
> Ultimately, this is a decision that each sponsor will make. It may be
> in the judgment of sponsors appropriate to jump into a Phase 3 trial.
>
> In closing, I would simply say that the goal is not specifically to
> get into a Phase 3 trial as soon as possible. The goal should be as
> soon as possible to complete Phase 3 trials that have robust and
> compelling evidence of a favorable benefit to risk.
>
> Thank you.
>
> \[Applause.\]
>
> DR. GULICK: Thank you, Dr. Fleming.
>
> Our final speaker of the morning is Dr. Bhore from the Division and
> the Agency.
>
> **Statistical Considerations for Topical Microbicide**
>
> **Phase 2 and 3 Trial Designs:**
>
> **A Regulatory Perspective**
>
> **Rafia Bhore, Ph.D.**
>
> DR. BHORE: Good morning.
>
> My name is Rafia Bhore. I am a statistician in the Division of
> Antiviral Drug Products at the FDA.
>
> Today I will be giving the FDA perspective on the statistical
> considerations when designing a clinical trial of topical microbicide
> for the prevention of HIV infection.
>
> \[SLIDE\]
>
> In this talk, I will first give an example of a Phase 2/3 clinical
> trial design of a topical microbicide in prevention of HIV infection.
>
> Next, I will discuss the issue of whether such a trial will include
> two arms or three arms. I will also talk about the p-value that is
> conventionally required, whether it is a single large trial or two
> trials, and the criteria to declare that the clinical study or studies
> are successful.
>
> I will also mention the statistical power considerations in designing
> a clinical study, give estimates of sample sizes as well as mention
> other considerations that will be important to ensure the success of a
> clinical study in preventing HIV infection.
>
> \[SLIDE\]
>
> In this hypothetical example, the objective of the clinical trial is
> to establish the safety and effectiveness of an investigational
> microbicide in preventing HIV infection.
>
> This is a three-arm study design. Test group participants are
> randomized to use the microbicide in conjunction with a condom for
> every sexual act. Control Group 1 will be randomized to placebo in
> conjunction with the condom, and Control Group 2 will only use the
> condom. This third arm has previously been referred to as the
> \"no-treatment\" arm by our FDA speaker, Dr. Teresa Wu. for the rest
> of this presentation, we will use these two phrases interchangeably.
>
> In such a design, we recognize that it will only be possible to blind
> the test group and the Control Group 1. Control Group 2 cannot be
> blinded and so will be open-label.
>
> \[SLIDE\]
>
> Should this study really have two arms or three arms? If two arms,
> then which control group should be included? Remember that the goal of
> this study is to establish the safety and effectiveness of the
> microbicide being investigated.
>
> \[SLIDE\]
>
> First of all, why is inclusion of a placebo arm necessary? The placebo
> arm will provide a means to blinding investigators and participants as
> to which product is being assigned, whether it is the investigational
> microbicide or the placebo. This kind of blinding, as we know from
> clinical trials, in general maximizes the likelihood of obtaining an
> unbiased estimate of efficacy of the drug that is being investigated.
>
> In a microbicide clinical trial, can we assume that the \"placebo\" is
> inert? In most cases, we do not know about the presence or absence of
> the antimicrobial activity of placebo, or it has not been proven in a
> clinical setting.
>
> So the question is: Is the effect of the placebo a protective effect
> or a harmful effect? If a placebo has a protective effect, then the
> investigational microbicide will have to be proven to be better than a
> placebo that is protective. This will make it more difficult to prove
> the efficacy of the microbicide.
>
> So far, some of our speakers have not considered the possibility that
> if a placebo is harmful, then a microbicide that is shown to be better
> than a harmful placebo may at worst be harmful itself, or the
> microbicide could have a neutral effect in preventing HIV infection.
> So we would like the Committee to keep this issue in mind during the
> discussion. Or, at best, the microbicide could be beneficial.
>
> Therefore, ideally, we want a placebo that is inert, and the placebo
> should have a neutral effect.
>
> \[SLIDE\]
>
> Next, why is the condom-only or no-treatment arm necessary? We know
> that the use of condoms is an established gold standard for the
> prevention of HIV infection. This arm is necessary because it will
> provide the real-world effectiveness of the microbicide in preventing
> HIV transmission. It will also provide data on the sexual behaviors
> associated with the use and non-use of microbicide products.
>
> Thirdly, recall that this is the single component of the other two
> arms that contain a gel and a condom\--gel being either the
> microbicide or gel being a placebo. We need to know what is the
> contribution of this gel component in preventing HIV transmission.
> This arm is therefore also important in order to help validate the
> safety and efficacy data from the placebo arm.
>
> \[SLIDE\]
>
> Now we will talk about the level of significance needed in designing
> such a clinical trial. In statistical jargon, \"level of
> significance\" is the probability of making a Type 1 error. A Type 1
> error is the error of incorrectly declaring that a drug is effective
> when it is not. So this is the error of getting a false-positive
> signal.
>
> In order to prove the effectiveness, we want a p-value which is based
> on the actual data to be smaller than the predefined probability of
> getting a false-positive signal.
>
> In simpler words, let\'s say, for example, a p-value less than .05
> means that there is a smaller than 5 percent chance of declaring a
> drug to be effective when in fact it is not.
>
> \[SLIDE\]
>
> So, conventionally, when designing Phase 3 clinical trials, one trial
> that is designed at a one-sided .025 level, or a two-sided .05, which
> is double of that, provides the evidence of one trial. We look for a
> p-value based on the data to be smaller than this number .05.
>
> In the regulatory environment, we conventionally require two adequate
> and well-controlled clinical trials each at a two-sided .05 level.
> Accordingly, two trials, each at the same level as before, will have
> an overall alpha of .00125, and hence, two trials will provide
> evidence worth two trials.
>
> So if one considers designing only a single large trial instead of two
> adequate trials, we would still require the overall level of
> significance to be the same as two trials, which is p-value less than
> .001. And that is the same as the previous line.
>
> In other words, the level of evidence with a single trial will need to
> be the same as that of two trials.
>
> Some sponsors have proposed to us in terms of designing a smaller
> single large trial that will provide the evidence worth one-and-a-half
> trials. This is a novel concept, and the Division of Antiviral Drug
> Products at FDA is open to discussing such alternative possibilities.
>
> \[SLIDE\]
>
> As I mentioned earlier, the conventional regulatory requirements for
> approving a drug for a single indication are two adequate and
> well-controlled clinical trials. So historically, this has been
> translated as follows.
>
> Each of the two trials will need to show a two-sided p-value less than
> .05. And if there are two separate microbicide trials, then the
> question is will they be run in parallel, or will they be staggered in
> time. If they are staggered, one needs to think about how much gap in
> time there will be. Since this is a prevention of HIV indication, one
> may not be able to do a second trial after the first trial is
> completed and the results are known.
>
> \[SLIDE\]
>
> Alternatively, if a single trial is conducted to show prevention, this
> single trial will need to show as strong and robust evidence as to
> separate trials. It may not even be repeatable due to ethical
> concerns.
>
> One trial will therefore need to show a two-sided p-value less than
> .001. And we showed the calculation of this number, .001, two slides
> ago.
>
> \[SLIDE\]
>
> Additionally, suppose that if one were to conduct only a single trial
> first, if we want to confirm the results of a single trial\--that is,
> if we want to replicate the results of the study in the future\--then,
> one important question is what is the probability of observing a
> statistically significant result\--for example, p-value less than
> .05\--if this clinical trial were to be repeated.
>
> So, assuming that the effect size that we observe in the first trial
> is the true effect, and if the first single trial has a p-value less
> than .05, then the probability of getting a significant result in the
> future is only 50 percent.
>
> Instead if the observed p-value the first time is .01, then the
> chances of seeing a significant result in the future, whether it is a
> future trial or in the actual environment, are higher. And in this
> situation, it is 73 percent.
>
> If this p-value is even smaller, and it is .001, the chances of seeing
> a significant result are much higher and increase to 91 percent.
>
> \[SLIDE\]
>
> Therefore, based on this discussion, when we consider the overall
> evidence of a single trial, a p-value that is less than .001 would be
> considered convincing; but a p-value that is greater than or equal to
> .01 would be inadequate. A p-value that falls in the gray area between
> .001 and .01 would be possibly adequate, provided that the results are
> consistent across various subgroups. This is also referred to as
> \"internal consistency of the data.\" In addition, if the p-value is
> in this gray area, we would need to see other supporting evidence that
> is strong.
>
> In the case of two trials, the collective evidence will be evaluated
> in a similar manner.
>
> \[SLIDE\]
>
> So if a three-arm clinical study is planned, what should be the
> criteria to declare that such a clinical study is successful?
>
> A win here means that the investigational topical microbicide is
> proven to be effective in the reduction of HIV transmission. We would
> declare a win if the HIV infection rate in the microbicide-containing
> arm is less than that in the placebo arm, and the HIV infection rate
> in the microbicide-containing arm is less than that in the condom-only
> arm. Each will need to show a p-value less than .001.
>
> And because there is no need for multiplicity adjustment, the overall
> Type 1 error, which is the probability of observing a false-positive
> signal, is maintained at .001.
>
> \[SLIDE\]
>
> But why do we need superiority versus the placebo arm? Let\'s look at
> two scenarios where the microbicide wins versus only one of the two
> controls, but it does not win over the other control.
>
> In the first case, if the HIV infection rates in the microbicide arm
> are lower than that in the condom-only arm, which is good, however,
> the rates in the microbicide arm are similar or could be even worse
> than that of the placebo, does this mean that the placebo is as good
> as the microbicide? This does not prove the efficacy of the
> microbicide.
>
> \[SLIDE\]
>
> In the second scenario, the HIV infection rate in the
> microbicide-plus-condom arm are lower than that in the placebo arm,
> but they are similar or even worse than the condom-only arm. What does
> this mean? It implies that the use of microbicide in combination with
> the condom did not provide any additional protection than a condom
> alone would provide. So the microbicide is not shown to be effective.
>
> \[SLIDE\]
>
> Therefore, in order to prove that the microbicide is effective in
> preventing HIV infection, it needs to be proven that the microbicide
> is better than both placebo and condom-only.
>
> \[SLIDE\]
>
> Now we will show some examples of estimates of sample sizes for a
> three-arm clinical design. The sample size of such a clinical trial
> will depend on a number of factors. Firstly, it will depend on what is
> the background rate of HIV sero-incidence. We will assume that this is
> the rate of the sero-incidence in the control arms. As mentioned in
> the FDA background document, we have seen numbers as low as .5 per 100
> person-years in the United States to numbers varying from 6, 7, and 9
> in countries outside the United States.
>
> Sample size also depends on the effect size. What is effect size?
> Effect size in simple terms means compared to the control, how
> effective is the investigational product. In the case of topical
> microbicides, sponsors are proposing that a new microbicide will
> further reduce the HIV sero-incidence rate by 33 percent to 50
> percent. We will show some examples in the next slide to clarify what
> does it mean by a 33 percent reduction or a 50 percent reduction in
> actual numbers.
>
> Thirdly, sample size will depend on the length of follow-up of
> participants\--whether they are followed for 12 to 24 months exactly
> for each participant or whether the study continues until the last
> participation completes 12 to 24 months.
>
> Since statistical power is directly related to the number of events
> observed\--that is, number of HIV seroconversions\--the more events
> are observed, the greater will be the power to detect the treatment
> effects. Therefore, it is advantageous to follow each participant
> until the end of the study so that the maximum number of events are
> observed.
>
> Thus, longer follow-up will maximize the power of the study without
> having to add more subjects.
>
> And finally, statistical power is also an important factor affecting
> sample size. We will discuss that later.
>
> \[SLIDE\]
>
> Here are some examples of sample size estimates. In these examples, we
> have assumed that the endpoint is timed to HIV seroconversion.
> Duration of the study is assumed to be 24 months, and the power for
> comparison versus each control is 90 percent. These are estimates for
> a single large trial conducted at the .001 level.
>
> Suppose the rate of HIV sero-incidence in any control group is 6 per
> 100 person-years\--and for simplicity, we will call this 6 percent. A
> 33 percent effect size means that the number 6 percent is reduced by
> one-third, so two-thirds of 6 percent gives 4 percent. This will give
> a total sample size if 12,520. This is the total sample size.
>
> Similarly, a 33 percent reduction from 7 percent rate of background
> infection means that the rate of HIV infection in the microbicide arm
> will be 4.67 percent. Or, if it is a 50 percent effect size, then a 50
> percent reduction from 7 percent means a 3.5 percent rate of infection
> in the microbicide arm.
>
> As you can see, if the expected background rate of HIV infection in
> the study population is higher, then the sample size is decreasing.
> Also, if the effect size is higher, the sample size decreases as well.
>
> However, if an unrealistically large effect size is assumed when in
> reality the microbicide has as small effect side, then there is a risk
> of underpowering the study. So the larger the effect size is assumed,
> the greater will be the risk of getting an unsuccessful study due to
> underpowering.
>
> Sample size is also dependent on the length of follow-up. Shorter
> study durations will require larger sample sizes, while studies with
> longer follow-up will have smaller sample sizes. So we encourage the
> sponsors to collect data with longer follow-up, which will likely
> require a lesser number of participants.
>
> \[SLIDE\]
>
> Because we want to ensure the success of the trial, we must take into
> consideration the statistical power when designing a study.
> Statistical power is a concept that is opposing to the concept of
> p-value. Statistical power is related to Type II error while p-value
> is related to Type I error.
>
> Statistical power is one minus the probability of Type II error, so
> Type II error is different from Type I error in that it is the
> probability of incorrectly declaring that the microbicide is not
> effective when in fact it actually is. So Type II error is also called
> \"probability of a false-negative signal.\" We want to minimize this
> probability of a false-negative signal and hence, we want to increase
> the power.
>
> \[SLIDE\]
>
> To determine power, we need to know the hypothesis to be tested.
> First, we want to test whether the microbicide-plus-condom arm has a
> lower HIV infection rate than placebo-plus-condom. Second, we want to
> test whether the microbicide-plus-condom arm has lower rates than
> condom-only. If we assume that the statistical power for each test is
> 90 percent, and we are seeking a 33 percent reduction in HIV infection
> from condom-only, then what is the overall power of getting a win for
> this study?
>
> We define a \"win\" if the microbicide wins against placebo and wins
> against condom-only.
>
> \[SLIDE\]
>
> This is a plot of the overall power of the study versus varying rates
> of risk reduction from placebo. When a background rate of HIV
> infection of 6 percent is assumed, we assume that this is the rate of
> HIV infection in the presence of the availability of condoms.
>
> And since we do not know or have not proven the activity of the
> placebo, HIV infection rate in placebo is a moving target. At point
> zero, the microbicide is identical to the placebo, which is this
> vertical line. And as you move right, the microbicide has higher HIV
> infection rates than the placebo. So placebo is better as you move to
> the right.
>
> And as you move to the left, the microbicide is much better than the
> placebo. When microbicide is much better than the placebo\--that is,
> 33 percent reduction, 50 percent reduction, 67, and so on\--then the
> statistical power of the study is at least 81.5 percent.
>
> In other words, the chances of the study to be successful are greater
> when the effect size of the microbicide is equal to or better than the
> placebo.
>
> However, if the placebo is as good as the microbicide, or if the
> placebo is much better, the statistical power of declaring a win will
> drop dramatically.
>
> \[SLIDE\]
>
> I will also mention a few other important considerations in order to
> ensure the success of the study. First of all, we recommend that the
> study be continued until the last subject enrolled completes at least
> 12 months on study.
>
> We also strongly recommend that the study personnel and sponsor be
> proactive in following the participants. This can be done by actively
> pursuing and identifying reasons for dropouts and continuing the
> follow-up after study drug discontinuation. If a participant is not
> followed after premature discontinuation of the study or study drug,
> this may raise a flag whether there are any drug-related safety
> issues.
>
> Given that the first generation of microbicides will be used for a
> long period of time, we have a number of points to clarify regarding
> long-term follow-up versus short-term follow-up.
>
> It is likely that most of the dropouts in a clinical study will be
> observed in the first year of follow-up, so participants who stay in
> the study through the first year will likely stay longer in the study
> through the second year.
>
> Additionally, long-term follow-up will help collect more person-years
> of data because of long-term exposure.
>
> And finally, if one observers higher loss-to-follow-up rates in
> long-term follow-up compared to a short-term clinical trial, this does
> not necessarily mean that the rates of loss-to-follow-up adjusted for
> time are higher with long-term than they are with short-term.
>
> \[SLIDE\]
>
> The second important consideration in design is monitoring the use of
> the condom and the microbicide. We recommend collecting data on the
> use of condoms as well as other barriers or drug use, because the
> evidence of efficacy is closely tied with the compliance of the
> product. There are four possibilities here: sexual acts with condom
> and with microbicide, without condom and with microbicide, and the
> other two are without microbicide and with or without condom.
>
> We suggest that the sponsor frequently collect information on the
> number of sexual acts with or without the use of condom and number of
> sexual acts with or without the use of microbicide so this
> recommendation will also hold for the placebo arm.
>
> \[SLIDE\]
>
> Finally, another consideration when determining the overall power for
> such a three-arm study design is the allocation ratio. Allocation
> ratio is the ratio according to which the total number of subjects are
> distributed or randomized to each study arm.
>
> Standard practice in clinical trial design is to allocate equal
> numbers of subjects to each group. This is called an allocation ratio
> of one is to one is to one.
>
> Alternatively, one could choose to assign unequal numbers of subjects
> to the three arms. For example, one may choose to assign 1-1/2 times
> as many subjects to the microbicide group than the control groups. So
> in this example, more participants are exposed to the microbicide, but
> the control groups have the smaller number, and both controls have the
> same number.
>
> This issue has been brought up because our preliminary analyses show
> that the alternative schemes of allocation ratios could likely
> maximize the power of a study to detect differences in HIV rates
> between test group and control groups. Also, such alternatives are
> proposed so that more safety data on microbicides could be collected.
> This alternative approach could be particularly applicable to the U.S.
> data where the goal is to maximize the amount of safety data that is
> collected in microbicide arm.
>
> \[SLIDE\]
>
> In summary, based on statistical considerations, I have discussed why
> a 3-arm design will ensure the effectiveness of the first microbicide
> ever for prevention of HIV and that such a study is studied
> appropriately.
>
> A single trial for the development of a microbicide in prevention of
> HIV is acceptable. However, in the interest of maintaining regulatory
> standards, a single trial will need show the same level of evidence as
> two separate trials. And this was reflected by the need to show a
> p-value less than .001.
>
> We also showed an example with estimates of sample sizes for a 3-arm
> single-trial design. Clearly, we know that sample size will depend on
> the number of assumptions, such as the background rate of HIV
> infections, the effect size of the topical microbicide, the length of
> follow-up, the level of significance, and the statistical power of the
> study.
>
> Topical microbicides are products that will potentially be used for
> the lifetime of a woman. Hence, an adequate length of follow-up of
> participants in a clinical trial will be extremely important in not
> only studying the safety of the product but also observing HIV
> infection rates due to long-term exposure.
>
> \[SLIDE\]
>
> I want to thank Dr. Teresa Wu and Dr. Debbie Birnkrant for their input
> in this thought process, and finally, thank you for your attention.
>
> \[Applause.\]
>
> **Questions from the Committee**
>
> DR. GULICK: Thanks, Dr. Bhore.
>
> We now have about an hour to entertain questions from Committee
> members.
>
> Our first four speakers are in the front row, and there is a mike
> there which they can respond to. Please come up to the front row, Dr.
> Van Damme. And then, Drs. Fleming and Bhore are at the table.
>
> So we will entertain questions from the Committee or points of
> clarification, and as usual, let\'s try to refrain from actually
> beginning to discuss the issues, because we have the whole afternoon
> to do that.
>
> Who would like to start us off?
>
> Dr. Mathews.
>
> DR. MATHEWS: I have a question for Dr. Van Damme. I was struck by the
> failure of the Phase 2 trial that you talked about to show the
> toxicity associated with the nonoxynol-9 preparation in terms of
> breach of the cervical vaginal mucosa, and I am wondering if it is not
> so much a sample size issue as a use condition issue in terms of
> frequency and so on, and if the problem is not necessarily solved by
> increasing the sample size but designing the Phase 2 trial in such a
> way that the use conditions would approximate what you would expect to
> see in a larger trial with a more heterogeneous population.
>
> DR. VAN DAMME: I do not have a definitive answer to that. I do think
> the sample size is important to enroll in that study where we
> considered the Phase 2 data for 320 women on which we had colposcopy
> events. The women who were in that study, as I said, were really out
> of Phase 3 study population, so they could use the product as they
> were going to use it into the Phase 3. Indeed, for instance, a center
> in Bangkok was part of that Phase 2 study, which had a much lower rate
> of use than other populations, but the biggest center in the Phase 3
> trial and also driving the results which was observed is a center
> where the women who were in Phase 2, were in Phase 3. So those are
> driving the data, and those women were there from the very start.
>
> DR. MATHEWS: And their behavior didn\'t change over the\--
>
> DR. VAN DAMME: Not that we could document, no\--do you mean from the
> Phase 2 to the Phase 3?
>
> DR. MATHEWS: Yes.
>
> DR. VAN DAMME: No.
>
> DR. MATHEWS: So what do you think actually explains the difference,
> then, why it was detected\--
>
> DR. VAN DAMME: I do think sample size. We don\'t have enough power to
> detect an effect. You need a huge sample size to detect such an
> effect, which we never do in a Phase 2.
>
> DR. MATHEWS: But the point estimates in the Phase 2 trial\--did they
> even suggest a difference?
>
> DR. VAN DAMME: A difference between the lesions in the two arms?
>
> DR. MATHEWS: Yes.
>
> DR. VAN DAMME: No.
>
> DR. MATHEWS: So if the point estimates didn\'t even make the
> suggestion of a difference, it strikes me that it is not just a matter
> of sample size.
>
> DR. VAN DAMME: Can you repeat your question?
>
> DR. MATHEWS: What I\'m saying is that that Phase 2 trial had something
> like 800 patients in it.
>
> DR. VAN DAMME: No. The data for the Phase 2 includes 320 women on
> which we did analysis.
>
> DR. MATHEWS: Okay.
>
> DR. VAN DAMME: And that could also be indeed one visit into the trial.
>
> DR. MATHEWS: All right. Thank you.
>
> DR. GULICK: Dr. Wood, and then Dr. Sherman.
>
> DR. WOOD: This question is for anyone from the FDA. Multiple
> presentations have all reinforced that any study of microbicides is
> going to be done in the background and the setting of condom use.
>
> Is there any requirement for looking at whether or not the placebo gel
> vehicles or the microbicide itself has any effect on condoms in terms
> of stability, breakdown, chemical interactions, those kinds of issues?
>
> DR. WU: That is a very good question, and at FDA, we regularly
> recommend the sponsor to conduct a condom compatibility study with
> both placebo and a microbicide to be tested.
>
> DR. GULICK: Dr. Sherman?
>
> DR. SHERMAN: Thank you.
>
> The question initially will be for Dr. Karim, although others may
> choose to address this as well. It has to do with the data that you
> showed on condom use since that is part of the assumptions and the
> background of any of these studies that there is going to be a
> baseline level of condom use and that everyone is going to be
> counseled to use condoms. You had indicated that 43.7 percent had been
> used after 5 weeks in the analysis you did.
>
> Can you expand on that in several ways\--first, what is the
> generalizability of these data to different populations around the
> world? Second, when you talk about use, is there any more specific
> data\--was it used 43.7 percent of the time by 47.3 percent of women
> every time they had a sexual contact, or is there considerable
> variability where one woman uses it 47 percent of the time\--because
> those things make a big difference in how we interpret that background
> protection.
>
> DR. KARIM: Let me answer the first question on the generalizability of
> those results. The sites were chosen in terms of both rural and urban
> areas. So I would imagine that the data are reasonably representative
> of South Africa but probably not representative of anything more than
> that. I wouldn\'t want to presume that 43 percent of condoms taken
> from public health services in any other country would be used within
> 5 weeks.
>
> But let me address your second question, which is the critical one,
> and it is probably better to go to the COL trial. You heard that the
> Durban site had the largest sample size contribution, and it is
> certainly true that the patients or the subjects in the COL trial had
> high levels of product use.
>
> When they were enrolled, we measured the condom use in the last sexual
> acts, and on enrollment in these sex workers, condom use varied from
> between 10 and 14 percent of sexual acts. Now, within that group, we
> have documented quite extensively that there is a very small subgroup
> who insist on condom use fairly routinely. But even in that group,
> they do not have 100 percent condom use.
>
> Then there are others, particularly the newer women coming into the
> truckstops, who simply haven\'t yet learned how to get condom use from
> the truck drivers, so they have very low levels of condom use.
>
> So the enrollment figure of 10 to 14 percent reflects that variability
> within the sex worker population. Upon enrollment, when we look at
> condom use within the first 4 months, it goes up to almost 40 percent.
> So there is no question that when you bring people into a trial like
> this, and all you do is you keep telling them about the importance of
> condoms and you keep giving them condoms all the time, they do
> increase their condom use. But what we do notice is that that is not
> sustained, and certainly we did not see women being able to implement
> 100 percent condom use to any significant degree.
>
> DR. GULICK: Dr. Barlett?
>
> DR. BARTLETT: My question is directed to Dr. Van Damme, Dr. Nunn, and
> perhaps also Dr. Karim.
>
> You have expressed concern that the follow-up rate in the condom-only
> group may be lower and that that may be a reason to have some
> apprehension about randomization to this strategy. I am wondering if
> there is any evidence from clinical trials that the follow-up rate
> would be lower, so ideally, if you have an evidence-based answer, and
> if not, do you have experience that would make you feel this way?
>
> DR. VAN DAMME: I\'m not sure that there is indeed evidence that women
> would leave the trial sooner or more than when they are assigned to
> the no-gel arm.
>
> I think Mark River \[phonetic\] from \[inaudible\] can report more
> accurately on their own trials in Cameroon where indeed there was a
> no-gel arm. This fear is based mainly on when we talk with
> investigators worldwide about how they feel the study population they
> will be recruiting will be looking at it. I myself was involved in a
> no-treatment arm in Antwerp, and I could already see that it was
> indeed more difficult to recruit women in the trial, but it is the
> fear also that when women are in a trial and are not using a product,
> it seems to then, \"Why am I in a trial, and what am I contributing?\"
> And we may counsel as much as \[inaudible\]\--some things which,
> despite intensive counseling and explaining of the procedures\--it is
> difficult to keep the women motivated and strictly to the science.
> Science is not always as easy to grasp.
>
> So it is mainly based on a feeling that is expressed by investigators
> in the field.
>
> DR. BARTLETT: Is the investigator from the Cameroon trial here?
>
> DR. VAN DAMME: The statistician is here.
>
> DR. BARTLETT: Would you mind addressing that question? I\'m sorry I
> don\'t know your name. If there is data, that would be great.
>
> I\'m sorry, I can\'t hear you. Do you want to come up to the mike?
> Thank you.
>
> DR. DOMINIK: I am Rosalie Dominik, and I am with FHI. We have the
> paper, and you specifically asked about the follow-up rates in the two
> groups, right?
>
> DR. BARTLETT: Right. I think that\'s what we were referring to.
>
> DR. DOMINIK: I was going to try to find it right in here\--but maybe
> we can come back on that.
>
> DR. GULICK: Yes, sure, we can come back. I\'m sorry to put you on the
> spot.
>
> DR. KARIM: I don\'t have a direct answer to your question. We have
> never done a trial like this before; that\'s why there is all the
> debate. But I can tell you that in trials that we have done, we have
> been able to maintain generally very high levels of follow-up. And
> certainly in the COL trial, we have had very high levels of follow-up.
>
> We also have very high levels of follow-up in our regular cohort
> studies. We have several cohort studies where there is no
> intervention, and we are able to maintain follow-up.
>
> I think it is very difficult to extrapolate both of those to a setting
> where some people are getting product and others are not. So I\'m not
> sure if it helps, but I am just giving you the chronology information
> that we do have.
>
> DR. NUNN: If I might just very briefly answer the previous question,
> because the question was asked as to whether in fact as well, if there
> was evidence from other areas about condom use.
>
> We are currently actually looking at the condom use in other
> countries\--Zambia, Tanzania, and Uganda\--and in fact we are finding
> much lower rates than in South Africa. Indeed, even after intensive
> counseling, it is not changing much. But there is a very different
> pattern according to what type of partnerships people are in,
> actually, as to whether they are using condoms or not.
>
> To the question about follow-up rates in the context of a
> no-treatment. One of the problems here\--and I am not thinking
> specifically about this sort of trial because we haven\'t conducted a
> microbicide trial before\--but in other trials in other areas of
> infectious diseases and so on, we have always had a treatment of some
> kind, a placebo of some kind, in fact in order to be able to reduce
> biases. So actually, it is in part based, as one of the other speakers
> said, on the perception of the local investigators about their
> concerns, particularly as the women are looking forward in
> anticipation to something which they can use apart from condoms which
> actually might be valuable to them. And I think their concern is if
> they were getting nothing, they would feel there was nothing in this
> trial for them.
>
> What I would say also is that in fact in a preventive therapy study
> for opportunistic infections in HIV-infected patients, a large study
> is going on in Zambia at the moment where we have noticed as time goes
> on that there is a tendency to drop off. The women in a post-natal
> women\'s study we are doing, as they are followed up for one year, two
> years, three years, are less likely to come as time goes on. They just
> begin to get fatigued within the study and lose interest, too, despite
> encouragement to continue to continue to come.
>
> DR. FLEMING: Before leaving this point, might I just add some
> evidence-based experience? I think Dr. Bartlett\'s question is very
> appropriate\--what do we actually know from experiences? The HPTN has
> nearly finished one major trial that might provide some insight into
> this. It is a 4,000-person comparative trial looking at an intensive
> behavioral intervention against a standard, and it is unblinded,
> open-label, as I said, 4,000 participants. And interestingly, in this
> experience, the challenge in retention has been much greater in the
> active experimental arm. We actually have a higher retention in the
> control arm. And as we have been monitoring this study, we have been
> having to work extraordinarily hard to actually bring the retention
> rates in the experimental arm u to the level in the open-label control
> arm.
>
> The second interesting point about this is in fact, I think,
> consistent with the point that I think Rafia was making in her
> presentation, and that is, this is a study in which the participants
> are followed for 3 to 4 years, and the loss-to-follow-up rate was much
> higher in the first 6 months. We probably lost 5 to 8 percent in the
> first 6 months. Out to 3 years, the cumulative loss-to-follow-up rates
> are only about 12 percent.
>
> So a large fraction of those that were lost over 3 years of follow-up
> were actually lost in the first 6 months, which provides some
> additional incentive for the fact that as you follow longer in time,
> you get a lot more events without in fact correspondingly have a lot
> more additional loss-to-follow-ups in that particular trial.
>
> But it is interesting in this one experience that the reverse of what
> we are hearing being predicted actually occurred in this 4,000-person
> open-label trial.
>
> DR. GULICK: Dr. Fleming, I have a follow-up question to that. Can you
> tell us what the intervention was in that study?
>
> DR. FLEMING: Yes. It\'s called the HTPN 015 trial, and it is a
> randomization in MSNs, men who have sex with men, looking at standard
> behavioral intervention against a more intensive behavioral
> intervention to try to reduce risk-taking behavior and improve
> protection against transmission.
>
> DR. GULICK: And what is the interpretation for the differential rates
> of follow-up? How do you explain that?
>
> DR. FLEMING: Well, it\'s always speculation as to whether or not
> people are leaving for various reasons. I think the best speculation
> in this setting might be that it is a more intensive, burdensome
> involvement to be involved and active, and that could in fact be
> influencing. But I have to say it is not perfectly clear what all the
> factors would be.
>
> DR. GULICK: Thanks.
>
> Dr. Paxton, a follow-up point.
>
> DR. PAXTON: Just a question\--you said that most of your
> loss-to-follow-up occurred in the first 6 months. Was that group
> substantially different in terms of their risk behavior when you
> looked at them?
>
> DR. FLEMING: It\'s a very good question as well. It\'s always very
> important to do everything possible to fully retain people, because in
> most instances, missing-ness is informative, i.e., those people who
> aren\'t followed are different from those who are.
>
> This particular trial, this 015 trial, had a series of eight to nine
> behavioral interventions over a 6-month period. There is a striking
> relationship in that those people who were predominantly going through
> all of the intervention were in fact then retained. Those people who
> were dropping out of the intervention early in fact were also much
> less likely to be retained and, when we looked at their baseline
> characteristics, were in fact associated with characteristics that
> typically would characterize them as being at higher risk.
>
> So there is loss of events and hence there is loss of efficiency when
> you have missing-ness, but of much greater concern is the bias that is
> induced if there is differential loss to follow-up in people who are
> leaving being different from those who are being followed. And some
> people have said, well, we\'ll correct this\--let\'s say there is 20
> percent missing-ness\--we\'ll correct this by increasing sample size
> by 20 percent. And I say, well, that gives you a more precisely biased
> estimate. Your only true correction is to really ensure that we have
> procedures in place to minimize loss-to-follow-up.
>
> DR. GULICK: A couple of follow-up points\--Dr. Bartlett and then Ms.
> Heise.
>
> DR. BARTLETT: So, Dr. Fleming, the HPTN 015 trial is being done in
> MSMs in the U.S. and Western Europe, and the loss-to-follow-up rate at
> the greatest is about 12 percent.
>
> DR. FLEMING: Yes. The overall retention through 3 to 4 years is about
> 88 percent, so there is an annual average retention rate of about 97
> percent annualized.
>
> DR. BARTLETT: But it would be fair to say that that\'s a really
> different population than what we are going to be talking about.
>
> DR. FLEMING: Indeed it is a different population.
>
> DR. GULICK: Ms. Heise?
>
> MS. HEISE: I think the field has very little experience to go on. I
> believe you have the only experience that you will share with us in a
> moment. But I do think there has been behavioral and social science
> data done at these sites are part of the preparatory work. And I think
> the concern is less about whether or not you can enroll people in
> let\'s say just a condom promotion study and follow them successfully,
> but what happens when you have a group of women who are very
> interrelated and one thing that everyone wants a lot and the others do
> not.
>
> In these trials, there is up to a year or more of preparatory work
> done in the community about the trial coming, and education on
> microbicides, and the possibilities. And it does create\--which is
> very difficult to counterbalance\--this real desire\--these are
> desperate women, and they desperately want something to try to use
> because they already have the experience that condoms don\'t work.
>
> So we have to work, or at least investigators have to work really hard
> to try to counterbalance the notion of the hope that something will
> work. When you have that strong a hope, and you have some groups of
> women who are getting the hope and some who are not getting the hope,
> that\'s what creates the problem, I think\--at least that is the fear.
> And I think in your trial, it actually wasn\'t borne out, if I recall
> correctly.
>
> DR. DOMINIK: Well, the study statistician actually isn\'t here. But
> there were 1,200 participants in this trial where participants were
> randomized to either the gel-plus-condom arm or the condom-only arm,
> and this was only a 6-month study, so it is a little different from
> some of the studies that we\'re talking about, but there was an
> extremely high follow-up rate achieved in this study\--in fact, there
> were only 20 participants lost to follow-up, but 13 of those were in
> the condom-only arm and 7 in the gel-plus-condom arm.
>
> Also, with respect to reported condom use, in the condom-only arm,
> participants reported using condoms in about 87 percent of acts versus
> 6 percent less often condoms were used in gel-and-condom group. Of
> course, that is just reported condom use. We don\'t really know true
> use.
>
> DR. GULICK: And did I understand correctly, just to clarify, that this
> is really the best data we have right now to try to answer this
> question?
>
> DR. DOMINIK: Somebody else would have to answer that.
>
> DR. VAN DAMME: Yes. As far as I know, it is the only microbicide trial
> which has been done. I talked about effectiveness with the
> no-treatment arm; as I mentioned, we did a no-treatment arm in the
> safety study before.
>
> DR. GULICK: Dr. Flores and then Dr. Haubrich.
>
> DR. FLORES: In addition to the potential differentials in
> lost-to-follow-up, I think we have to be very concerned about
> potential differentials in actual behavioral impact of being in an
> active arm versus being in a control no-treatment arm. And I would
> argue that we could expect that in the placebo arm, the effect on
> placebo is zero, both in efficacy and safety if that is equal to the
> no-treatment arm.
>
> If this were a vaccine trial where you compare to vaccines, and one
> had no effect, I would argue that you have the tendency to combine the
> two control arms and therefore have an impact on the power of the
> study to analyze. I\'m not suggesting to do that, but I think if we
> really feel that it is possible to have a control/no-treatment arm
> that would be somewhat a surrogate of a placebo in addition to
> placebo, then we need to make sure that in addition the potential
> share of product, the potential differential in follow-up rates, and
> behavioral impact are going to have to be an important factor to take
> into account.
>
> DR. GULICK: Again, let me suggest that we try to avoid getting into
> the discussion at this point and stick to questions. Those are
> important points that we\'ll get back to in the afternoon.
>
> Dr. Haubrich and then Ms. Heise.
>
> DR. HAUBRICH: My question is for our statistical presenters. One
> scenario that in Dr. Fleming\'s talk I didn\'t see addressed would be
> if, in the no-treatment control, the condom-only arm actually ended up
> doing better than both other groups because in the gel receivers,
> there was a reduction in condom use because they perceived that the
> gel was better\--it\'s a new thing, they don\'t need to use condoms,
> they can get more money from their clients, et cetera\--so the two
> questions are how do we deal with that, because you could say you
> could try to look at that by looking at condom reported use behavior,
> but if reporting of condoms or sexual acts is anything like adherence
> to antiretroviral therapy, we have solid data now, based on MEMSCAPS
> \[phonetic\] that it is notoriously underreported.
>
> So how would we deal with that, and what would be the outcome if a
> study showed in fact that the treatment was better than the control,
> but both were significantly less than the no-treatment condoms alone?
>
> DR. FLEMING: I\'m just trying to best understand the exact scenario.
> It sounds similar to what was in the six scenarios I gave the upper
> left-hand scenario where the condom arm was definitely better than the
> open-label, but the microbicide arm didn\'t show up as being better
> than the condom-only arm; is that essentially the circumstance you\'re
> talking about?
>
> DR. HAUBRICH: Well, unless I\'m looking at the wrong slide, it looks
> like the condom arm and the treatment arm are the same\--
>
> DR. FLEMING: Yes\--2 percent, 2 percent, 3 percent.
>
> DR. HAUBRICH: \--and the control.
>
> DR. FLEMING: So if you just give your scenario in terms of percents,
> what setting are you asking us to\--
>
> DR. HAUBRICH: No. It\'s similar to that except that, say, the
> treatment is better than the control, so 2 percent, 1 percent, 3
> percent.
>
> DR. FLEMING: Well, in fact if that occurred, which is even a more
> extreme example, what is evident when you would compare the placebo to
> the open-label is that either the placebo itself is extremely
> beneficial or adherence to the blinded arms are very much higher so
> that the risk levels are much less. In that setting as well the one
> that I gave that is less extreme, you would come away with a clear
> indication that the antimicrobial effect of the intervention is not
> adding, so you certainly wouldn\'t be marketing that microbicide,
> although it could give clues that other elements of the intervention
> carried by the placebo, specifically, the physical barrier, the
> lubrication effects, et cetera could be in fact protective.
>
> And I mentioned briefly that there are many other settings other than
> topical microbicides that the FDA has considered with sponsors the
> merits of having both placebo control and open-label control in
> settings where there are uncertainties about whether the placebo is
> inert and in settings where understanding where globally effectiveness
> is important in addition to efficacy. And in one such setting in the
> past year, this very scenario is what arose. There was no additive
> effect of the antimicrobial agent, but the placebo was much better
> than the open-label.
>
> DR. GULICK: Dr. Bhore has a follow-up.
>
> DR. BHORE: Yes. I want to clarify the question asked by Dr. Haubrich.
>
> Are you trying to ask about a scenario where the no-treatment arm
> shows greater reduction in transmission than the other two arms? Is
> that what you are asking?
>
> DR. HAUBRICH: Yes.
>
> DR. BHORE: Well, if that happens, then let\'s give an example in terms
> of numbers. Let\'s say the infection rate in microbicide is 3 percent,
> placebo is 3 percent, but for condom-only, it is only 1 percent, so
> condom-only or no-treatment\--
>
> DR. HAUBRICH: What I actually meant is let\'s say 4 percent in the
> treatment\--2 percent in treatment, 4 percent in control, and 1
> percent in the condom-only. So that essentially what happens is people
> stop using the condoms in the two gel arms so their\--
>
> DR. BHORE: So that is an example of the scenario I showed where I said
> the microbicide turns out to be better than the placebo arm, but it is
> almost the same as condom or it is worse. So 2 and 1 percent, we
> don\'t know if that\'s statistically significant, and in that
> situation, then, you have to ask the question: Well, microbicide is
> showing to better than placebo, but we don\'t know if the placebo was
> harmful. Is that why it showed placebo had higher rate, or whether
> truly the microbicide is good? So if the microbicide is showing 2
> percent and no-treatment is showing 1 percent, the question is what is
> the microbicide adding to the condom-only, to the condom component. So
> that raises a dilemma.
>
> But of course, we would have to look at the collective evidence if
> such kind of data arises, because we would look at consistency of the
> data internally and whether there is any other supporting evidence. So
> this could become a review issue when we look at the data.
>
> DR. GULICK: Ms. Heise and then Dr. Washburn.
>
> MS. HEISE: I have two questions, and I direct them to whomever might
> have data to address them.
>
> One is we have talked about threats to validity in terms of
> loss-to-follow-up, and I heard Dr. Bhore say that if we go longer, we
> get more events and whatever. But I\'m wondering what we know about
> rates of pregnancy in these cohorts. My assumption is that in many
> cases, the women who become pregnant during the trial, so over the
> 2-year rate, would go off product and then be lost to a potential
> event. And my experience is that even women who say they will use
> contraception and are not necessarily desiring to have a pregnancy in
> the 2-year, that many women within the developing country settings
> that we are working in actually do become pregnant.
>
> So I was wondering if anyone could comment on whether there is any
> data about the potential impact of pregnancy on follow-up rates and
> how that would influence shorter follow-up times versus longer
> follow-up times.
>
> That\'s the one question.
>
> DR. NUNN: I\'ll give a partial answer to this question and also just
> make a brief comment on the previous one about the condom use.
>
> A point that I hoped to have put across earlier in my presentation was
> that we do get tremendous variation between different sites in Africa.
> I mean, condom use in South Africa compared to condom use in places
> like Zambia and so on is very, very different in rural areas of
> Zambia. We are talking about a situation where getting people to use
> condoms is actually very difficult.
>
> As far as pregnancies are concerned, in the early data that we have
> actually gotten from our feasibility studies we are conducting, we are
> showing, for example, in a site in Johannesburg that in fact we are
> getting very, very few pregnancies because they are using effective
> contraception in that population. But the data that we are getting
> from Tanzania and from Zambia is quite different, where in fact they
> are not using the same level of contraception, and we anticipate that
> in a trial context, quite a high proportion of women will become
> pregnant in the course of a trial. And of course, the longer the trial
> goes, the greater the chance that that will be the case.
>
> In Tanzania, we actually asked the women about their intention to
> become pregnant in the next 12 months, to look to see whether we could
> exclude those who intended compared to those who didn\'t. We actually
> found that those who intended to become pregnant were less likely to
> become pregnant than those who didn\'t, so it didn\'t actually work.
>
> \[Laughter.\]
>
> DR. VAN DAMME: I\'m not sure I really understand the question. In COL
> 1492, we did tests on pregnancies, yes, quite a lot.
>
> MS. HEISE: And did they continue on product, or were they lost\--I
> mean, did they stop product?
>
> DR. VAN DAMME: We did not consider them lost. They were discontinued
> from product. They could stay in the follow-up trial, but they were
> discontinued from the product, yes\--unless a woman expressed\--may I
> say this here\--unless a woman expressed that she wanted a termination
> of pregnancy.
>
> DR. KARIM: I don\'t remember the exact pregnancy rate in the COL
> trial, but I can tell you in one cohort where we followed young women
> age 18 for about 2-1/2 years, close to one out of four became pregnant
> during that period\--and these are very young women who are in their
> most reproductive period, and the use of contraception in that group
> is quite low.
>
> I do think that that is a major consideration, that these women when
> they become pregnant remain at risk of HIV, but they are not using
> product anymore. And in the intention-to-treat analysis, of course,
> that pushes down our ability to show a difference.
>
> So it is a major consideration when we have very long follow-up
> periods.
>
> DR. GULICK: And data from the Cameroon study?
>
> DR. DOMINIK: The earlier Cameroon study that was a one-year study of
> an N-9 film versus a placebo film that also had about 1,300 women,
> there were only 5 women overall who became pregnant during that study,
> but that was a sex worker population.
>
> It was also a very small number of pregnancies in the 6-month Cameroon
> trial, but I don\'t have those exact figures.
>
> DR. GULICK: Thank you.
>
> Dr. Washburn and then Dr. Englund.
>
> DR. WASHBURN: This is a question for any of the presenters who might
> have any information about this. Commercial condoms that are available
> in drugstores, many of them have lubricants on them. Is there any
> evidence whether those lubricants affect HIV transmission?
>
> We recommend to our patients that they use condoms to prevent HIV
> transmission outside the context of these studies, so one would hope
> that those lubricants are at least neutral\--so an idea comes up that
> we can talk about this afternoon.
>
> DR. GULICK: Dr. Birnkrant, do we have any data?
>
> DR. BIRNKRANT: Well, there is, I believe, a lack of data with regard
> to N-9 impregnated condoms. That is, it is not really known whether
> N-9 impregnated condoms are any better than condoms without N-9 in
> them.
>
> With regard to more inert lubricants, I don\'t think we have that type
> of data to show that the lubricated ones are more effective than the
> non, except when it comes to breakage rates, perhaps.
>
> DR. GULICK: Someone is signaling me from the audience. If you have
> some data, we would be happy to hear it\--and please introduce
> yourself, too.
>
> DR. FARLEY: I am Tim Farley from the World Health Organization.
>
> I don\'t have data which addresses this directly, but I can tell you
> the most common lubricant in condoms is just a silicone oil. I am not
> aware of any information that indicates that that is protective
> against HIV.
>
> The other issue which is a concern, of course, is if people are using
> N-9 condoms, but as far as I know, all the studies that have been in
> the field and are thinking of going in the field are specifically
> going to be providing non-N-9-lubricated condoms.
>
> So I think we can be reassured that the lubricant in the condoms which
> are used is not active in any way.
>
> DR. GULICK: Thanks, Dr. Farley.
>
> I have Drs. Englund, Stanley, and then Paxton.
>
> DR. ENGLUND: I pass.
>
> DR. GULICK: Okay. Dr. Stanley.
>
> DR. STANLEY: I am just trying to get a handle on the behavioral
> aspects, and I guess perhaps Dr. Nunn or Dr. Karim\--can somebody
> summarize for me what we know about changes in condom use behavior
> upon enrollment in all the clinical trials that we have been talking
> about and particularly when they are getting something additional? We
> really need to get a handle on understanding that in this population
> because that is where these studies are going to be done, and I am
> just having a hard time getting a grasp on that\--I mean, if people
> looked at before enrollment and then after and things like that.
>
> DR. KARIM: I can only reiterate some of the data which we know from
> the COL study. The COL study used coital logs in order to measure
> condoms. And we actually determined later on that it wasn\'t a very
> accurate measure in that women were sometimes seen filling out the
> logs while they were waiting in the waiting room.
>
> So we do have that as a genuine measurement problem. What we do know
> from the COL trial is that condom use on enrollment\--and in fact, we
> had done several studies before this cohort was enrolled looking at
> condom use\--we know that condoms were used in aggregate in about 10
> to 14 percent of sexual acts. It varied over the years that we
> measured it.
>
> However, we do know that when we put them into the trial, in the first
> 4 months when we looked at it, condom use did go up very
> substantially. Whether that is because they thought we expected them
> to say that they had used the condoms that we had just spent all this
> time trying to tell them they should be using, I can\'t answer that,
> but I would be surprised if condom use didn\'t go up. However, it was
> not sustained, and that was the other part.
>
> DR. GULICK: Others? Again, I\'m sorry, I don\'t know your name. Please
> introduce yourself at the mike before your follow-up comment.
>
> DR. STEIN: Dr. Stein, Columbia.
>
> I had some data also from the sex workers in the COL 1492 which I
> haven\'t discussed. I have this from Dr. Gita Ranjee \[phonetic\],
> Joanne Mantel \[phonetic\], and Linda Mayer \[phonetic\], who did a
> follow-up series of focus groups with women who had been on the COL
> 1492. They had been told the results of 1492, which was negative, and
> they had also been told repeatedly that the microbicide was different
> from the placebo and that they were to use a condom. And I have
> actually some of the conversation\--I was going to enter into this
> later\--some of the conversation in those focus groups.
>
> DR. GULICK: I\'m sorry\--could you speak right into the mike?
>
> DR. STEIN: They felt that the condoms were cleansing and probably kept
> out what was harmful in the semen, and that so good did it feel that
> they rejected the male condom in favor of the gel. And they had, of
> course, been strongly and repeatedly counseled against doing just
> that.
>
> So we do have some information that after being on the gel for some
> time, they said, \"Good,\" which is very good, of course, for the
> future of microbicide testing, but is problematic in terms of the
> trial.
>
> DR. GULICK: Was there any data from the Cameroon study? I\'m sorry we
> keep coming back to you\--but in terms of changes in condom use before
> and after enrollment into the study.
>
> Dr. DOMINIK: At baseline in the original, the 1991 study, about 45
> percent of participants said they had used a condom during their last
> act; and condom use during the trial was reportedly sustained at a
> very high level of around 90 percent.
>
> DR. GULICK: In both arms.
>
> DR. DOMINIK: Right. But that was a blinded study.
>
> In the study where we had an unblinded arm, about 60 percent of
> participants reported that they had used a condom during their
> previous act at baseline; and then, during the trial, in the
> condom-only arm, there was about 87 percent condom use, and in the
> other arm, the N-9, 81 percent condom use was reported.
>
> DR. GULICK: Okay. Is this a follow-up comment?
>
> MS. HEISE: This is more data.
>
> DR. GULICK: More data. We like that.
>
> Ms. Heise?
>
> MS. HEISE: Unfortunately, it is not here, but there have been two
> global reviews, one by UNAIDS and one by the London School of Hygiene
> and Tropical Medicine, that specifically look at all of the data both
> in terms of condom use rates pre-intervention and condom use rates
> different types of interventions.
>
> And one thing\--even across widely differing scenarios, I think there
> are two truths that come out of both of those studies. One is that the
> rate of consistent condom use that you can achieve is most defined by
> the type of partner that you are talking about. So that, for example,
> the very same people in this very same intervention done trying to get
> people to use condoms with a casual, a new, or a paying client achieve
> much higher rates of consistent condom use than where it is being
> introduced with a regular partner.
>
> So for example, even in these rates where you have sex workers who are
> achieving 90 or 80 percent consistent condom use with clients, they
> aren\'t using them with their boyfriends or their husbands.
>
> So when you talk about condom rates and what can be achieved, you have
> to think about who you are enrolling and what type of partner they are
> talking about. And that is consistent across every, single study.
>
> The other thing you see is that people over-report condom use,
> especially in the context of trials. So you have lots of examples
> where people are saying they are using them 100 percent of the time,
> but they are getting pregnant or they are getting STDs. So we know
> that overreporting of condom use in terms of social desirability in
> this trials is a problem that is very difficult to manage. And I can
> give the committee any of those reviews if you are interested.
>
> DR. GULICK: Dr. Van Damme, a follow-up?
>
> DR. VAN DAMME: Yes. I can confirm with Lori that also in the COL 1492
> trial\--again, these are self-reported data\--that indeed condom use
> with clients was achieved at a much higher level than we could achieve
> with what we call regular partners in the trial.
>
> DR. GULICK: So just to clarify this point, and then I am going to come
> back to my list, I promise\--your question, Dr. Stanley was how much
> data do we have on condom use before enrollment into a study and then
> after enrollment into the study. And if I understood, the data from
> the Cameroon study was that rates went up, but they went up in each
> arm.
>
> Is that correct? You said it was about 60 percent of baseline and then
> on the study, it was 81 to 87 percent in the two arms.
>
> DR. DOMINIK: Yes. That is true for COL 1492, too.
>
> DR. GULICK: Thank you.
>
> Waiting patiently\--Dr. Paxton?
>
> DR. PAXTON: Actually, I have a question, and I\'m not sure to whom to
> address it, but it\'s about the potential for gel-sharing.
>
> I personally find the theoretical arguments about how this might occur
> and the rationale behind it to be quite compelling. But I was
> wondering, for example, from the world of antiretroviral treatment in
> resource-poor settings, is there any data that we have from that
> showing that people might share their drugs? I remember when that was
> starting several years ago, people would said people will take their
> drugs and give them to somebody else they know who is infected.
>
> Did that in fact occur?
>
> DR. GULICK: Dr. Haubrich has some data.
>
> DR. HAUBRICH: I have no data, but I have anecdotal experience from our
> training with African military groups where the availability of
> antiretrovirals is extremely limited, and they said sharing is quite
> common.
>
> DR. GULICK: Okay. Dr. Nunn?
>
> DR. NUNN: I just wanted to say\--it wasn\'t an antiretroviral
> situation; it was actually antibiotic prophylaxis where women had been
> enrolled into a study, their partners discovered in fact that the
> women were in the study, and they didn\'t like it at all, and they
> either said, \"I\'m going to have some of that drug, or you aren\'t
> going to be in the study,\" or in fact they actually told either women
> to get out and leave home.
>
> So in fact there was the sort of feeling\--this was men and women, of
> course\--but there was the sort of feeling of why should some people
> have it and not others. I know in some studies now with
> antiretrovirals, we have to look very carefully, like giving
> antiretrovirals to children without giving it to their parents, so in
> fact the design actually makes sure that we are incorporating the
> parents and getting them treatment as well, because you can\'t
> realistically expect them to say we are giving you what could be
> effective treatment, but we\'re going to deny it to another member of
> the family.
>
> So I think we are aware of the problem, but I don\'t think there is
> any other data on antiretrovirals from recent experience.
>
> DR. GULICK: Dr. Barlett, a follow-up comment.
>
> DR. BARTLETT: Just a historical comment to Dr. Paxton\'s question. We
> were involved in the original Phase 2B/Phase 3 study of AZT, and
> indeed, there was some sharing of drug among study participants in
> that trial that was done in the U.S. And if anything, the bias that is
> introduced is to diminish the difference between groups. So with
> regard to the U.s. context, we saw that as well.
>
> DR. GULICK: Dr. Englund, a follow-up?
>
> DR. ENGLUND: Two things. First of all, I think there is good
> documentation that there is drug-sharing. In pediatric studies and
> studies ongoing right now in Kinshasha \[phonetic\] in Zambia, we will
> only treat children when the parents are simultaneously being treated
> because of documentation of drug-sharing. So that is well-known.
>
> And that brings me to my question for perhaps our honored guest, and
> that is are there age differences. We are hearing good data showing
> that our younger girls are the ones who are getting infected, and that
> certainly is what I see in inner city Chicago as well as in Africa.
> And certainly who we would aim an intervention at potentially, I saw
> your study enrolled girls down to age 16, which doesn\'t quite capture
> it, but it\'s getting down there.
>
> What are we seeing in terms of age differences in condom use and the
> pressure that these younger girls may be getting?
>
> DR. KARIM: I actually don\'t have data from Hlabisa on condom use in
> young girls, but I have data from Wulanladla \[phonetic\], another
> rural area closer to Durban where we have been following girls as
> young as 12. These are girls who are coming in either for family
> planning or they are coming in as pregnant women for antenatal care.
> And we have been following them up now for the last 8 months or so.
>
> Condom use in this young age group is negligible. It is so low that we
> are only occasionally finding them using condoms. So although we are
> now using hundreds of millions of condom pieces, my suspicion is that
> most of those are being used in concordant sexual acts and largely in
> older groups.
>
> The big problem that we have with these young girls is that they are
> having sex with much older men, where they are really quite powerless
> in terms of their ability to insist on condom use. There is also a
> tendency in this group for slightly more violent or more aggressive
> sexual behavior as well.
>
> DR. GULICK: Dr. De Gruttola, and then Dr. Brown.
>
> DR. DE GRUTTOLA: I have a couple questions for Dr. Van Damme or Dr.
> Karim or anyone else who may have the information.
>
> Dr. Karim mentioned that following pregnancy, the product may be
> discontinued in the course of one of these studies, and that would
> lead to an attenuation of the effect, potentially. I also wonder if
> there are issues about following women who are pregnant if it is more
> or less difficult to follow. Obviously, if there were effects of the
> intervention on pregnancy as well as on transmission, differential
> follow-up could complicate interpretation. So I just wondered what the
> experience was in Dr. Van Damme\'s study or anyone else in terms of
> following women who are pregnant and in terms of continuing use of
> product during pregnancy.
>
> DR. VAN DAMME: In the trial, they were not allowed\--as far as we
> could control it\--to continue product use once they were pregnant. So
> I don\'t think we can speak on that.
>
> DR. DE GRUTTOLA: How about follow-up of the women after they became
> pregnant?
>
> DR. VAN DAMME: That was more difficult since women who are pregnant,
> there was \[inaudible\], since we discontinued their product, of
> staying in the follow-up of the trial.
>
> DR. DE GRUTTOLA: So did you have a sense that you were losing the
> majority of them to follow-up of the pregnant women, or\--
>
> DR. VAN DAMME: I do not have \[inaudible\].
>
> DR. DE GRUTTOLA: I see.
>
> DR. GULICK: Dr. Karim had a follow-up.
>
> DR. KARIM: Just to comment\--we were one of the sites and the largest
> site in that trial. The one big problem we had was once the women
> became pregnant, they left the truckstop, and that was the way in
> which we maintained the follow-up. So that was a real big problem for
> us to keep them in the study.
>
> However, they do eventually come back to the truckstop, so we would
> have some blood at some point in those subjects, but they haven\'t
> been using product for quite a while in the meantime.
>
> DR. DE GRUTTOLA: But it would certainly help in terms of completeness
> of follow-up, as you point out.
>
> DR. VAN DAMME: A lot of the pregnant women also choose to terminate
> the pregnancy, so they come back into the trial.
>
> DR. GULICK: Dr. Wu had a follow-up comment, and then we\'ll come back
> to your next question.
>
> DR. WU: Yes, I would like to make some comments regarding pregnancy
> and being retained in the trial.
>
> DR. GULICK: Can you speak up?
>
> DR. WU: Typically, for any drug, for any microbicide, before being
> administered to humans, they have to undergo a reproductive toxicity
> study. There are several stages. Usually, the first stage is for
> fertility, the second stage is to check embryo toxicity. And most
> topical microbicides have to go through this test before they can be
> given to women of childbearing age.
>
> However, if they are willing to go all the way up to the third stage,
> that is, perinatal toxicity testing, also conducted before getting
> into human trials, then pregnant women can be given this microbicide,
> because in animal toxicity, all three stages have been cleared in
> terms of toxicity.
>
> However, most sponsors only conduct up to two stages and leave the
> third stage sometime during Phase III clinical trial. Then they do
> concurrent animal testing. Therefore, once the woman becomes pregnant,
> the woman would discontinue drug administration, but once the child is
> born, after a certain period of time, they are allowed to come back.
> Some sponsors have used this type of clinical trial design, and FDA is
> supportive of it.
>
> DR. GULICK: Thanks.
>
> Back to you, Dr. De Gruttola.
>
> DR. DE GRUTTOLA: I had one question on Dr. Van Damme\'s slide on
> CONRAD\'s approach to design of these studies. In that slide, you
> listed a one-year retention of 80 percent, and obviously, that high
> loss-to-follow-up could be a concern regarding bias as well as
> attenuation of power. And I believe you mentioned that there was some
> evidence of problems of retention that would make this a plausible
> rate, so I was wondering if you could comment on that.
>
> DR. VAN DAMME: This is based on the experience also within the COL
> 1492 trial, and in CONRAD\'s trial, we will again recruit women at
> high risk which can now be sex workers or general population women
> under the high risk criteria. And there is strong evidence in real
> life that these are very difficult populations to really keep in your
> trial all the time, for up to 98 percent. Those women are mobile; they
> often lack the motivation to stay in the trial. There are multiple
> reasons why, at one moment or another, they decide they may want to
> leave the trial.
>
> So we try to have our sample size calculations based on real life
> experience.
>
> DR. DE GRUTTOLA: I have a question there. If you expect your event
> rate to be considerably less than your loss-to-follow-up rate, do you
> have concerns about bias\--Dr. Van Damme\--or Dr. Karim\--whoever
> would like to respond.
>
> DR. GULICK: Victor, do you want to repeat the question?
>
> DR. DE GRUTTOLA: Yes. I just wondered if the loss-to-follow-up rate is
> expected to be about 20 percent, but the event rate considerably less
> than that, I would think there might be a concern about bias as well
> as loss of power, since even a modest amount of differential
> loss-to-follow-up could impact on the study and impact on its
> validity.
>
> So I just wondered if Dr. Van Damme or Karim or anyone else had any
> comment on this issue of bias and validity in the face of a
> loss-to-follow-up rate that may be higher than the event rate.
>
> DR. NUNN: I\'d like to make a comment which actually is picking up one
> of the points in my presentation, that we are concerned that that
> could well be the case.
>
> In most populations in Africa, even in rural populations, not just in
> urban populations or populations with sex workers, there is migration,
> there is mobility. I was involved in a cohort study which has now
> being going on for 13 years in Uganda in which we saw 7 percent of the
> population actually moving out of their address each year, some coming
> back again as time went on. And with this in mind, this is one of the
> reasons in fact that we are considering within the UK Microbicide
> Development Program looking at a shorter duration to overcome this
> problem\--in other words, as short as possibly 6 months\--because we
> believe that then we could actually considerably reduce the
> loss-to-follow-up rate and the biases associated with it and get a
> much closer estimate of true efficacy as distinct from perhaps
> effectiveness. We would be nearer efficacy than effectiveness. And we
> are actually considering that right now.
>
> The other possibility is actually a site such as one of our sites
> which is a sugar plantation where people are much, much more
> constrained and not moving around. But in many other populations, we
> are already finding there is a great deal of mobility in populations.
>
> DR. KARIM: I\'ll just make two points. I don\'t need to tell this
> group that it is really difficult to maintain follow-up in healthy
> subjects. It is a very different scenario from doing long-term
> follow-up on ill patients.
>
> So in prevention trials, generally, it is difficult for us to maintain
> very high levels of follow-up.
>
> I will say that the big concern would be\--and this is my second
> point\--if the follow-up were differential in the arms, and if there
> might be some relationship between the outcome and the follow-up. I
> think in the one instance that we are dealing with, which is HIV
> seroconversion, fortunately or unfortunately, it is a silent
> condition, so it is unlikely to be the event that precipitates the
> loss-to-follow-up, I would hope. But it is a concern and it is a very
> deep concern in all the prevention trials that we are doing, and I
> share it with you.
>
> DR. GULICK: Okay. We are going to need to begin to wrap up our
> question-and-answer period.
>
> Dr. Fleming has one really important follow-up comment.
>
> DR. FLEMING: And I think Dr. De Gruttola has just hit on a very key
> point, and just to reiterate what he was referring to\--how
> problematic is it in settings where the number that are lost exceed
> the number that have events. And I would just like to reiterate to be
> careful not to assume that if you follow people longer, you are in a
> worse situation.
>
> Just to briefly use the actual data from 015 as an illustration, in
> the first 6 months, for every 100 people, we had 8 lost and one event.
> In the period from 6 months to 3-1/2 years in that same cohort of 100
> people, we lost about 4 additional people and 4 additional events. We
> did much better by following over a long term to be able to be
> accumulating number of events versus number lost to follow-up.
>
> So be very careful not to assume that just because longer-term
> follow-up means more people will be lost, you are actually going to be
> inducing more bias. That may not be the case.
>
> DR. GULICK: Dr. Bhore, a follow-up?
>
> DR. BHORE: Yes. I want to reiterate the same point as Dr. Fleming,
> which is that it is quite likely that most of the lost-to-follow-ups
> will happen early on, and those who stay long enough will likely stay
> longer. And there has been data in many clinical trials of longer-term
> follow-up in other disease areas.
>
> Secondly, if you adjust the rate of lost-to-follow-up by time for
> shorter-term trials versus longer-term trials, the adjusted rate may
> not necessarily be higher in the longer-term trials than in the
> shorter-term.
>
> DR. GULICK: Dr. Brown, waiting patiently.
>
> DR. BROWN: I think the discussions this morning have raised a lot of
> ethical questions, and I\'ll try to limit myself to one or two.
>
> Obtaining informed consent has always been difficult for me. I have
> worked in populations where a chief of a tribe gave informed consent
> for the tribe. I think we are nowhere near that extreme in these
> studies, but I would like to ask the first two speakers how they are
> able to avoid investigator bias in the presentation of the study to
> the patient in the hopes of getting informed consent.
>
> By the very nature of their work, these women have a person who has
> control over them because they are going to buy a service from them,
> telling them to do one thing; an investigator who, at least at a
> superficial level, is telling them the opposite thing\--that is, to
> wear a condom\--and yet down deep the investigator knows the more
> condoms that are worn, the harder the study will be, and it might wind
> up destroying the study if enough people do what they are supposed to
> do.
>
> I am just wondering how you handle those issues, and do you really
> believe you get informed consent?
>
> DR. GULICK: Dr. Karim or Dr. Van Damme?
>
> DR. VAN DAMME: It is a very good point. Do we get really informed
> consent\--I think we really do try to explain to the women as much as
> we can and is feasible and achievable what the study is about. One of
> the two that I used in COL 1492 trying to get an idea about whether or
> not they really understand is when I was in the centers, I would do
> random sampling of the women who were there and just ask them, \"Can
> you explain to me what this is all about?\"
>
> But as you pointed out, there are different things. I think the staff
> working on the trials are trained enough not to bias and encourage not
> using condoms. But there are things which are very difficult to
> believe, like a doctor or a clinical staff who tells you that, yes,
> this is a trial going on, and there are definitely positive side
> effects for the women in the trial. So they assume that indeed it is
> good, and those women also hope it is good. And by being in the trial
> and having regular controls and STI treatment, indeed they do feel
> better, and they may contribute to the gel.
>
> So I think it is always kind of double-edged, where you trade off and
> try to do the best you can by explaining over and over. As I said, we
> also introduce some questions on the basic designed at the end of the
> informed consent session, which we repeat throughout the trial to be
> sure that women stay on track and try to have them forget as little as
> possible that this is a trial, and we do not know the effect; it may
> have no effect or a negative effect. We do the best we can, I think.
>
> DR. KARIM: I\'ll just make two quick points, and I can refer you to a
> paper that we published in the American Journal of Public Health
> looking at this issue. In that study, we took women who were
> participating in a perinatal trial, and we assessed the voluntariness
> of their consent as well as the informed-ness of their consent.
>
> What we found was that the women were very highly informed and were
> making the decision based on information. But what we found was that
> they were in a subtle way feeling coerced to participate because they
> felt that if they didn\'t participate in the study, the quality of the
> antenatal care that they would get at this hospital would not be as
> good, that they would have to join the rest of the queue.
>
> So there are subtle pressures, there are push and pull factors in the
> sort of setting that we are talking about. And it is true that the
> patients who are participating in our studies get a better standard of
> care. That is one of the incentives.
>
> However, I think it is less of an issue in prevention trials, in a
> setting where the patients are not beholden on the health care service
> and the research is not linked to the health care service. So in
> prevention trials, the issues are slightly different. There, some of
> these pressures remain, but they are not as acute. And generally, from
> our experience in the COL trial and in several other studies, we have
> done quick assessments of the informed-ness of the patient, and what
> we find generally is that if you take the time and trouble, they do
> understand what is going on.
>
> And lastly, I want to point out that no matter what I think about
> condoms undermining the studies, the people that we have, the
> community educators that we hire and the nurses who are actually
> involved with the patients really care, they care deeply about these
> patients and these subjects, and they would go out on a limb to do
> what they can for these subjects.
>
> These are not drug trials. These people are participating in these
> trials as people who are working from the community because they
> genuinely feel that they want to do something about this epidemic.
>
> So I think it is less of a concern if I was doing the counseling. I am
> very confident when the community educators are doing it.
>
> DR. GULICK: Thank you.
>
> I have a few quick questions myself. Dr. Van Damme or Dr. Karim, when
> a woman is randomized to receive the microbicide, how much of a supply
> does she receive at each study visit?
>
> DR. VAN DAMME: That depends on her own needs, so she would tell us how
> much she needed, and she could get as many as she wanted. The boxes
> contain 30, one for each day. Some sites put a limit, say, you can
> only get three boxes, and then you have to come back to the clinic, to
> avoid sharing of the product being on the market. That was driven by
> the center itself.
>
> But in principle, women could get what they thought they needed during
> that month, and some of the women are very active.
>
> DR. GULICK: So essentially no limit.
>
> DR. VAN DAMME: Essentially no limit.
>
> DR. GULICK: Okay.
>
> Dr. Wu, you mentioned \"universal placebo.\" Could you say a little
> more about that? Is that something that is being driven by regulatory
> guidelines?
>
> DR. WU: No. This is an idea which came from sponsors. The so-called
> universal placebo means it is the same placebo. It is unrelated to any
> of the known topical microbicides they wish to test. One company is
> willing to supply this to other companies, and therefore the data can
> be shared with other sponsors. This is the so-called universal
> placebo.
>
> DR. GULICK: So this was developed by industry and is now being shared
> among\--
>
> DR. WU: At least so far, we know it is being used by at least the two
> sponsors.
>
> DR. GULICK: And does the universal placebo need to fulfill some
> regulatory requirements itself?
>
> DR. WU: Yes. The highest burden is on the first sponsor who is going
> to test. First of all, they have to undergo a limited amount of a
> non-clinical study and also a Phase 1 study to make sure it is safe
> before they can be applied to humans. So there is some requirement for
> that.
>
> DR. GULICK: Okay. My last question is for Dr. Bhore. If I understood
> correctly in thinking about the three-arm design, one of the goals is
> to show an incremental benefit of the microbicide above condom use,
> above baseline condom use.
>
> DR. BHORE: It is not the baseline. Each arm is receiving condoms, and
> two of the arms are getting let\'s say the gel if it is a gel, and the
> third arm is not getting any such gel. So the third arm is getting the
> condom only. The goal at the end of the trial is to show that the
> infection rate in the microbicide-plus-condom arm is lower than that
> in the condom-alone arm, and the rates are lower than that in the
> placebo-plus-condom arm. So it is not what happens at baseline, at the
> end of the trial, whatever is planned.
>
> DR. GULICK: And that\'s my point. So I understand the design, but your
> assumption is that condom use remains the same in all three groups
> during the study.
>
> DR. BHORE: Yes. That\'s why we would need to see the behavioral data.
> It is going to be a complex issue to analyze.
>
> DR. GULICK: So this is something that we\'ll take up more in the
> afternoon, I believe.
>
> Okay. We are really to the end of the hour, so are there any really
> burning important questions that must be asked right now?
>
> DR. BHORE: I had a comment on the condom use raised by Dr. Brown.
>
> DR. GULICK: Okay.
>
> DR. BHORE: It is possible that the investigators and the study
> personnel could influence the counseling in terms of condom use. So
> for example, two of the arms would be blinded, and one is open-label,
> and if the study personnel were to influence the use of condoms by
> differential counseling in the blinded arm versus the open-label arm,
> this could create problems in interpreting the data.
>
> However, if we had three arms, we would feel at least somewhat
> comfortable that the two blinded arms would have the same kind of
> condom use patterns because they are blinded, and the investigators
> and study personnel hopefully cannot distinguish between a microbicide
> product and the placebo product.
>
> Therefore, blinding is a very useful thing to do in clinical trials
> because it minimizes that kind of bias introduced by study personnel.
>
> DR. GULICK: Dr. Wood, we will have one last question from you.
>
> DR. WOOD: Since condom use clearly can change and is highly variable
> among populations geographically, the question I have goes to the
> studies that have already been done, and that is the incidence of STIs
> as a surrogate marker for condom use in clinical trials. We have heard
> about pregnancies, but has there been anything where people analyzed
> the incidence of STIs among arms as a surrogate marker for condom use?
>
> DR. VAN DAMME: The secondary objective of the trial was to
> \[inaudible\] gonorrhea, chlamydia \[inaudible\], and we saw no
> effect.
>
> DR. GULICK: So you saw no differences in the two arms.
>
> DR. VAN DAMME: No differences between the two arms.
>
> DR. GULICK: Okay. That was very informative. Thanks to everybody.
>
> It\'s 12:15. We\'ll reconvene at 1:05. Let me just say that we have a
> number of people signed up for the open public hearing, and we need to
> organize this in a way that we can get through as much as we can in an
> hour. So would people who signed up to speak please come back 10
> minutes early and meet with Tara Turner to go over the podium and the
> speakers?
>
> Thanks.
>
> \[Whereupon, at 12:15 p.m., the proceedings were recessed, to
> reconvene at 1:12 p.m. this same day.\]
>
> [A F T E R N O O N S E S S I O N]{.underline}
>
> \[1:12 p.m.\]
>
> DR. GULICK: Welcome back from lunch.
>
> We had one clarification that Dr. Van Damme wanted to make.
>
> DR. VAN DAMME: Yes. I would like to clarify something about the
> retention rate, and I\'m sorry I didn\'t grasp that correctly before
> the lunch break.
>
> We do not plan to lose 20 percent of the women; we plan to have 80
> percent retention after one year, so 80 percent of the women
> completing one year. The other 20 percent can leave the trial, but we
> will have endpoint definitions, but they can decide to leave the trial
> because they move, because they become pregnant, or whatever. So it\'s
> not that they are really lost to follow-up without any endpoint
> definition.
>
> So we will have a majority of those women endpoints.
>
> DR. GULICK: Thanks for that clarification.
>
> We\'ll go now into the open public hearing part of the meeting, and we
> have a number of people who have signed up to speak. I will call
> people in order, and it would probably be most convenient for you to
> use the podium\--and we are going to be a little bit strict about time
> today.
>
> Our first speaker is Dr. Richard Bax, from Biosyn, Incorporated.
>
> **Open Public Hearing**
>
> DR. BAX: Thank you.
>
> I am Richard Bax, Chief Scientific Officer at Biosyn. Previously, I
> have been involved in the development of lots of antibiotics, such as
> kefluoroxin \[phonetic\], kefataxin \[phonetic\], marupenam
> \[phonetic\]. And I led the development of the eight indications and
> three formulations of famcyclovir \[phonetic\] and pencyclovir
> \[phonetic\] for Smith Kline Beecham, the new formulations of
> augmentin, and bactriban. I have been at Biosyn for 3-1/2 years.
>
> \[SLIDE\]
>
> Biosyn is the leading microbicide company. We have three
> compounds\--one in Phase III, C31G, which is shortly to enter a Phase
> III in Ghana and Nigeria under FHI; also, under NICHD in the U.S. for
> a contraceptive gel claim. We also have just started under CONRAD a
> Phase I study of UC781, which is an NNRTI inhibitor for use as a
> microbicide which has great promise. And we also have from the NCI a
> protein called synavarian \[phonetic\] which blocks GP120 in the
> preclinical situation.
>
> \[SLIDE\]
>
> What I am going to be talking about in the next 6 minutes is what
> Biosyn and others such as FHI\--and they will talk for
> themselves\--want to do. We want a Phase III trial design which
> prevents introduction of unknown biases because of the unblindedness.
>
> We are using the HEC common or universal placebo in our studies both
> in C31G and later with UC781, which will provide a very useful frame
> of reference for other studies, and the HEC placebo that we are using
> promises to have the least effect of any placebo.
>
> We believe that the 12-month maximum duration maximizes compliance and
> good clinical practice and reduces participant fatigue, and also will
> reduce significant changes in risk behavior of those at 24 months
> compared to 12 months.
>
> \[SLIDE\]
>
> We want to compare our active product, C31G, to a pretty inactive
> placebo to do a simple, statistically correct study. We do not believe
> that the addition of a condom-only arm will actually provide the kinds
> of controls that are required\--in fact, it will likely introduce
> bias.
>
> \[SLIDE\]
>
> Here are the choices for a three-arm study for no treatment, for
> placebo gel, active gel with condom controls. And as you can see, each
> of the three groups has different choices. Different choices lead to
> different behaviors. And we have no idea because of the uncertainty of
> compliance and of the sexual practice log whether or not those biases
> have been introduced post hoc of the randomization, and we will never
> know.
>
> It seems to me that a statistician is a cynic in a world of
> uncertainty, and the addition of the condom-only arm will increase
> that uncertainty.
>
> \[SLIDE\]
>
> We want to produce the best, most effective, most credible clinical
> trial which will assess the effectiveness of this product against
> placebo. There are certain credibility machineries within clinical
> trials which include ethical statistical practices, which we will
> adhere to; comprehensive protocol development and review with experts
> and the FDA and interim analysis; and the application of the baseline
> difference avoidance tools, and also, most importantly, replicate
> studies.
>
> It appears to me that there are many more important issues for
> microbicide trials than we are discussing today. They include,
> clearly, study selection, site selection, how the study is conducted
> and, most of all, compliance.
>
> I think the most important factor is that what will happen is that it
> will be easy to actually show that effective microbicides are not
> effective, rather than that not effective microbicides are effective,
> and that point is certainly endorsed by Dr. Andrew Nunn.
>
> \[SLIDE\]
>
> So I believe that the progress to date of the microbicide community
> into Phase III, which is the only possible way a microbicide will
> become available, has been at best regrettable and at worst appalling.
> I believe that now is the time to do a statistically correct, simple
> study which has a chance of showing an effective agent is effective
> rather than talking about a third arm with lots of uncertainties,
> raising the hurdle unnecessarily and also talking about significantly
> long trials, which also are undoubtedly going to introduce biases.
>
> The last point I would like to make\--and it is an important
> point\--is that there is a constant in medicine, and that is that the
> greater the likelihood of an adverse event like death due to HIV, the
> greater the benefit of the treatment or the medicine.
>
> In the United States, I believe there are approximately 20,000 HIV
> transmissions a year estimated due to heterosexual sex. In the
> developing world, there are 16,000 per day. I believe that the
> risk-benefit of such a product is very important and very different in
> the developing world, but we should apply the right science, the right
> statistics, the right trial, and do it now.
>
> Thank you.
>
> \[Applause.\]
>
> DR. GULICK: Thanks, Dr. Bax, and thanks for sticking to the time as
> well.
>
> Our next speaker is Dr. Polly Harrison, Director of the Alliance for
> Microbicide Development.
>
> DR. HARRISON: Thank you.
>
> I want to preface what I am going to say with two observations. One,
> the origin of this presentation\--it comes out of a n interactive
> process that has been going on over the last few months as these
> issues have come to a peak, shall we say, and this paper and the
> conclusions I am going to present represent the consensus among 17
> participants from nine different entities. So it is a consensus
> document, and I want you to understand it as such.
>
> Because time is limited, and a number of things have already been
> said, I will not focus on those; I will just proceed through the
> slides and pick out the high points or the points that have not been
> addressed.
>
> \[SLIDE\]
>
> There are some contextual issues that have not arisen in the course of
> the conversation today. One is that when we talk about HIV/AIDS, we
> are talking about one of a family of emerging and neglected diseases
> that are effectively orphaned by the pharmaceutical industry because
> the bottom line is not perceived as sufficiently rewarding.
>
> This creates a set of issues for all of us that have commanded the
> interest of the world community, so there is now a process that the
> European Medicines Authority and the WHO have engaged in, which is to
> examine how we can adjust for the different risk-benefit ratios we are
> seeing globally with the kinds of regulatory processes that we all
> engage in.
>
> We urge\--our recommendation is, if you will see the action
> item\--CDER\--the Center for Biologics is already involved in this
> activity\--we would recommend or hope that CDER would become engaged
> as well.
>
> \[SLIDE\]
>
> The control arm\--there has been a lot of conversation about that, and
> I\'m not going to go into the pros and cons of the no-treatment arm.
> I\'ll just go to the bottom line.
>
> It was the conclusion of the group that the contextual realities\--and
> in the interest of full disclosure, I must identify myself as a
> medical anthropologist, so I am concerned with the behavioral
> realities, as I think many of us are\--we believe that the contextual
> realities around the fields that we are trying to discover trump what
> would be nice to know. The closure that we have come to is that if the
> 035 trial goes ahead with a no-treatment arm, that would be
> salubrious, perhaps, for the field in terms of satisfying a number of
> questions\--in fact, whether indeed that is an interpretable addition
> to a trial design\--but that the other trials that are approximately
> concurrent would go on in the same time frame. In other words, they
> will not be blocked by this enduring question.
>
> \[SLIDE\]
>
> Now, the duration issue. Again, I won\'t deal with the strengths; they
> have been discussed already today, and I won\'t repeat them. But I do
> want to point to one thing that I think has not been mentioned. One
> argument for a longer period of on-treatment evaluation and
> post-treatment follow-up is if the seroconversion rates are uneven
> over time.
>
> The evidence that we have\--and admittedly, it\'s not a lot\--is that
> they are not uneven over time, and so that in effect disqualifies this
> criterion, perhaps, as an argument for a longer follow-up period.
>
> \[SLIDE\]
>
> I again won\'t deal with the limitations. The bottom line for us was
> that quality trumps quantity for quantity\'s sake. In other words, we
> believe that the quality of the data that can be derived from a
> shorter period of follow-up will be superior to the actual number of
> datapoints gathered over a longer period.
>
> The recommendation of the group was that there should be a maximum of
> 12 months on-treatment evaluation per participant.
>
> \[SLIDE\]
>
> Strength of evidence\--I am not going to talk about p-values.
>
> The bottom line here\--and I think maybe we have sensed it in the
> course of the morning\--is that in a way, we are in a data-free zone
> when it comes to how we put all the ingredients of the ultimate
> strength of a trial, the ultimate power, together, the action item
> that we perceive as desirable here is that you trade off the arm, the
> condom-only arm, the no-treatment arm, for a\--\"relaxed\" is wrong
> there; it should be \"a more stringent\" p-value\--in other words, you
> can ask more of your p-value of two arms, and you can perhaps add more
> subjects per control and placebo arms.
>
> \[SLIDE\]
>
> The final thing is the definition of a \"win\". Again, we have a
> double-standard, if you will, for 035 and other trials.
>
> We urge that the criteria for defining a \"win\" with respect to 035
> be that beating one control arm would be adequate. We have three. If
> you beat one control arm, that\'s adequate if the other goes in the
> right direction\--and Dr. Fleming alluded to that earlier this
> morning.
>
> With the other trials that are ongoing, we ask for flexibility with
> respect to dropping the no-treatment arm, and in that case, we would
> expect that the one arm would have to be beaten well.
>
> \[SLIDE\]
>
> Adherence\--that is not something that the FDA has to do, but it is
> something to which the FDA is entitled in terms of quality of data. It
> is critical for interpreting results, for formulating claims, for
> labeling, for registration. It matters very much. And we don\'t have
> any true measure of adherence, so it is the job of the field to do
> better with the approaches that we have, to replace them with more
> rewarding techniques, and finally, to learn from others. And I would
> submit to you that we do have some learning on which to build.
>
> The experience with the female condom is such that we can learn, and
> one of the most important lessons that perhaps we can learn is that if
> we engage the community and integrate it into the process of the
> trial, our chances of getting good data will be much enhanced.
>
> Thank you very much.
>
> \[Applause.\]
>
> DR. GULICK: Thank you, Dr. Harrison.
>
> Our next speaker is Dr. Ian McGowan from the David Geffen School of
> Medicine at UCLA.
>
> DR. McGOWAN: Mr. Chairman, ladies and gentlemen, I\'d like to begin by
> thanking the FDA for giving me the opportunity to briefly discuss the
> subject of rectal microbicide development during this session.
>
> I would also like to acknowledge support from Ken Mayer \[phonetic\],
> Peter Anton \[phonetic\], and Michael Gross in preparing this very
> brief talk.
>
> Oscar Wilde described a type of \"love that dare not speak its name,\"
> and based on the proceedings so far today, I think we could add anal
> intercourse, rectal mucosal vulnerability to HIV, and rectal
> microbicide development as possible other types of behavior that dare
> not speak its name.
>
> However, the primary focus of this meeting is a discussion of the
> methodological challenges in designing vaginal microbicide efficacy
> studies, so perhaps to some, the topic of rectal microbicide
> development may seem irrelevant or at least a distraction.
>
> I hope that in the remaining 6 minutes and 4 seconds, I can persuade
> the Committee and the audience that we really need to keep this issue
> of rectal microbicide development as an important component indeed of
> vaginal microbicide development as well as on its own basis of rectal
> microbicide development.
>
> \[SLIDE\]
>
> I would like to address three questions. First of all, why develop
> rectal microbicides; secondly, what are some of the challenges; and
> finally, what is the current status of rectal microbicide development?
>
> \[SLIDE\]
>
> Why develop them? I think it is self-evident to many in the audience
> that anal intercourse remains the primary risk factor for HIV
> transmission amongst MSM. What is perhaps less appreciated and
> poorly-defined epidemiologically is that the prevalence of anal
> intercourse amongst the heterosexual population is underappreciated
> and indeed represents a significant risk for HIV transmission.
>
> Much anal intercourse, particularly in the heterosexual population, is
> unprotected. The mucosa is incredibly vulnerable to transmission, and
> based on N-9 experience, vaginal products may just not be suitable for
> rectal administration.
>
> \[SLIDE\]
>
> These are some data, not comprehensive but I think illustrative,
> looking at prevalence of anal intercourse. The baseline data from the
> HPTN EXPLORE study demonstrated, perhaps not surprisingly, that
> approximately 50 percent of men who have sex with men practice anal
> intercourse.
>
> Again, perhaps surprisingly, Michael Gross was able to define in his
> study of high-risk women a prevalence rate of 32 percent; in
> heterosexual college students, 20 percent; and in a California-based
> adult survey, 6 to 8 percent. I would argue that in the interpretation
> of microbicide studies, vaginal microbicide studies, we will need to
> be cognizant of this fact.
>
> \[SLIDE\]
>
> What, then, are the challenges?
>
> Well, I think the first challenge is just to create awareness that
> there is a need for this type of development and an awareness of this
> type of confounding variable in the interpretation of vaginal
> microbicide studies.
>
> I don\'t think we\'re very clear yet about strategy. Are we going to
> have vaginal products, rectal, or combination products? And a very
> thorny issue is how do we begin the safety evaluation of this type of
> microbicide.
>
> \[SLIDE\]
>
> We know from previous speakers today that the pipeline is quite rich,
> particularly in the discovery and preclinical phase, less so in the
> more advanced phases. But I think when we look at this potential
> pipeline of rectal products, albeit labeled as vaginal at the moment,
> I think we need to think about how we are going to screen this
> pipeline for candidates to move into Phase 1, how we are going to
> actually design these Phase 1 studies, and perhaps more pertinent to
> today\'s meeting, are Phase 1 rectal studies needed perhaps to support
> a vaginal microbicide indication.
>
> \[SLIDE\]
>
> Another issue which my group at UCLA is particularly interested in is
> are the conventional safety paradigms for looking at compounds in
> Phase 1 sufficient for rectal microbicides. We have all had lunch, so
> I hope you will bear with me\--this is the appearance when we
> undertake a flexible sigmoidoscopy. Can we bring the lights down a
> bit, because I am going to show a histology slide.
>
> This actually is a very normal-looking endoscopic appearance. And if I
> actually show you a histology slide from the same patient, that indeed
> is also very healthy-appearing. The fact of the matter is this patient
> actually has HIV infection. And when I undertake quantitative
> immunohistochemistry for CCR5, thus profound regulation, it is even
> greater than seen in inflammatory bowel disease and definitely more so
> than seen in control patients.
>
> My point is not to talk about pathogenesis but to illustrate that you
> cannot just rely on macroscopic and perhaps histological appearances
> in this type of study. The more interesting question is what to
> replace or what to add to these conventional ways of defining safety.
> I don\'t have an answer yet, but hopefully some of the studies that
> individuals, ourselves included, are undertaking might begin to
> address this issue.
>
> \[SLIDE\]
>
> What is the current status of rectal microbicide development? This is
> perhaps the briefest side in the presentation. I think the community
> now know that N-9 is not suitable for microbicide. Carraguard in a
> very small study appeared not to induce epithelial damage. But there
> are no Phase 1 microbicide studies planned at this point in time.
>
> A recent development in the last month was the observation by Tsai
> \[phonetic\] and his colleagues at University of Washington that
> sinavirin \[phonetic\] was able to block rectal transmission of a SHIV
> \[phonetic\] 89.6 variant virus. That is very encouraging but I think
> suggests that we should be doing more to move this type of product
> into Phase 1 studies.
>
> \[SLIDE\]
>
> To summarize, I think there is an urgent need to develop rectal
> microbicides for the MSM population as well as to acknowledge that the
> heterosexual population is at risk of transmission from anal
> intercourse, and that this is an underappreciated behavioral variable,
> particularly in Phase 2/3 studies of vaginal microbicides.
>
> I would even go further to argue that I think it is very important
> that these compounds will be used both vaginally and rectally, whether
> it is labeled or not, and that the FDA should really include or ask
> for a Phase 1 safety evaluation of rectal toxicity to be included in
> the NDA filing package.
>
> And finally, we still have a lot of work to do to define an
> appropriate preclinical and clinical development track for this type
> of product.
>
> Thank you very much for your attention.
>
> \[Applause.\]
>
> DR. GULICK: Thank you, Dr. McGowan.
>
> Our next speaker is Dr. Don Waldron, from the Population Council at
> Rockefeller University.
>
> DR. WALDRON: Thank you, Mr. Chairman.
>
> It is a pleasure to address you. I am Dr. Don Waldron. I am the
> Medical Director at the Population Council at Rockefeller University,
> and I want to share with you some of our experiences and where we are
> going in the microbicide research conducted by the Population Council.
>
> \[SLIDE\]
>
> We started the process early in the eighties and identified a large
> molecular structure that would actually block HIV. We did in vitro
> studies in cell cultures, and we found it to be protective against
> HIV, and followed that up with in vivo mouse and monkey experiments
> and also demonstrated again blocking.
>
> We knew that we were going to go into clinical trials, so we developed
> a placebo, methyl cellulose, which we found through in vivo studies
> was not protective against HIV.
>
> \[SLIDE\]
>
> We then conducted a series of Phase 1 trials in many countries,
> particularly in South Africa, which is the country that we are
> interested in at the current moment for Phase 3. The results showed
> that Carraguard was safe and acceptable.
>
> We are currently doing a couples study for male tolerance and
> acceptability, and those results are under analysis, and I don\'t have
> anything to share with you on that.
>
> We also have two studies underway in HIV-positive cohorts, and those
> results will hopefully shed new light as to what does happen when
> people have HIV.
>
> \[SLIDE\]
>
> We then did Phase 2 experiences where we had some preliminary
> observations, and those data are still under analysis. There were two
> trials conducted, one in Thailand with 165 women, and in South Africa,
> where we had 400 women. They were two-arm, they were intent to treat
> trials, Carraguard against placebo.
>
> They were shown to be safe, and acceptability was again confirmed. We
> didn\'t see any difference in adverse events, STIs, between those two
> arms.
>
> Condom use was similar in both arms, although in Thailand, we noticed
> that the condom usage was significantly higher from baseline. I don\'t
> have those exact figures with me at this time, which we might have
> brought to bear in earlier conversations that we had.
>
> Recruitment and retention was similar for both arms in both Thailand
> and in South Africa.
>
> We had no seroconversions in Thailand, whereas in South Africa, we had
> an equal number of seroconversions, eight in each arm. This was a
> 12-month trial.
>
> \[SLIDE\]
>
> I just want to share with the question of condom usage that we wanted
> to look at exactly at the end of the trial what was our overall usage
> for the gel-plus-condoms, and we see that it is relatively the same
> whether we were using placebo or whether we were using Carraguard, and
> that very few of the patients were using nothing, and condoms-only was
> equivalently the same as using nothing. So roughly 8 to 10 percent of
> the people were using just condoms only, and again, 8 to 10 percent
> were using nothing to protect themselves.
>
> So that somewhere on the order of 60 percent of the people were using
> some form of protection whether it be gel with condoms or it was the
> actual gel only.
>
> \[SLIDE\]
>
> Now we are at the stage of doing a Phase 3 design, and we have several
> considerations that we are putting in place, and we are discussing
> those amongst ourselves and with other outside agencies.
>
> It is going to be a classic placebo-controlled, two-arm, doubleblinded
> ITT trial in roughly 4,500 noninfected women in South Africa. The
> active arm will be Carraguard with a methyl cellulose placebo. The
> maximum trial duration is 48 months with no patient being in any
> longer than 24 months. We are examining a design where we will have
> closing of the trial 12 months after the last patient\'s first visit,
> regardless of where we are into trial.
>
> \[SLIDE\]
>
> The trial criteria\--these are very glossy\--are that basically, we
> will exclude women who test positive for HIV\--that is obvious\--and
> pregnant women. Women who have STIs, unlike in the Phase 2 trial where
> they were not accepted, will be accepted in this trial. Primary
> endpoints will be HIV seroconversion, and the safety endpoints will be
> STIs and vaginal lesions.
>
> \[SLIDE\]
>
> Compliance is a big issue, and we have heard it throughout this
> meeting. Compliance is going to be tested using several methods. There
> will be visit questionnaires administered by clinical staff;
> applicator tracking using bar codes; compliance with visit schedule,
> which I haven\'t heard mentioned, but that\'s an important compliance
> issue for us; and applicator usage tests are currently under
> evaluation in New York, and we are hoping to look at those further.
>
> We are looking at using some of those criteria and whether or not we
> can more clearly define the ITT analysis and exclusion criteria and
> patient removal from the trial itself.
>
> That\'s all I wished to share with you at this point.
>
> \[Applause.\]
>
> DR. GULICK: Thank you.
>
> The next speaker is Dr. Tim Farley from the World Health Organization.
>
> DR. FARLEY: Thank you, Mr. Chairman, and thank you to the FD for
> giving me the opportunity to address you.
>
> I may say that I am the person responsible in WHO for the microbicide
> work, and we took over responsibility for the COL 1492 trial, seeing
> that to its conclusion when it was transferred from UNAIDS, so my
> experience in this field is to an extent influenced very much by the
> COL 1492 trial, as is all of ours.
>
> \[SLIDE\]
>
> I was going to talk about three key things. The first one, which is
> measures of product effect\--efficacy, effectiveness, and use
> effectiveness\--I am going to skip, because the other issues I want to
> talk more on\--however, if you want to ask me some questions about it
> afterward, then it won\'t count into my 7 minutes.
>
> \[SLIDE\]
>
> Moving straight to the issue which has been discussed quite
> considerably today, which refers to the issue of choice of control arm
> or control arms. Some of these points have been made before, but I
> think they are worth emphasizing.
>
> The randomization ensures balance of factors which are related to
> individual risk and patterns of condom and product use. However, once
> the study group has been revealed to the participant, the
> randomization will no longer be able to balance changes in behavior
> which are induced by knowing which group the person is in. In order to
> be able to maintain the post-randomization balance, we need good
> masking and good blinding, and that is why we use a placebo-controlled
> doubleblind trial.
>
> This is the gold standard of all evaluations whenever we can, and it
> is the preferred design whenever it is feasible. The beauty of it is
> that the inferences from the study, particularly if you do an
> intention-to-treat analysis, are very compelling, and it also gives an
> unbiased estimate of the product effectiveness. This, for example, was
> seen in the COL trial.
>
> It doesn\'t mean to say that you should not collect data on behavioral
> factors, compliance, and so on, but it must be recalled that those
> additional data are really there for exploratory or explanatory
> analysis, looking at internal consistency and so on. But the headline
> analysis of overall effect does not depend on those behavioral data.
>
> \[SLIDE\]
>
> If you have a no-product arm, it is absolutely essential when there is
> no placebo product available. That\'s absolutely clear. It is a
> no-brainer. If there is no placebo product, or it is not possible to
> make one that is going to preserve the blind, then you need to use a
> no-product arm.
>
> The problem here is that you must collect very high-quality and
> extensive and reliable data on product and condom use, because you
> have to make adjustments for this, and your primary analysis, your
> primary inference, must be based on these data where you are adjusting
> for rectal intercourse, you are adjusting for different patterns of
> condom use, condom non-use, and so on.
>
> However hard we try, there will always be doubt as to the validity of
> these data. And I would suggest that in any trial, you are going to
> get some misclassification. You are going to get reported behaviors,
> but there is going to be a misclassification.
>
> What is the effect of this misclassification? Well, effectively, you
> are going to dilute your estimated treatment effect.
>
> So I can see a situation where we have a product where it has a
> certain effectiveness, you have a placebo which is totally inert, and
> you have a no-condom arm, but because of the effect dilution because
> of the misclassification, you may find that your product is
> significantly better than the placebo but is not significantly better
> than the no-product arm, simply because you need to do this
> adjustment. I think that the inferences from this are going to be very
> difficult, and it is going to be difficult to have these two
> inferences, as I said, within the same study.
>
> So if you have two control groups, fine. It is very, very costly; it
> adds cost to the trial, and I think we need to consider the costs of
> these trials. These trials don\'t come cheap, and at the moment, the
> majority of studies are mainly being funded by public sectors, and the
> funds are not unlimited.
>
> I believe that you get no benefit for interpretation by adding a
> no-product arm when you have a placebo. I think it is potentially
> confusing. And I would like to cite the example of COL 1492. Had there
> been a no-product arm in that study, I don\'t believe that it would
> have helped any of the inferences which came out of the COL study, the
> headline being that N-9 had a higher incidence of HIV infection than
> the placebo. It may have helped to say something about the placebo,
> but it wouldn\'t have changed the overall inference about the study.
>
> Now, the other issue I want to address is the issue of strength of
> evidence, which has come up a number of times today. Actually, I\'d
> like to say just one thing back on the two control groups. I think it
> is an issue that sponsors might like to consider. If somebody wants to
> do an active versus placebo versus a no-product arm, they should be
> allowed to do it. I wouldn\'t advise against it. I certainly don\'t
> think that the FDA should require it because it is going to have
> costs, it is going to cause a great deal of difficulties for other
> studies as well. So I think that the FDA may allow it, but to require
> it I think would be an extremely bad thing to do.
>
> On the issue of strength of evidence, the discussion that we had this
> morning about how two independent studies at .05 is desirable, is the
> FDA\'s usual standard; however, there are difficulties with this, and
> of course, there are questions as to whether an ethical review
> committee is likely to approve going to a second trial once the first
> one has been done.
>
> The statistics in going from two studies at P less than .05 to a
> single study at .0013 are impeccable. The problem is that the ethics
> are appalling.
>
> If it is unethical after a first trial which is convincing at .05 to
> do a second study, then it is equally unethical to do a study of the
> size of .0013. Halfway through that trial, the data which are
> available would be convincing as that first study.
>
> So I submit to you that it is equally unethical to do a study
> requiring that level, that small P value.
>
> I also think that ethical review committees\--certainly mine in
> WHO\--would not approve it. They would not allow us to do a trial
> where we are requiring significance at the .0013 level. And I suspect
> that the ethical review committees in the sites where such a trial
> would be done would also reject that.
>
> I think we need to consider what are we protecting ourselves against
> here. Remember, this is the probability of a false-positive. This is
> falsely declaring a product which is not effective as effective.
> Normally, conventionally, we limit that at one in 20, possibly a bit
> less, but to limit that as to one in 1,000 I think is off-the-wall,
> quite frankly.
>
> I am much more concerned about the false-negative here of not showing
> an effective product actually has an effect\--not falsely showing at
> one in 1,000 that a product which is not effective actually is
> effective. And there is a balance between power and size, and I would
> rather put it on power than on protecting against the false-positive.
>
> Now, I fully agree that a single study at P less than .05 may not
> convince, and the COL 1492 trial came in just significant at P less
> than .05. Not everybody was convinced that N-9 was harmful by that, so
> I take the point that one study at P less than .05 is maybe not there.
>
> What would I suggest? I don\'t know exactly what would be an
> appropriate P value to have. I certainly think that one in 1,000 is
> way off-the-mark. I also think that maybe one in 100, less than .01,
> is probably off-the-mark.
>
> What I think you need to do is to discuss with ethicists, with
> regulators, with public health experts, with advocates, in a range of
> countries, particularly countries where the HIV epidemic is really
> raging and there is a need for this, and ask them the question very
> simply: Look, let\'s assume we had a trial that was significant at the
> .05 level, and it is internally consistent and so on. Would you think
> it is ethical to do a trial?
>
> If they say yes, you ask the question again: What about at P less than
> .04\--would it be ethical\--yes or no?
>
> There is going to come a time\--P less than .01, maybe P less than
> .02\--when everybody says no, it is no longer ethical. So I suggest
> that you convene a consultation of that nature\--I will convene it for
> you if you want\--and then we can get an idea of where people feel
> very uncomfortable from an ethical point of view to do the second
> trial. And that is what I think you should aim at for your P value for
> a trial.
>
> Thank you very much.
>
> \[Applause.\]
>
> DR. GULICK: Thank you, Dr. Waldron.
>
> Our next speaker is Amy Allina, from the National Women\'s Health
> Network.
>
> MS. ALLINA: Thank you.
>
> My name is Amy Allina. I am from the National Women\'s Health Network
> which is a nonprofit organization that advocates for national policies
> that protect and promote all women\'s health. We don\'t accept
> financial support from pharmaceutical or medical device companies, and
> we are supported by a national membership of 8,000 individuals and
> about 300 organizations.
>
> I want to start by thanking the FDA for organizing and holding this
> meeting and for giving us the opportunity to speak about the
> importance of this topic to women.
>
> The National Women\'s Health Network began working on HIV/AIDS as a
> women\'s health concern in 1987. Even before the advent of AIDS, the
> Network had articulated the need for sexually-transmitted disease
> prevention options for women, testifying before Congress as early as
> 1978 on the importance of research to develop these products. So we
> have been at this a long time.
>
> In the 25 years that we have been working on these issues,
> particularly in the last 15 years with AIDS, the need for attention to
> women\'s prevention options has become increasingly urgent.
>
> In a survey conducted just last year, our members identified
> microbicide development as a top priority on the Federal health
> research agenda. The Network is a participant in the Alliance for
> Microbicide Development and a partner in the Global Campaign for
> Microbicides, and we endorse the recommendations that you heard
> earlier from Polly Harrison, from the Alliance, and also that the
> panel at least received prior to the meeting from the Global Campaign.
>
> Given the tight agenda today, I am not going to repeat those
> recommendations. You have all heard them and read them, I am sure. But
> I do want to address one in particular which is the recommendation
> that FDA shouldn\'t require as a matter of policy that sponsors
> include a condom-only arm in addition to the placebo control. There
> has been a lot of discussion about that already, and I\'m going to try
> not to repeat too much of it, but there are a couple of things that I
> want to say about why we agree with that recommendation.
>
> FDA staff certainly and possibly also some members of the Committee
> have heard the Network advocate in other settings for the agency to
> require new products seeking approval to be tested against existing
> products rather than just against a placebo. And in light of that, our
> endorsement of the recommendation that FDA should not require sponsors
> of candidate microbicides to compare their products to condoms alone
> in addition to a placebo control might seem contradictory. So I want
> to be clear about the differences that lead us to support the
> recommendation.
>
> Our argument that some new products should be tested before approval
> in trials which compare them to existing products has been based on
> our belief that FDA should demand more information and apply a
> stricter approval standard when there are already products approved
> and available for the same indication, when we are talking about the
> so-called \"me-too\" products. In that circumstance, consumers and
> health care providers who are considering using or prescribing the new
> product will need to know not just that it is safe and effective but
> whether it provides added benefit over existing and often less
> expensive options that are already available to them. But that
> argument is obviously not relevant in the current context of
> microbicide development.
>
> There is no existing product to which a microbicide can appropriately
> and usefully be compared, and although condoms are an effective and
> important option for many individuals and couples, we all know that
> some women are not able to negotiate condom use with every encounter
> and with every partner.
>
> We also share many of the concerns that have been articulated already
> today that the requirement that all microbicide clinical trials
> include a condom-only arm may be an obstacle in some cases to
> producing interpretable data.
>
> We agree with earlier speakers who have said that inclusion of a
> condom-only arm might provide useful information in some cases; in
> other situations, however, we believe it would further complicate
> interpretation of trial results.
>
> So for those reasons and because of our concern that the requirement
> of all trials include two control arms might slow progress of this
> really urgent research, we urge FDA to maintain flexibility on this
> point and not to require all sponsors to include a condom-only arm.
>
> I\'ll finish here and just say that I\'d be glad to answer any
> questions from the panel about my statement.
>
> Thanks.
>
> \[Applause.\]
>
> DR. GULICK: Thank you very much.
>
> Our next speaker is Dr. Rosalie Dominik from Family Health
> International.
>
> DR. DOMINIK: Thank you for the opportunity to present on behalf of
> FHI. FHI\'s decades of research and experience with contraceptive and
> microbicidal products has provided us with valuable lessons regarding
> the conduct of trials in resource-poor settings.
>
> Our experience with microbicide research in Cameroon encompassed three
> different study designs\--an observational study in 1991 to 1992 of
> women choosing spermicidal suppositories versus those choosing other
> methods of contraception; a blinded randomized control trial in 1995
> and 1996 of women using N-9 film versus placebo film; and an unblinded
> RCT in 1999 and 2000 of women using N-9 gel versus a no-gel
> condom-only control.
>
> Comparisons of the first two trials demonstrated the strength of the
> randomized design in controlling for the intrinsic selection bias that
> can occur in observational studies. These studies also demonstrated
> the difficulties in interpreting self-reported data on sexual
> behavior. Analysis of the third trial demonstrated the limitation of
> interpretability of unblinded trials.
>
> \[SLIDE\]
>
> We believe it is useful to focus on the labeling claims that one hopes
> to make for an effective microbicide to guide the decisions about
> study design. We expect that the label for the first approved
> microbicide might include a summary message that looks something like
> this: \"Use of microbicide gel reduces a woman\'s risk of HIV
> infection during vaginal intercourse. To best protect against the risk
> of HIV infection during vaginal intercourse, use a condom during every
> act of intercourse. Use of microbicide gel provides additional or
> backup protection against HIV infection.\"
>
> \[SLIDE\]
>
> To obtain evidence to make such a claim, we need to design a study
> that can answer the primary research question of whether use of the
> microbicide reduces the risk of HIV acquisition compared to nonuse,
> holding all other risk factors constant. That is, the two groups of
> women being compared should have, for example, the same average
> frequency of intercourse and the same level of condom use.
>
> A blinded RCT of the microbicide gel versus a truly inactive placebo
> would be of course the gold standard for answering this question.
> Unfortunately, we may never be able to definitively demonstrate that
> we have a truly inactive placebo, but the comparison of the active
> microbicide to the carefully-selected placebo, the best available
> placebo, will provide the most useful data for answering our primary
> research question.
>
> \[SLIDE\]
>
> The other control arm that has been discussed is of course the
> condom-only arm, and we have talked about differences that the two
> groups will have in motivation, resulting in\--also when you have the
> condom-only arm, you have a group that only has two options to choose
> from versus a group that has four options to choose from with each act
> of intercourse.
>
> I mentioned earlier that in the unblinded N-9 trial that FHI carried
> out in Cameroon, women in the condom-only arm reported using condoms
> in about 87 percent of acts, while women in the gel arm reported using
> condoms about 6 percent less often.
>
> \[SLIDE\]
>
> Now I would like to walk through two examples showing the impact of a
> 10 percent difference of condom use on comparisons between the
> microbicide arm and the condom-only arm, assuming that when used,
> condoms reduced the risk of HIV acquisition by 95 percent.
>
> First assume that we have a microbicide that would reduce the risk by
> 50 percent compared to an absolutely inert placebo, and if we designed
> a study to have 90 percent power to detect this 50 percent reduction
> in risk of HIV acquisition, what would happen if the microbicide used
> condoms in 65 percent of acts, and the condom-only arm used condoms in
> 75 percent of acts.
>
> In this case, the power would drop from 90 percent to about 50
> percent.
>
> \[SLIDE\]
>
> If condom use instead were 80 percent in the microbicide arm and 10
> percent higher, 90 percent, in the condom-only arm, the chance of
> finding a significantly lower risk of HIV acquisition in the
> microbicide arm would be only about 15 percent. And in this case,
> there would actually be about a 20 percent chance of observing a
> higher incidence of HIV in the microbicide arm than the condom-only
> arm.
>
> \[SLIDE\]
>
> So this example helps to illustrate why we are concerned that
> requiring that a microbicide arm be shown to be significantly better
> and have significantly less HIV infection compared to a condom-only
> arm could lead to failure to promptly identify a product that truly
> protects against HIV.
>
> \[SLIDE\]
>
> The second example addresses another potential danger that can arise
> due to behavioral differences between the two arms. In this example,
> we assume that the microbicide truly has no effect on HIV risk
> compared to a true placebo, and we look at what can happen if the
> participants in the microbicide arm use condoms more often than those
> in the condom-only arm.
>
> So if condom use is 90 percent in the microbicide arm and 80 percent
> in the condom-only arm, there would actually be a 65 percent chance of
> observing a significantly lower risk of HIV acquisition in the
> microbicide arm even though the microbicide is truly ineffective. This
> 65 percent chance of falsely concluding the microbicide is effective
> is far greater than the 2.5 percent chance of a Type 1 error in this
> direction that one would expect if risk-taking behaviors were truly
> balanced between groups.
>
> \[SLIDE\]
>
> Even though we don\'t believe a condom-only arm should be required, we
> do believe that a comparison between a placebo arm and a condom-only
> arm may provide some useful information about the activity of the
> placebo. If we are willing to assume that the bias due to behavior
> changes will operate in only one direction\--that is, that those in
> the condom-only group will use condoms at least as much as those in
> the placebo group\--then the inclusion of a condom-only arm may
> provide some evidence that the best available placebo gel might
> actually provide some protective effect, but because of the unblinded
> nature of the trial, it may not be entirely convincing.
>
> The HPTN 035 trial will help to define the role, if any, of a
> condom-only arm in subsequent microbicide trials, and FHI is
> supporting the 035 team in conducting this NIH-sponsored trial.
>
> \[SLIDE\]
>
> So in conclusion, what we most want to know is does use of the
> microbicide reduce the risk of HIV acquisition. Once we have a product
> that reduces the risk of HIV when used, public health researchers can
> turn to studying the best way to promote use of that product in
> combination with a host of other preventive measures. Showing the
> protective effect against a carefully-selected placebo should provide
> reasonable evidence that a product protects against HIV if used. A
> blinded two-arm trial of a microbicide versus the best available
> placebo can provide sufficient evidence to support a claim that use of
> a new microbicide can reduce the risk of HIV acquisition.
>
> Thank you.
>
> \[Applause.\]
>
> DR. GULICK: Thank you.
>
> Our next speaker is Dr. Zena Stein from Columbia.
>
> DR. STEIN: Thank you for giving me the opportunity to talk, and as I
> come at the end of many arguments, I just want to say two things.
>
> One, we are talking about biological efficacy of the microbicides we
> are testing, and we have some biological information about inert
> substances, the placebo. And the purpose of the trials, I would say,
> is to look for human evidence that supports the biological evidence of
> efficacy, not to go beyond that.
>
> Now, if we have done the classical approach, and then sexual factors
> lack useful microbicide, we have an enormous area for distortion of
> reports and diaries and statements.
>
> So the wonderful idea of a blinded microbicide, putative microbicide,
> which would feel the same and look the same and smell the same for a
> women and for the investigator, and to set it up in a little white
> introducer, it will make the difference between the putative
> microbicide and the putative inert substances invisible.
>
> It allows you basically to cancel out all those factors in
> effectiveness and lead you to infer efficacy. You don\'t care how much
> adherence or how much frequency of use or any of those things, because
> it should be the same between the putative microbicide and the
> putative inert substances.
>
> When you start bringing in a condom, another arm, you are asking
> another question, and maybe it is an important question that should be
> asked afterward. But now we ought to know do we have a microbicide
> which supports the biological difference between efficacy of the
> microbicide and efficacy in the inert substances.
>
> The reason I entered this dialogue publicly is because my slide, which
> is basically the same options as Dr. Karim offered us\--we tried to
> put down all the options we could think of, and we decided that A, B,
> and C in which the placebo and the condom-only do the same thing, that
> that would give you confirmation that all the others\--D, E, F, G, H,
> and I\--would give you confusion, which is why we said stick to the
> placebo and the microbicide; otherwise, you\'ll get confusion.
>
> I didn\'t like the idea of support where you don\'t get a difference
> between the microbicide and the placebo. You haven\'t supported your
> biological assumption of efficacy, so don\'t do it.
>
> At the bottom here, \"These interpretations assume a) that true levels
> of condom use do not vary across trial arms\"\--and this is a point
> that Dr. Farley and other people made, and the reason I came here to
> try to say something new is the point I mentioned earlier, that we
> have some evidence from the COL 1492 group that in fact women loved
> the microbicide or the placebo; they used it and they dropped the
> condom arm. I think they will do that. It is very good news for
> microbicide, but it will hopelessly contaminate any attempt to
> measures in this trial what condom-only does because again, it changes
> the risk behavior. If some of them are \[inaudible\] random and risk
> behavior, you put them into the trial, and they change their risk
> behavior, and you are just left reflecting with what to do with that
> kind of mess.
>
> Now, the other point\--I am allowed a second point\--it is only when
> you get a placebo, the microbicide versus placebo is only as good as
> what you know about the placebo. We\'ve got this new universal
> placebo. If every trial would use a universal placebo, the same one,
> you could make comparisons across trials. If one trial uses this
> placebo and another trial uses this placebo, you will not be able to
> make comparisons across trials.
>
> I would even suggest that, for instance, if Carragin \[phonetic\]
> wants its own special methyl sulfate arm, put another arm, put the
> universal placebo arm. You will learn more from that because the
> behavior is much the same, and you will be able to compare other
> trials. That kind of insert of an arm would make sense. But the insert
> of an arm which is open, which confuses the behavior, confuses the
> difference between efficacy and effectiveness, I consider a waste of
> time.
>
> And I agree with everybody here saying that FDA should open its mind
> to whether it wants this or that behavior. If it wants to actually
> concentrate on biological efficacy versus effectiveness in one product
> and another, there is no point in confusing the issue with a
> condom-only. That is asking another question and perhaps asking it in
> different ways, and this might not be the way to measure it.
>
> I am also convinced by what Dr. Dominik said. A paper of Foss
> \[phonetic\] et al. which many of you might know, suggests that where
> condom use is only 15 percent or less in the population, and you have
> a reasonably effective microbicide, on the whole, you can\'t do
> wrong\--put your microbicide in. If you get a microbicide that is as
> much as two or three times the placebo, you can use it happily,
> because so many populations use so few condoms that you can only win
> with that.
>
> And remember that on the whole, the difference we get in effectiveness
> in protection against HIV only seems to work when people really use
> the condom at 100 or 90 percent in the various estimates we have based
> on discordant couples. You have really got to use that condom a lot to
> make a difference in the transmission.
>
> So I think that condoms are in. It satisfies us ethically, but the
> real question is does the microbicide versus the inert substance make
> a difference for HIV infection. If it does, we\'ll all put our flags
> up, and we\'ll have something to go with as soon as possible.
>
> Thanks.
>
> \[Applause.\]
>
> DR. GULICK: Thank you.
>
> Our final speaker to have signed up is Dr. Malcolm Potts, who is from
> the University of California at Berkeley.
>
> DR. POTTS: I speak as a physician. I am from Berkeley, and as the
> former president and CEO of Family Health International, where we
> initiated the first-ever microbicide trials, I have been a strong
> advocate of microbicides for over two decades. In 1990, I triggered
> the UK MRC interest in microbicides.
>
> Like many people, I initially accepted placebo control trials with
> condom counseling as licit. After a great deal of thought, I have
> slowly and painfully come to the conclusion that such trials may be
> flawed scientifically and ethically.
>
> Ethically, I am deeply troubled by a basic contradiction. While the
> justification for recommending condom counseling is that we offer
> volunteers the highest possible standard of care, the pivotal findings
> from any clinical trial are derived entirely from volunteer women who
> we know for certain are not using condoms.
>
> I think we have misled ourselves into believe that if we recommend
> condom use, it is acceptable to use placebos. But the number of women
> not using condoms unless exposed to HIV infection in a
> placebo-controlled trial cannot be lower\--cannot be lower\--than it
> would be without counseling.
>
> Further, a condom counseling design could actually increase the number
> of placebo users who will be infected and die, because counseling
> inflates the number of subjects needed.
>
> Having had executive responsibility for a great many clinical trials,
> I am vividly aware that the more difficult the logistics, the higher
> the loss to follow-up, the more volunteers you need to recruit. We are
> talking about populations that are so different from those described
> by Dr. Fleming that they might as well live on another planet.
>
> If we use placebos, then condom counseling complicates the study but
> does not solve the ethical problem for the women who provide the data
> on efficacy who are randomly allotted to exposure to a lethal,
> incurable disease.
>
> Condoms indeed are the best advice for those who use them, but those
> people dilute the results. I haven\'t heard a proposition for how to
> help most groups. I think that is our ethical dilemma.
>
> In contraceptive trials, we do not use placebos presumably because an
> unintended pregnancy is an unacceptable burden. Can we use placebos
> when that is the outcome? Some women will not respond to condom
> counseling because their compliance with any instruction is low. This
> is exactly the group that we want to exclude from any clinical trial.
>
> More likely, in my judgment, the non-condom users are simply unable to
> negotiate condom use with their partners. I feel deeply uncomfortable
> trying to shuffle my ethical responsibilities by relying on
> underprivileged volunteers to make mistakes.
>
> Scientifically, as a possibility, we may reject an otherwise
> lifesaving microbicide which might have worked amongst those women who
> enjoy greater autonomy in their lives but which failed in this
> nonrepresentative subgroup of volunteers.
>
> The Code of Federal Regulations under which the FDA operates is
> explicit. The test \[inaudible\] compared with known effective therapy
> and the administration of placebo or no treatment would be contrary to
> the interest of the patient. To ask a woman whose husband will beat
> her if she asks him to use a condom to accept a placebo is
> unambiguously contrary to her interest. The offer of a microbicide,
> even of unproven effectiveness, might be preferable.
>
> The trouble, of course, is that we cannot predict in advance who is
> able to respond to condom counseling and who will not; and for those
> who will respond, condom counseling is indeed the highest possible
> standard. If we don\'t use placebos, we can\'t measure efficacy. But I
> suggest that ethics trumps any desire for statistical measures.
>
> Perhaps we can obtain useful information by direct observation of
> women using a potential microbicide for another purpose. Professor
> Short in Australia and Conrad in the United States have shown that
> lemon juice is an effective microbicide. In some parts of the world,
> sex workers have a tradition of using lemon juice. Next month, a team
> from UC Berkeley will work with colleagues in Nigeria to explore the
> consistency of use in one such group.
>
> Whatever the study design, the outcome measure of interest will be use
> effectiveness, not biological effectiveness. Dr. Stein has just
> mentioned the very useful paper by Dr. Foss and colleagues that shows
> that while condoms are likely to be more effective than a microbicide,
> microbicides are more likely to be used consistently.
>
> Personally, I think the overlapping use effectiveness might justify a
> straight Phase 3 comparison where a microbicide would be tested
> against condoms as a gold standard for protection.
>
> I think we can demonstrate that a microbicide will not damage a
> woman\'s vagina by escalating dose studies in volunteers not exposed
> to infection, and we can make a plausible case that a microbicide has
> some degree of effectiveness based on in vitro studies.
>
> Ultimately, we are called upon to make difficult judgments. Do we
> emphasize the needs of the women who we know will not use condoms or
> the needs of those swept up in a trial who will use condoms? As I
> said, I can\'t find a method that will cover both.
>
> Do we think it is possible to collect enough in vitro and collateral
> clinical data to judge the efficacy of microbicides will be in the
> same range as condoms? I think we can; others obviously will disagree
> with me.
>
> Can we approve a method because it is comparable to condoms, but we do
> not know its true efficacy?
>
> I am opposed to a condom-only arm, but with or without condoms, given
> the numbers and durations of trials suggested today, it is my judgment
> that non-FDA-approved trials probably in Africa and Asia will provide
> useful data before an FDA-approved trial is completed.
>
> My plea to this Committee is to recognize that ethically-acceptable
> ways of designing clinical trials to test the efficacy of microbicides
> are not cut-and-dried, and sincere people can have a variety of views.
> I am confident the Committee will be cognizant of all possible
> alternatives.
>
> Thank you.
>
> \[Applause.\]
>
> DR. GULICK: Thank you, Dr. Potts.
>
> That concludes the people who signed up to speak at the open public
> hearing. Just to let people know, there were three written submissions
> submitted to the Committee. Those were emailed and faxed to Committee
> members, and they are in your packet as well. One is from Laurie
> Sylla, from the Yale University School of Nursing, one from Dr. Robert
> Munk from the New Mexico AIDS InfoNet, and one from Anna Forbes from
> the Global Campaign for Microbicides.
>
> Is there anyone who didn\'t sign up for the open public hearing who
> would wish to make a statement at this time?
>
> \[No response.\]
>
> DR. GULICK: Okay. We will close the open public part of the meeting,
> and we\'ll turn to Dr. Birnkrant for the charge to the Committee.
>
> **Charge to the Committee**
>
> **Questions to the Committee**
>
> DR. BIRNKRANT: Thank you.
>
> I would like to begin by commenting on this morning\'s presentations.
> I know that I found them extremely interesting, and I know that my
> colleagues also found them interesting, and I know that they will lead
> to productive discussions this afternoon.
>
> I also want to thank the speakers during the open public hearing for
> their presentations as well.
>
> There were a number of different views presented this morning and this
> afternoon, but that\'s good, because it makes us think about all types
> of possibilities, and we\'ll take some of these ideas back to the
> agency, mull them over and apply them to some of the advice that
> we\'ll be giving to sponsors.
>
> So although there may not have been consensus with regard to
> particular issues, there was consensus, though, with regard to
> urgency. And as the speakers this morning and this afternoon pointed
> out, there is an extreme urgency to develop a topical microbicide
> rationally and get it on the market as soon as possible.
>
> Another point I want to make is that what we are discussing today may
> apply only to the first generation of topical microbicides. That is,
> the need for a three-arm trial with two controls may be more
> appropriate for the first microbicide, but may be less appropriate as
> more microbicides reach the market. And we are well aware of that.
>
> A couple of comments with regard to flexibility, standards, and
> risk-benefit. With regard to flexibility, the FDA has shown that it
> can be flexible in a number of areas, in a number of drug approvals
> that have taken place in the past. But with regard to microbicides, we
> can show flexibility in that we are willing to accept the one clinical
> trial as opposed to two adequate and well-controlled trials, we are
> entertaining the idea of having a P value between .01 and .001, et
> cetera.
>
> With regard to standards, some people call our standards \"hurdles,\"
> but I like to look at them as standards set for the world. And what
> are these standards? Well, our regulations in the Food, Drug, and
> Cosmetic Act that was amended in 1962 tell us that we need substantial
> evidence for a product to reach the market.
>
> And what is the substantial evidence? Well, it has been interpreted as
> being not only safety but efficacy, and the efficacy should come, it
> has been interpreted, from adequate and well-controlled trials.
>
> We have interpreted that traditionally as two, but we have a guidance
> document that does allow for one large clinical trial that is
> multi-center, internally consistent, and highly statistically
> significant.
>
> What does it mean, though, to have these standards? These are
> standards to allow us to approve a drug that is safe and effective in
> which we have a lot of confidence. And these standards, although they
> are U.S. regulatory standards, should apply to the whole world in that
> if it is a safe and effective drug for the United States, safety and
> efficacy should be the same whether you are in a developed country or
> a developing country.
>
> So we feel as though the standards are absolutely the same.
>
> With regard to risk-benefit, we look at risk-benefit on an indication
> basis, so we develop risk-benefit standards for various diseases. It
> may be different for cancer as opposed to sinusitis. But when it comes
> to HIV prevention, the risk-benefit is the same throughout the world.
> It doesn\'t matter if a drug is coming to the FDA for review and
> approval or coming to another regulatory body outside the United
> States.
>
> The risk-benefit should be the same in that there should be greater
> benefit than risk to the population.
>
> Lastly, what are the risks of putting a less-than-effective
> microbicide on the market? Well, they are great. And why are they
> great? Because they may lead to high-risk behavior and thus increased
> transmission rates, and they may also lead to condom migration. And we
> wouldn\'t want people migrating from condoms to a much, much less
> effective and safe product.
>
> With that, I\'d like to turn to the questions.
>
> The first question deals with trial design, which we have been
> wrestling with actually for a number of years. And as I said this
> morning, we are bringing it to the Committee today because we have
> received some proposals for Phase 3 and Phase 2 trial designs
> recently.
>
> This morning, we and others presented the Phase 2/3 run-in design,
> which is somewhat different than traditional drug approval that
> proceeds from Phase 1 to Phase 2, where activity is shown, and then to
> Phase 3.
>
> What we are looking for the Committee to discuss is the pluses and
> minuses of these different types of trial design and perhaps to
> suggest alternatives to helping us provide sponsors with advice on
> Phase 3 clinical trial design.
>
> DR. GULICK: So shall we take them question-by-question, or do you want
> to run through them all?
>
> DR. BIRNKRANT: I think we can do it question-by-question, because they
> have multiple components, so it may get too complicated if we run
> through them all at this point.
>
> DR. GULICK: Okay. And then, just one other point of information before
> we start. Could you or someone else review again the HPTN 035 study,
> the design of it and where it is in terms of development? We have
> heard a lot about that study over the course of the morning.
>
> DR. BIRNKRANT: Maybe Dr. Karim can do that.
>
> DR. GULICK: Thanks.
>
> DR. KARIM: Thank you.
>
> The HPTN 035 trial is an NIH-sponsored trial that is part of the
> Prevention Trials Network. It is a four-arm trial which involves two
> active products. One is Buffergel \[phonetic\] and the other is Pro
> 2000 \[phonetic\]. And it involves two control arms\--a placebo
> control arm and a no-treatment control arm.
>
> The trial itself is being conducted\--or, we plan to conduct it\--in
> approximately\--well, at this point, starting off with four countries
> and eventually expanding to seven sites throughout the world.
>
> The current sample size and design that we have proposed is a Phase 2
> leading into or running into a Phase 2B design, and we propose to
> study approximately 3,100 subjects in this study.
>
> We are proposing that in conducting the study, each product would have
> to be shown to be effective either against the placebo arm or the
> condom-only arm in order to be regarded as efficacious.
>
> Thank you.
>
> DR. GULICK: And Dr. Karim, what is the status of the study? Has it
> begun?
>
> DR. KARIM: No, the study has not begun. We are just preparing the
> final submission, what we hope to be the final submission, to the FDA,
> and it has gone to the NIH for regulatory approval. We anticipate
> enrolling the first patients early in the new year.
>
> DR. GULICK: So the design is finalized, and it has gone to the FDA and
> NIH for final approval.
>
> DR. KARIM: That\'s right.
>
> DR. FLEMING: I might just add to that, some of the more detailed
> statistical properties were those that I was presenting on the slide
> in the presentation in terms of the ability of this design to fairly
> reliably identify ineffective interventions and reliably identify
> effective interventions, at least in terms of either providing
> conclusive evidence of benefit or evidence of need for continuation of
> study. And NIH convened an external body in I think it was March to
> review this design, and it was endorsed by that body; that was one of
> the more recent actions.
>
> DR. GULICK: Okay, thank you.
>
> So let\'s turn to the question at hand, which is to comment on two
> different proposals, and then we\'ll take some suggestions. So let\'s
> as a Committee consider the first design\--a Phase 2 run-in Phase 3
> trial design.
>
> Pros and cons? Dr. Paxton?
>
> DR. PAXTON: Well, I think there are some significant pros to that
> approach. One is that for those of us who have done significant trials
> abroad, logistically, it is much easier to not have to come to a
> complete full stop and let your patients go while you do your analyses
> and all that.
>
> I think the advantage of doing a Phase 2 run-in the way this is, you
> don\'t stop, as was shown in one of the prior slides. You do manage to
> keep the women who were in the Phase 2, and they do continue to give
> you more information in your Phase 3. So I consider that to be a very
> significant pro.
>
> Are we allowed to talk about the B part, too, or do we just want to
> talk about A right now?
>
> DR. GULICK: Let\'s take one at a time, and then we\'ll come back to
> that.
>
> DR. PAXTON: Okay.
>
> DR. GULICK: Other comments on this design?
>
> Yes, Dr. Fleming?
>
> DR. FLEMINg: I think with the Phase 2 run-in to the Phase 3, one of
> the advantages of this design is we had mentioned the benefits of
> Phase 2 are multifold, one of which is to provide an extended
> experience in safety beyond what you would have in Phase 1, to be
> basically in a position to justify the exposure of large numbers of
> participants in a Phase 3 setting.
>
> So this Phase 2 run-in in essence allows one to restore that type of
> insight that you would have hoped to have gotten if you had had a
> separate Phase 2.
>
> The limitations of the design are that in essence it is a Phase 3
> trial, so you are basically, then, at this point jumping to a Phase 3
> from a Phase 1. If in fact you believe that you understand what is
> necessary in order to design this trial and conduct it in a
> high-quality fashion, and you have a belief in plausibility of
> efficacy, it is a very appropriate next step.
>
> So if you are confident that you have the right question, you have the
> right way to carry the study out, and you are adequately optimistic,
> you believe that you have established plausibility of efficacy, it
> makes sense to move into this step.
>
> On the other hand, if there are key issues about quality of study
> conduct and implementation that are not fully understood that end up
> being better understood during the early phase of this trial, it can
> be very problematic in interpreting the result.
>
> DR. GULICK: Dr. Fletcher and then Dr. Sherman.
>
> DR. FLETCHER: In thinking about this Phase 2 to Phase 3, I think I
> need some help from my statistical colleagues to think about
> protection against proceeding when you shouldn\'t. Let me see if I can
> lay out a scenario.
>
> Let\'s say you had done the traditional Phase 1 to Phase 2 to Phase 3,
> and in the Phase 2 study, you were left with, let\'s say, equal rates
> of seroconversion, which I think would be evidence, then, that the
> product has no evidence of effect, and therefore, why go on to Phase
> 3.
>
> How would you have that same protection against going on to Phase 3
> where now you expose a large number of individuals to a product that
> is not effective with a Phase 2 to Phase 3 lead-in? I don\'t quite see
> that.
>
> DR. GULICK: Dr. De Gruttola, do you want to respond?
>
> DR. DE GRUTTOLA: Yes. I think what Tom said\--this is basically a
> Phase 3 study; you are just calling the first part of it a Phase
> 2\--and like with any Phase 3 study, you can have stopping rules that
> allow you to stop for futility. So if you have enough information to
> say that in this study, you are very unlikely to conclude efficacy,
> you could stop. That doesn\'t mean you have necessarily proved it
> doesn\'t work, because to prove it doesn\'t work may require the full
> information; but you may have enough information to say that in this
> study, you are not going to get an answer and to allow you to put an
> upper bound on what the efficacy is likely to be.
>
> So I think if you just think of it as a Phase 3 study in which you are
> going to do kind of an extensive first interim review to make some
> decisions about whether to fully enroll or not, and the information
> you may use may, like in any Phase 3 study, include both toxicity and
> stopping for futility, that that is a way to think about it.
>
> DR. FLEMING: I think this is a terrific question because it really
> gets at the essence of an issue that needs to be understood as you
> think about the appropriateness of launching this Phase 2/3. I fully
> agree with the explanation that Victor has given, and let me just try
> to add a little bit of specifics to make clear what the implications
> are of what he was saying.
>
> Some people have said if, for example, you do a Phase 2B trial as a
> separate trial, and it is based on one-quarter the number of
> events\--and as you know, in an analysis such as this, information is
> number of events; if you have 100 events and 100 people, that is the
> same information as 100 events and 10,000 people in terms of
> statistical power to discern treatment effects\--so if you are going
> to do a Phase 3 trial with 400 events, or a Phase 2B trial with 100
> events, just do an interim analysis in the Phase 3 trial at 100
> events, and don\'t you recover the same information.
>
> The essence of the answer is not at all necessarily. I always say to
> sponsors that if you do a Phase 3\--and this Phase 2/3 is a Phase 3,
> as Victor said\--write the check for it, because in essence, if you
> want to preserve the power to the Phase 3 trial, you have to be very
> cautious about what you consider to be extreme results early on.
>
> So very typical monitoring boundaries would stop a trial for lack of
> benefit when you have what\--when you basically have an estimate of no
> effect when you are halfway through. Whereas you do get much earlier
> than that evidence about lack of benefit in a separate Phase 2B trial
> that would be based on just 100 events where, if you recall, we were
> saying there a negative study would be an estimate of efficacy that,
> based on only 100 events, might be anything less than 15 percent.
>
> So because of the need for conservativism in a Phase 3 trial to
> preserve the power and the preserve the false-positive error rate, you
> actually do end up going further into that trial, even if you are
> using interim monitoring, before you would, so to speak, shut off the
> faucet.
>
> So again I come back to a Phase 2 run-in for a Phase 3 is a good idea
> in certain settings\--when I am really confident I have the right
> question, I know how to design the trial in the right way, I know how
> to be able to achieve adherence, I know how to retain, I know how to
> enroll, and I believe plausibility of efficacy has been established.
>
> So the question in this setting is can you do than when you have had a
> 100-person Phase 1 trial. If the sponsor thinks so, this is the right
> thing to do.
>
> DR. GULICK: Dr. Fletcher, a response?
>
> DR. FLETCHER: Actually, it was to almost that last point you made. So,
> if the development paradigm then becomes Phase 1 to the Phase 2/3, I
> am wondering, then, how you establish proof of concept or plausibility
> of efficacy if Phase 1 is really to establish dose and bad adverse
> reactions and those types of things. Where does that plausibility come
> in in this paradigm to move from a 100-person study to a
> 4,000-or-so-person study?
>
> DR. FLEMINg: Yes. That too is a critically important question, and as
> you know, the standard approach to this is to do a Phase 2 trial where
> we would be looking at biological markers. Those biological markers
> may not be valid surrogates that reliably tell us about clinical
> effects, but they give us clues, they establish proof of principle,
> they establish plausibility of efficacy.
>
> We are at a substantial disadvantage in this setting without such
> information. We simply don\'t have those types of measures for
> plausibility of efficacy.
>
> It then comes down to essentially how much risk is someone willing to
> take, and it is substantial risk, especially if you are going to deal
> with a study as the 035 study was planning to be, as a definitive
> trial looking at a 33 percent reduction in transmission with four arms
> that was on the order of 10,000 people and a \$100 million
> expenditure. That\'s a huge leap to make from a Phase 1 study without
> a proof of principle result.
>
> It is not unlike what we have struggled with in the vaccine area for
> HIV for a long time. We have been awaiting having adequate evidence of
> efficacy. Now, at least there, we have immune base markers, although
> there is a lot of controversy about is it humoral or cell-mediated or
> what nature or whatever\--we don\'t even have that in this particular
> setting.
>
> It is\--and now I am jumping ahead to 2B\--but it is one of the
> reasons to say, then, proof of principle could in fact be based on the
> very endpoint. Doesn\'t that make sense to use HIV infection itself as
> the way to establish proof of principle in a somewhat measured
> intermediate step that is smaller in size?
>
> DR. GULICK: Dr. Sherman and then Ms. Heise.
>
> DR. SHERMAN: I am interested in the concept of this 2/3 run-in, and
> looking at the outline that was in Dr. Wu\'s presentation, you have
> two parallel arms running together. Do you plan to merge those arms in
> the data analysis? In other words, will that Phase 2 run-in arm become
> part of the main dataset as a practical piece of data, and is that
> valid at the final endpoint of the study because there is going to be
> differential dropout and bias between those two groups?
>
> DR. FLEMING: The answer is for those who advocate this design, their
> answer is yes. Is that valid? Yes. It is valid subject to the way it
> is being proposed here, which is that these interim data would be made
> available only to a data monitoring committee. That data monitoring
> committee would then assess whether various safety thresholds had been
> met, and if so, the study would continue, and all those participants
> would be included.
>
> If, however, these data were released separately to the sponsor, then,
> many of the issues that we believe are important in monitoring trials
> would be violated if that same dataset were then used as part of the
> overall trial.
>
> So the advantage of it being a separate run-in\--if the sponsor wishes
> to have full access to the data, that\'s entirely possible, but then
> you would start over. But the way this was being proposed, which is an
> acceptable approach that some of the sponsors were saying, is that
> this would only be viewed by a monitoring committee. Now, granted the
> sponsor doesn\'t have weigh-in in this now, except for the procedures
> and the criteria they set out in advance. The monitoring committee
> would then review this, ensure that the safety criteria were met, in
> which case then it would be acceptable to use all of the participants,
> including the two run-in participants, in the overall analysis.
>
> DR. GULICK: Ms. Heise?
>
> MS. HEISE: I have two points. One thing that I think is important in
> terms of evaluating the appropriateness, as Dr. Fleming said, of a
> Phase 2 run-in is whether the conditions apply that you actually know
> you can do the study. And I think that one of the things that is
> important for people to realize is that at every site where these
> trials are being mounted, there is a preparatory study called a
> feasibility study, a site preparation study, where in effect they are
> enrolling women, seeing whether or not they can follow them up,
> looking at retention, seeing what level of incidence is achieved with
> the condom counseling and the like.
>
> So it is not like you are going from a Phase 1 study to this fullblown
> study without having field-tested any of it. I think that is an
> important thing. Frequently, that is at least a year-long feasibility
> or preparation study.
>
> Then, the second thing\--and someone should correct me if I am
> wrong\--I think that it is not just a Phase 3 study with an interim
> analysis. I think what is being proposed is that there are certain
> types of safety tests, whether it be a colposcopy, cytokines, all
> kinds of things, which are done on the women in the Phase 2, on a
> subset, because it is very, very complicated in these settings to do
> 3-month colposcopies on 10,000 or 12,000 women.
>
> So there are things that are being done to start to elaborate some of
> our safety concerns that are happening in this Phase 2 part of it,
> which is what we really think of as an expanded safety, as opposed to
> traditionally, in which you would be looking at sort of a
> pre-effectiveness.
>
> So in our kind of development pathway in the field, I think you get a
> series of safety trials with women at very, very low risk, then women
> who are at slightly higher risk, then women who have HIV as well and
> perhaps other STIs, and you keep trying to get closer and closer to
> the women who will be enrolled in the larger trial. So this Phase 2 is
> kind of your last step at trying to establish as best you can that you
> have all the safety information that we know how to get at this point
> prior to going on and look during an interim analysis.
>
> DR. GULICK: A response, Dr. De Gruttola?
>
> DR. DE GRUTTOLA: Yes, I would like to comment on that, because you can
> call it Phase 2, but it really is part of a Phase 3 study, and in
> fact, you can do intensive safety analyses on a subset in a Phase 3
> study as well and then review that information before you continue to
> enroll.
>
> I think the reason why the terminology is important is the reason that
> Dr. Fleming mentioned, that usually in Phase 2, you have time to
> evaluate the study, including the sponsor, and make decisions about
> how you are going to conduct a Phase 3 study. And in this case, if you
> do those safety analyses, and during the interim review, you find out
> that there is a problem, then you have a dilemma. Either you stop and
> start over again, which means now you have really a Phase 3 study that
> stopped, even though you called that part a Phase 2; or you modify the
> study in order to deal with some of the safety issues that have
> arisen, but that is complicated in a setting where the sponsor is not
> supposed to be receiving that safety information, and it raises
> questions about whether you really should combine the Phase 2 part of
> the Phase 3 study with the rest of the Phase 3 study.
>
> That\'s why I think that in certain ways\--although I understand the
> point that is being made, that this run-in part is different, and
> there is a lot more safety analysis, and it is closer to a Phase
> 2\--to think of the whole thing as a Phase 3 study may be helpful in
> terms of the kinds of commitments that need to be made. There is no
> reason not to do it if you believe you have all the information
> necessary to design the study, but if you are still worried about
> safety and doing a lot of intensive safety analyses in the Phase 2
> portion, then you wonder, are you sure that the results of that
> information are not going to lead you to wish you had done another
> study or had designed things differently at the start.
>
> DR. GULICK: Dr. Flores?
>
> DR. FLORES: I would like to get some clarification on whether the
> purpose of dragging Phase 2 into Phase 3, in addition to the safety
> evaluations that would be more intensive, also has an operational
> component that might actually allow some filtering in terms of the
> quality of the study, the ability to enroll and retain, and the
> potential that some sites actually may start early and others may take
> several months before they start. Is that also part of the purpose of
> this?
>
> I noticed in one of the previous study\--I believe it was the COL
> study\--that one of the sites dropped out early on and had to be
> replaced. Is that a consideration in this design, or are we just
> talking about, as Dr. De Gruttola said, a Phase 3 with initial safety
> evaluation?
>
> DR. GULICK: Dr. Fleming?
>
> DR. FLEMING: Another great point. I think, Jorge, without question, as
> we continue in our clinical trials research, we learn. And as we
> learn, we try to implement what we have learned in our future studies
> to improve the quality and reliability of those studies. And when we
> do a separate Phase 2 trial, as I was trying to indicate in the
> presentation that I made earlier today, clearly what we are trying to
> do is look at safety and look at plausibility of efficacy through
> effects on biological markers. But we are also trying to glean
> whatever insights we can from these types of studies and other
> preparedness studies to allow us to be in the most informed and best
> way possible to carry out the most reliable Phase 3 study, including
> issues that you mentioned, too\--the ability to enroll in a timely
> way, the ability to retain participants at high levels, the ability to
> achieve high levels of adherence to the microbicide and high levels of
> adherence to other interventions.
>
> If we launch a Phase 2/3 study without having adequate insights on
> each of these issues, we\'re taking a chance, because if we in fact
> learn these insights during the course of the study, we can make
> refinements; but if we are sufficiently far into it, some of the
> inadequacies that emerged early on are going to be there with us
> throughout the entire dataset.
>
> And, as Victor pointed out correctly, if in the Phase 2 experience, we
> find substantial safety issues that lead us to make nontrivial changes
> to the regimen, it becomes very problematic to interpret the aggregate
> data.
>
> So I keep saying the time to do this is when you do need to verify
> safety, and you may do so, as Lori was saying, by a more intensive
> monitoring of these participants. If you are quite optimistic this is
> going to be a favorable review, this 2/3 is an acceptable approach. If
> you are very uncertain, and there is a very realistic chance that
> revisions will need to be made, you are better-off for that to be a
> separate step that the sponsor can fully weigh in on and then make an
> informed judgment about how to better design this very expensive Phase
> 3 trial before it is initiated.
>
> DR. GULICK: Dr. Barlett, then Dr. Haubrich.
>
> DR. BARTLETT: I was going to comment that it seems that from an FDA
> standpoint, each of these trial designs could be viable within the
> limitations that have been articulated by Dr. De Gruttola and Dr.
> Fleming, and really, the risk is being borne by the sponsor, and the
> sponsor needs, with full transparency and understanding of this, to
> make decision. But from an FDA standpoint, these could all be viable.
>
> DR. GULICK: Dr. Haubrich?
>
> DR. HAUBRICH: It seems like the biggest thing you don\'t have from
> your Phase 2 study is an estimate of event rate which would help you
> plan how many people you need in your Phase 3. Is it legitimate during
> a DSMB review of the Phase 2 to adjust your sample size and still use
> all the patients that you\'ve got?
>
> DR. FLEMING: In fact I would argue in general that is one piece of
> information I would surely liked to have had up front but I can
> accommodate for more readily.
>
> If you recollect some of these calculations, I think the CONRAD
> situation was saying they were targeting a 50 percent reduction with
> 80 percent power. That takes 65 events. If they had said 90 percent
> power, it would be 88 events. The example I gave was a 33 percent
> reduction with 90 percent power; that\'s 256 events, all of those to
> achieve an .025 traditional strength of evidence.
>
> All of that is already known up front. What we don\'t know is the
> event rate, and that event rate requires us to then adjust either the
> sample size or the duration of follow-up. That is a totally legitimate
> thing to do except for the fact that if it turns out the event rate is
> one-third of what you thought, the sponsor may not be happy when they
> get the message that your study is fine\--you just have to triple the
> sample size.
>
> So you are well-advised to get a decent estimate of that up front so
> that you don\'t end up hitting the sponsor with such a radical change
> during the course of the study. I would argue, though, that that is
> something I can live with as that refinement.
>
> Something I am much less comfortable living with is changes in how to
> effectively carry out this study during the course of the study or to
> deliver the regimen to achieve maximum efficacy by getting maximum
> adherence, and reduce safety by getting a proper way of dosing this.
> That is the thing that is harder to correct midstream, because now you
> are changing fundamentals in the study design.
>
> DR. GULICK: Okay. Let me try to summarize what we think so far.
>
> The first thing we did was to remember why Phase 2 exists, and Phase 2
> is here to expand our safety information and to gain preliminary
> efficacy information, typically with effects on biomarkers.
>
> There are also other insights from Phase 2 which help inform the
> design of Phase 3.
>
> There was a lot of enthusiasm around the table for this kind of design
> in this setting, realizing, as Dr. Fleming pointed out, that we need
> insights into the plausibility of efficacy in this stage, that you
> have to be confident of your design and what your plans are; and other
> details such as adherence and of course safety are paramount in
> importance for moving forward with this kind of design.
>
> Other positives to this design mentioned are that it really extends
> and maximizes the safety information in terms of exposure, because it
> prolongs exposure in the set of individuals who enroll under Phase 2.
> As was pointed out, this could also be done in intensive subset
> analyses.
>
> It also has benefits in terms of logistics and feasibility among the
> sites, and it is thought to be efficient and a timely way to do this.
> And the overriding sense of urgency in the field supports this kind of
> approach as well.
>
> In terms of limitations, as Dr. De Gruttola summarized, this design is
> really a Phase 3 study, so you are jumping from Phase 1 to Phase 3,
> essentially. And the main limitation of that is risk itself, and there
> are several. There is risk in terms of condensing the time of
> development condenses your ability to make insights as to things that
> might turn out to be important for the design of Phase 3, but you are
> proceeding so rapidly that you actually didn\'t have time to make
> those observations and adjust accordingly.
>
> As others pointed out, there is a potential risk to patients in that
> going from a few hundred patients to a few thousand patients
> potentially involves more risk.
>
> And of course, there is risk to investment and to money here, going
> from a small study to a large one.
>
> Also, if a safety problem is detected early on in Phase 2, that may
> actually sink the plans to go forward to Phase 3.
>
> As was said, there are problems with details and uncertainties, but
> many of these, particularly the safety and early efficacy rules, could
> be addressed by writing in early appropriate stopping rules into the
> protocol, particularly for futility. And as was mentioned, it might be
> possible to adjust for event rates although other significant changes
> would be problematic, such as differences in dosing schedules or
> adherence rates than what was initially planed.
>
> All together, it was felt that if this kind of design were
> implemented, the first part of the study, it is critical to keep those
> data and information only accessible to a blinded interim review
> committee, that they should not be generally accessible by the sponsor
> or others, and then it would be appropriate to use that information in
> support of the Phase 3 endpoints as well.
>
> Okay. Let\'s try another one.
>
> Stand-alone Phase 2 targeted at high-risk groups, i.e., commercial sex
> workers, followed by a Phase 3 study. Please comment on the
> feasibility and, more generally, other design issues with this.
>
> This is the more traditional development.
>
> Dr. Haubrich?
>
> DR. HAUBRICH: I think there are several advantages to looking at
> high-risk populations. Number one, I think some of the safety concerns
> might become evident earlier if there is a dose response as was seen
> in the 9 study \[phonetic\] that was presented, where I believe the
> people who used it the most had the worst outcome. So in that sense,
> it could actually provide insight to safety.
>
> At least my understanding from reading some of the material that was
> presented is that the Phase 1 studies are going to be fairly short in
> duration, and if appearance of lesions and stuff like that takes time
> and exposure to develop, you could be going into a Phase 2 study
> without having enough safety data; that may not appear until later.
>
> So it seems that targeting high-risk populations could be advantageous
> from that standpoint. And jumping ahead a little bit to C, it seems to
> me that a Phase 2 lead-in might include some targeted populations to
> try to pick up early on some of these safety events as well, although
> it might confound the overall thing I talked about before, which is
> the rate of events, because it might be higher in that subgroup.
>
> DR. GULICK: Other comments on the traditional?
>
> Dr. Mathews.
>
> DR. MATHEWS: I think this question raises some issues that we have not
> made as explicit as perhaps we should. I am referring to the concept
> of efficacy, effectiveness, and proof of principle, which have been
> sort of thrown into most discussions today. It was only made explicit,
> I think, in Tom\'s presentation where you explicitly stated that
> effectiveness was the comparison between condom and microbicide, and
> efficacy the placebo versus microbicide. But I think those concepts
> really mean a lot more than that.
>
> My understanding of an efficacy trial is one which you plan so that
> you have high adherence throughout the trial, and the trial is done
> under the conditions which are most likely to show an effective, and
> usually, it requires a homogeneous population that is studied, such as
> commercial sex workers, for example. Whereas effectiveness means a
> heterogeneous population who may be doing other co-interventions and
> so on throughout.
>
> So I have wondered throughout the day exactly what an efficacy trial
> looks like in this way, and at the point the field is in right now,
> such an efficacy trial is really a proof of principle trial since
> there is nothing out there that has been shown to work yet.
>
> So I think those have implications for who is studied, how long they
> are followed\--for example, if people are followed for 24 or 48
> months, and adherence wanes, which it probably does, at least it does
> in antiretroviral trials, those factors need to be taken into
> consideration\--the intensity of the monitoring, and also another
> issue, for example, whether incentives should be provided to assure
> compliance with study visits and so on, which may not be part of a
> larger effectiveness trial.
>
> So this question, should Phase 2 be done in a high-risk group, I would
> say whether it is Phase 2 or Phase 3, what is the purpose of the
> trial. If it is to establish efficacy, I think it should be done with
> the shortest duration of follow-up consistent with achieving high
> adherence, with very frequent follow-up consideration for incentives.
>
> And the issue of homogeneity really raises issues about the
> characteristics of sites, because if, for example, in one site of
> commercial sex workers, condom use is very high, but in another very
> low, you haven\'t really achieved a homogeneous study population
> despite the fact you thought you were studying high-risk individuals.
>
> DR. GULICK: Dr. Stanley.
>
> DR. STANLEY: I think it\'s important to target high-risk individuals
> in the Phase 2, because this is different from a drug to treat
> something. This is an agent that is used at the individual\'s
> discretion as often as they wish. And therefore, to prove safety, you
> have really got to expose folks to high levels of this that might
> reflect that end of the curve of folks who will be using it a lot in
> real life.
>
> So I think that it is a little difficult to take somebody who is not
> at risk and expose them to high levels of this and cause damage,
> whereas if you have people who are going to be placing themselves at
> high risk and are going to be using a high level of this, they are the
> ones who are prime candidates for looking for safety.
>
> DR. GULICK: Dr. Paxton?
>
> DR. PAXTON: I guess I am going to just reiterate what Dr. Stanley
> said. I think this is a very efficient design to take the most
> high-risk women and study them first, because we learned from COL 1492
> that there can be significant differences between high-frequency users
> and low-frequency users, and this way, we would find that out much
> more quickly.
>
> Of course, a minor consideration is that you might end up losing a
> product that might have worked well on somebody who has low-frequency
> use. However, I would argue that women who do use it very frequently
> are going to be using it, so therefore, maybe you still deserve to
> lose it.
>
> So I think that that is a very efficient thing, and in a Phase 2
> trial, again, since it is mainly safety and not so much efficacy;
> safety is the main thing we are looking at there.
>
> DR. GULICK: Dr. Barlett, then Dr. Fletcher.
>
> DR. BARTLETT: I\'d like to ask Drs. Stanley and Paxton with regard to
> practical issues of doing this study in high-risk women, are these
> women\--presumably, you might be recruiting them at international
> sites, and they would require more intensive follow-up with colposcopy
> and other issues. Does that affect this decision and make it any
> harder?
>
> DR. STANLEY: Not to me, because if you are doing a time-limited Phase
> 2, you have got to apply those resources to it.
>
> DR. PAXTON: Right. And we have experience with using sex workers and
> having them come in for colposcopy and the like, and yes, I think it
> is feasible\--if that\'s the question being asked as to if we could
> comment on feasibility and can it be done, yes. And should it be done,
> I would also say yes.
>
> DR. GULICK: Dr. Fletcher.
>
> DR. FLETCHER: I wonder if there might not be another advantage to this
> Phase 2 and high-risk commercial sex workers, and that could be an
> overwhelming demonstration of effectiveness. I have already gotten my
> certificate from Dr. Birnkrant, so maybe I can be a little bold
> here\--
>
> DR. GULICK: Let\'s be careful here.
>
> DR. FLETCHER: \--yes. Could you comprehend licensure after Phase 2?
> What if this were a 400-person Phase 2 study, and you had P less than
> .00\--maybe even .01\--in terms of seroconversion and excellent
> internal consistency, and everything just said this product works.
>
> While you still may have a safety issue, in the past, FDA has
> certainly used Phase 4 to provide further evidence of safety. So what
> I am wondering is beyond just looking at safety as Dr. Stanley talked
> about because of frequency of use, might it also be an avenue that,
> for a product that showed overwhelming evidence of effectiveness\--or,
> I guess it would be efficacy\--could it be approved at that stage with
> requirements for further demonstration of long-term safety?
>
> DR. GULICK: Dr. Birnkrant, do you want to respond? He\'s asking you.
>
> DR. BIRNKRANT: That\'s funny\--we were asking you that question.
>
> \[Laughter.\]
>
> DR. BIRNKRANT: Because as it is written, not up on the screen but on
> the paper, we were concerned about the feasibility of conducting a
> Phase 3 trial after results were obtained from the Phase 2 that looked
> promising.
>
> So do people feel as though a Phase 3 trial could then be conducted
> following promising results from a small Phase 2 study in a high-risk
> population?
>
> DR. GULICK: Dr. Haubrich?
>
> DR. HAUBRICH: I think we have all seen in the HIV field things that
> look very promising even with highly significant P values and very
> small numbers of patients that have turned out not to be true. The
> whole issue in antiretrovirals evolved to using surrogate markers and
> interim approval drugs based on fairly small Phase 2 studies when
> other studies are planned and on the way.
>
> I think it would be very dangerous to set that precedent here,
> although I think highly tempting to do so if a small study, even if it
> looked promising, would then preclude the use or any further Phase 3
> study that compared to placebo. We have all argued the differences all
> morning of why there is so much confounding, and you need to do good
> placebo-controlled studies, and then to blanket, if you approved a
> product based on a 400-patient study, that would then make it
> unethical to carry out any other placebo-controlled studies then. So I
> think that would be a very dangerous thing to consider.
>
> DR. GULICK: And I think the flip side of that is the safety issue.
> Clearly, judging safety based on a 400-patient study in a product that
> could be used literally by millions of people for years is difficult
> to do.
>
> Dr. Sherman?
>
> DR. SHERMAN: That said, a freestanding Phase 2 and a single Phase 3 is
> very appealing as an approval mechanism. If both of them
> separately\--you do have two studies; one is a small Phase 2 in a
> high-risk group\--it seems to meet several of the needs that we
> discussed in this committee before.
>
> DR. GULICK: Ms. Heise?
>
> MS. HEISE: I think there is a concern that we need to consider safety
> issues among women who may have high frequencies of use. I think there
> is a separate issue, though. The assumption that people often make
> that there will be a higher event rate in a trial among sex workers
> has not been borne out in fact, because what we do know is that when
> we do our condom counseling with sex workers, these women are actually
> in a better position to be able to negotiate condom use with proper
> support.
>
> So the working assumption that many people had in this field 10 years
> ago was that the obvious quote-unquote \"population\" to enroll in
> these trials was sex workers, there would be a higher incidence rate
> in the trial than if you had women in the quote \"general
> population.\"
>
> What we have found, and there is actually data to support this, is
> that frequently, because of the concomitant condom use that is
> achieved in these trials, you actually have incidence rates higher. It
> doesn\'t address the safety issue, but I just wanted to point out that
> in this kind of design, you would actually have two separate
> populations probably. You wouldn\'t be able to have a population where
> you enrolled and used the same clinical and the same site and the same
> outreach workers and the same everything because you would be doing a
> safety trial among high-risk women, and you would most certainly
> probably want to do part of your large phase retrial among women
> recruited through family planning clinics or VCT clinics or whatever.
>
> So I think there are real feasibility issues in the sense that with
> the run-in kind of scenario with safety, you are talking about a site
> infrastructure that you have developed over time that you are
> maintaining and that you are continuing, whereas with this, you may
> well be talking about two totally different sites, two different
> infrastructures, and two different teams.
>
> DR. GULICK: Okay. So, as Dr. Bartlett pointed out, the consensus
> really is that we find both of these designs acceptable and that they
> each of pros and cons.
>
> We were very accepting of the traditional approach with all the
> pluses, and people began to gravitate right away to, well, how do you
> really prove proof-of-concept in Phase 2 if you did a stand-alone
> study, and the suggestion we leapt to was to look at an appropriate
> Phase 2 population that you could really study efficacy in. And the
> feeling was this should be somewhat of a homogeneous population.
>
> Commercial sex workers were suggested although, as Ms. Heise just
> pointed out, that may be debatable in terms of risk of exposure.
> Certainly this would be a population who may use the product at a
> higher rate than others. And as others pointed out, you could counsel
> for adherence, make sure you had adequate follow-up, pick your sites
> to achieve a homogeneous population, traditional Phase 2, trying to
> prove the principle before you go into Phase 3.
>
> All the negatives we mentioned before with the timely way of going
> from a Phase 2 run-in into Phase 3 become pros for the traditional
> approach. That is, now you do Phase 2, and you describe early insights
> that help you design your best Phase 3 studies. So those are obviously
> pros.
>
> The two main cons that were cited for this design, number one\--we
> didn\'t even state it because it is so obvious\--but this is slower.
> This clearly would take years longer than the previous approach. And
> as we heard from the beginning presentations today, the urgency of
> evaluating microbicides is great.
>
> And then, as pointed out, feasibility of doing this, looking for this
> highly homogeneous population may be difficult to truly prove this
> proof-of-concept that an early candidate drug would work.
>
> Then, you specifically asked us would a very convincing Phase 2 not
> allow us to go to Phase 3, and again, some discomfort with making the
> jump from a very convincing small Phase 2 study right into approval,
> both with efficacy and safety information.
>
> And then, as Dr. Sherman suggested, possibly a convincing Phase 2 plus
> a Phase 3 might do the trick.
>
> Shall we consider Point C\--are there other alternative designs that
> people would like to suggest?
>
> Dr. Fleming?
>
> DR. FLEMING: I\'ll be brief, because I spoke about it at some length
> in my own presentation this morning.
>
> A variation, an alternative, would be the 2B intermediate trial which
> would be in philosophy more like Step B, because it would be a
> separate step. It would in fact be a study that typically would be
> one-third to one-fourth the size of your full-scale highly-powered
> Phase 3 trial. Its advantage is that it would provide for significant
> insights in quality of trial conduct issues for the ability to
> implement these insights in the design of any subsequent Phase 3
> trials. It would provide extended safety experience in a controlled
> fashion. It would clearly provide very strong proof-of-concept
> insights for efficacy.
>
> And there is a little bit of semantics here. If we look, for example,
> specifically at the implementation of this design in the 035 setting
> where, as Salim was talking about, it is a 3,100-person trial
> targeting the ability to get roughly 100 events for every pair-wise
> comparison, that actually is larger than some of the Phase 3 trials
> that we have heard about from others that are targeting bigger
> differences.
>
> So in fact, it is semantics\--it is a Phase 3 trial for a more
> aggressively assumed treatment effect, but for a more conservative but
> nevertheless important treatment effect, it would in fact be more
> likely a Phase 2B trial.
>
> DR. GULICK: I guess one issue that hasn\'t come up at all is a
> crossover design particularly for women who would be randomized to
> either the placebo after some period of time or, if we decided to
> proceed with that design, the no-treatment arm. That\'s a way to
> continue obviously people who randomize to, quote, \"less attractive\"
> arms in follow-up in the study if they are assured with being either
> re-randomized or getting something later on in the design. That is an
> effective way to address that.
>
> DR. PAXTON: Is it really effective, though? It seems to me that since
> HIV is a definite endpoint, and once somebody has reached that, you
> can\'t get rid of it\--there is no washout period.
>
> DR. GULICK: No; I don\'t disagree with that. I guess I was referring
> to\--let\'s say we recommended or a study was designed with the three
> arms, and there was the no-treatment arm, that part of the design of
> the study up front could be to offer that group the intervention later
> at some point.
>
> Dr. Wood?
>
> DR. WOOD: In terms of alternative designs, I just wanted to throw out
> there the idea of possibly in terms of design scheme and
> randomization, rather than randomizing individuals, consider
> randomizing communities or populations. This could potentially be done
> during a Phase 2 study in which you have two centers of sex workers
> but one center is going to be randomized to receive the microbicide
> and the other will be randomized to receive the placebo control gel.
> That would allow you to look at safety issues in terms of intensity
> and frequency of use. Hopefully, the populations would be homogeneous
> in one sense in that they are commercial sex workers having intensive
> exposure. You might have a greater rate of events between communities
> if you have a community approach. And it might allow for a better
> assessment potentially of efficacy as well as an assessment of use
> effectiveness in a population that might allow generalizability when
> you went to a larger Phase 3 trial.
>
> We haven\'t talked about that, but I just want to throw it out there.
> I don\'t know if it makes it logistically harder or more difficult to
> do, but if it allows you to get a clearer answer by using populations
> and making things cleaner in terms of having the randomization at that
> level as opposed to the individual level, is that something to be
> considered.
>
> DR. GULICK: Okay. So a brief consensus here\--again, as John Bartlett
> pointed out, all of these designs may be appropriate. We identified
> pluses and minuses. As Dr. Fleming said, some of this is semantics. A
> Phase 2 study of 2,000 people is really more likely a Phase 3. And
> then we heard some suggestions about crossover and randomization of
> centers or countries as opposed to individuals.
>
> Okay. Shall we move to Question 2?
>
> DR. BIRNKRANT: That was helpful. We can move to Question 2.
>
> DR. GULICK: As long as we are helpful.
>
> DR. BIRNKRANT: Question 2 is a discussion of the debate between a
> three-arm design versus a two-arm design. And as I had mentioned, this
> may apply to the three-arm design, that is, more for first-generation
> microbicide than to subsequent ones that reach the market.
>
> With regard to a two-arm design, though, we do have a question as to
> whether or not the control should be placebo or a no-treatment arm.
>
> DR. GULICK: So it is probably easier to discuss this as a group rather
> than take them one by one.
>
> DR. BIRNKRANT: Yes.
>
> DR. GULICK: Dr. Stek?
>
> DR. STEK: I want to echo the comments that were made earlier about the
> inability to properly evaluate a no-treatment arm. I am a
> gynecologist, and I know how difficult it is to get accurate
> information about sexual activity, and I think we just make an
> uninterpretable result.
>
> However, I would like to point out something that really hasn\'t been
> brought up about who is not going to be using condoms. It was pointed
> out that in the African experience, the women who are at the highest
> risk are those who are trying to get pregnant, so they will not be
> using condoms. And I know that some of these products are probably
> going to be designed to be contraceptive as well, but also, there are
> products that should be available for women who want to avoid HIV
> infection and are attempting to get pregnant.
>
> I know that studying any kinds of medications or anything with HIV in
> pregnancy is very complicated. However, I think that we should not
> ignore this problem. I would urge this to be incorporated in the study
> design. As far as I know, the products that are under consideration
> have not undergone the more advanced reproductive toxicity
> evaluations, and I think that that probably should be done.
>
> There are a number of reasons why this is really important. Women are
> going to become pregnant. They always become pregnant on any kind of
> HIV study that I have been involved in. And the risk, we think, is
> probably the highest for bad outcomes with exposure very early in
> pregnancy before women have had a chance to discontinue the treatment.
>
> Also, there is the issue of perinatal transmission. We think that
> acquiring HIV during pregnancy greatly increases the risk of
> transmission to the fetus as opposed to someone who has already had
> HIV for a while.
>
> So I know it is a difficult issue, but I think that it should be
> considered to not discontinue treatment in pregnant and do the studies
> that would be required to assure safety in use in women who are
> attempting to get pregnant.
>
> DR. GULICK: Dr. Stanley.
>
> DR. STANLEY: Well, I have a real problem trying to compare a potential
> microbicide with just condom use only, because that is relying on
> behaviors, and behaviors are going to change depending on the options
> that they are given, as many of the speakers pointed out.
>
> The reality is that once there is a microbicide on the market, there
> is a population that will probably stop using condoms as we heard from
> the African experience. So what are you gaining by comparing two
> options that in fact are not stand-alone options that are going to be
> out there in the real world once a microbicide is approved.
>
> So I think you confound the issue. I think that you have the potential
> to rule out an effective product. Even the FDA said that if you have
> the three arms, you do have to know what condom use is. Well, you are
> not going to know because some of these patients are telling you what
> they think you want to hear, not necessarily what they are really
> doing on a day-to-day basis. So you will never know what their condom
> use is, and I think that trying to include that arm is really a
> confounder.
>
> DR. GULICK: Dr. Bartlett, and then Dr. Paxton.
>
> DR. BARTLETT: I just want to echo what Dr. Stanley said. I was moved
> by Dr. Dominik\'s presentation about how the results could be affected
> by the lack of blinding and the differential condom use, even though
> in the small Cameroon study, it didn\'t appear that there was a big
> difference. But if there is a difference, it certainly could have a
> big impact on the result.
>
> DR. GULICK: Dr. Paxton, and then Dr. Fleming.
>
> DR. PAXTON: I think I am adding my voice to the chorus that we heard
> today. I think that we have heard significant and very plausible
> concerns about including a condom-only arm in that we will probably
> have unintended and, most importantly, unmeasurable effects of that
> arm.
>
> Another thing that was alluded to but not specifically brought up but
> which we have in our packets is what the actual cost would be of these
> things in terms of money, but that also leads into issues of time, and
> we realize that we don\'t have as much time as we would like to have.
>
> So my personal belief is that what the FDA should require should
> probably just be the two-arm microbicide versus placebo trial.
> However, I echo what Tim Farley said. I think that the possibility of
> allowing for a three-arm trial\--the scientific part of me would like
> to actually look at this to see what we can measure in a three-arm
> trial, but I don\'t think that that should be required by the FDA for
> these trials to go forward.
>
> DR. GULICK: Dr. Fleming and then Dr. Flores.
>
> DR. FLEMING: I guess I would say in conducting a Phase 3 definitive
> trial, it is really critical to answer the fundamental questions that
> are unknown. And as I think about ultimately, what do I want to
> know\--I want to be able to do clinical trials that will assess what
> the real world role of an intervention would be. That is the
> traditional approach that I would always take. And a topical
> microbicide is really a regimen, and as regimen, there are I would say
> at least three areas of ways that it can affect a woman\'s risk of
> transmission.
>
> One is the intended anti-microbial effect. Another domain of ways that
> it can be affected is through other elements of the regimen,
> specifically, its physical barrier effect, its lubrication effect, and
> other effects as well. Those are other true protective effectives that
> the regimen can have. A third is that it may in fact have an intrinsic
> effect on the nature of risk-taking behaviors that an individual is
> embarking on. If in fact it has such an intrinsic effect, I would
> argue that that too is something that I eventually need to understand.
>
> Now, what do I know from the comparison with the placebo? Somebody
> said it is an unbiased estimate of product effectiveness. And Chris,
> I\'m going to come back to your earlier comments. We may use these
> terms in slightly different ways, so I\'ll just be precise in the way
> that I am using it.
>
> I would think of efficacy as what is the effect of the microbicide in
> that hypothetical setting in which risk is identically controlled. To
> my way of thinking, that would mean that I want to include in that not
> only the antimicrobial effect, but if in fact the microbicide has
> other protective effects through lubrication, physical barrier, et
> cetera, I would want that in my efficacy, and my concern is that that
> requires knowledge that the placebo is inert. I don\'t know that. So I
> don\'t know that a comparison with placebo is actually going to give
> me an unbiased estimate even of efficacy.
>
> So I come at this saying I don\'t want to make assumptions about what
> I don\'t know. I would like to have the clinical trial be done in ways
> that can provide insights.
>
> The other aspect is if in fact there is a true intrinsic change in
> risk-taking behavior, whether it is an increase or a decrease, it is
> something that I would want to know. Somebody had mentioned at the
> break that condoms are so effective that certainly we want to be sure
> that we aren\'t doing something that reduces adherence to condoms.
> Let\'s say that the adherence to condoms by virtue of being assigned
> to a microbicide, which is an intervention that you might think is
> protective, leads you to reduce your adherence to condoms from 90
> percent to 80 percent, so you are doubling the number of people who
> aren\'t using condoms.
>
> Somebody said that in the statistical calculation, that is going to
> decrease my power. It should decrease my power, because if that\'s the
> truth, then the overall net benefit of this intervention is
> diminished.
>
> We spent more than a decade talking about what is the standard for
> strength of evidence for an HIV vaccine. I was talking to one of my
> colleagues recently as I was defending what we are talking about as
> our standards for approval of microbicides, and I was saying we are
> targeting a 33 percent effectiveness ruling out no difference.
>
> This person said, \"What? For vaccines, we are talking about having
> point estimates high enough to rule out a 33 percent protection,\"
> because specifically, the point was that if you are on an HIV vaccine,
> and risk-taking behavior because of your sense of protection here is
> increased even by a modest amount, that would offset the overall
> benefit, and as a result, modestly protective vaccines may in fact not
> provide net benefit.
>
> So with that as a backdrop, suppose you were in the setting which I
> described in my transparency, which was the middle setting on the
> left-hand side. Supposed you finish the study with only a placebo
> control. You have a 2 percent annual transmission rate in the
> microbicide and 2.5 percent in the placebo. That\'s a relative 20
> percent reduction, just barely marginally on the area of statistical
> significance, that wouldn\'t in fact be evidence that would readily be
> judged to be conclusive. And if somebody says, wait a minute\--you are
> estimating a 20 percent protection, when we actually think it is
> likely that there could be an associated reduction in implementation
> of condoms? How do I know that that in fact is adequately
> protective?\"
>
> And I come back and tell you, But we had a third arm. We had an arm
> that in fact compared directly to an open, unblinded experience. And I
> accept that the overall level of use of condoms can change. I want it
> to be real world. I am not trying to make that third arm the same
> level of use of condoms. I want to find out what happens when you are
> on an intervention that you think is protective against standard of
> care. And if in fact I have that third arm, and what in fact I found
> out is there is every bit as much protection\--it is 2, 2.5 and 3\--I
> am greatly reassured, first of all because I am getting a sense that
> the overall 20 percent reduction of efficacy might in fact be an
> underestimate of efficacy because there is actually an additional
> level that the placebo blinded out.
>
> Secondly, I can be reassured that I am not in fact losing this net
> benefit with condoms. I would think we should be very worried as we
> look at globally establishing efficacy of these interventions that we
> recognize that a microbicide regimen is a regimen that involves the
> anti-microbial effect, other protective effects, and a behavioral
> component, and if we aren\'t confident that we are able to maintain
> within a reasonable level adherence to condoms that we know are highly
> protective, then we don\'t have a regimen that is going to be
> effectively aiding the population, at least in the way it is being
> implemented. Shouldn\'t we know that?
>
> The bottom line is I don\'t think there is a single right answer to
> this. I would accept, after all the discussion, that the agency should
> view there to be some flexibility in how these studies are designed. I
> don\'t consider that every study needs to have a placebo and an open
> label. But I do think that there is a need for a foundation of at
> least one or two early-generation studies that will provide us
> insights not only about what the comparison is to placebo but what the
> overall more net benefit and effects would be that other studies can
> then build on and wouldn\'t necessarily also have to have the dual
> control.
>
> DR. GULICK: Dr. Flores.
>
> DR. FLORES: My basic problem with your concept, Tom, is that we don\'t
> know whether the trading in condom use is going to be similarly
> proportional in the three groups, and that is the big conundrum here.
> Because they are in a different arm altogether, there may be a totally
> different rate of lack of adherence to condoms.
>
> The other problem I have with this concept of requesting or requiring
> it the first time around, I am not making it necessary later as if the
> trials are just going to keep rolling over in the same population and
> using exactly the same placebo, perhaps; I am just repeating the same
> thing. Either it is a concept that should apply to all the studies or
> to none.
>
> DR. FLEMING: But Jorge, I think the very concern that you have is the
> essence for why I think there need to be foundation studies to address
> the point.
>
> What you were saying is you are concerned that there may be a
> different level of condom adherence in the two blinded arms from the
> open arm, and I am accepting\--I share your concern. I don\'t know
> whether there is or not. I want to allow the real world to occur. And
> if, in fact, what we saw in the Cameroon study can be extrapolated so
> that there is an 87 percent adherence in the open, unblinded arm and
> an 81 percent adherence in the overall blinded arms, that true
> difference should be allowed to occur.
>
> This is going to give me a sense in the real world whether or not the
> benefits that I get from my comparison with placebo from the
> antimicrobial effects of the microbicide will offset some unintended
> negative effects that would be associated with the reduction in
> adherence levels to condom use.
>
> DR. GULICK: Okay\--don\'t worry, I have a lot of people who want to
> speak, and we\'ll take them in order. So, everyone who is anxious, I
> got your names.
>
> Ms. Heise.
>
> MS. HEISE: I\'m always the most anxious.
>
> DR. GULICK: You are in good company.
>
> MS. HEISE: Two things. I think that exactly for the reason that you
> say, your solution to the problem is wrong, because what you are
> concerned about is what every public health official is concerned
> about, which is how will the combination of the biological effect of
> this product, whatever it may be, interact with behavioral and
> risk-taking behavior to influence protection or infection rates.
>
> By adding a condom-only arm in this trial, you cannot answer that
> question because basically, what you are assuming is that that
> actually does give you a sense of the real world. But when we are
> counseling women in this trial, we can\'t tell them anything about the
> likely effects of this product. In fact, we are spending enormous
> amounts of time to convince them that they shouldn\'t have any faith
> in this gel. And therefore, trying to say that a trial where you are
> actively trying to dissuade people from relying on a microbicide will
> approximate people\'s adherence or risk-taking behavior once we have
> some evidence that we can counsel that this does reduce risk, I think
> is false.
>
> I think the way to answer that question is you establish whether or
> not\--you use straight, placebo-controlled trial\--is there some
> evidence of effectiveness. Then, you do, and I think we are going to
> have to do, a number of Phase 4, or whatever you want to call them,
> use effectiveness studies about how this microbicide interacts with
> all sorts of things in different settings to understand under what
> circumstances adding it to an existing package of interventions is
> helpful or not.
>
> But adding on the extra cost, time, and so on of a condom-only arm
> that is not interpretive doesn\'t get you where you want to go.
>
> The second thing I want to say is that I think it\'s actually a shame
> that the FDA did not invite someone to give data and background on
> some of the behavioral issues, because they are some of the most
> important issues. And I would suspect that there is probably not a
> single one of us around this table who may or may not be an expert in
> what is known or not known about some of these behavioral issues.
>
> I do think that one thing we do know from the behavioral data\--and
> this is from data from nine studies that have been done, which are
> reviewed in an article in the Global Campaign testimony. There have
> been nine studies done to date that look at how people react when they
> are randomized to being offered condoms only versus condoms, female
> condom, diaphragm, or some other combination of multiple methods.
>
> What you find in both those studies where the endpoint are STDs as
> well as from two decades of contraceptive research is that just the
> fact of offering choice increases adherence. And in fact in the
> studies where they were randomizing people between condoms-only and
> condoms, N-9, or female condom, condom use actually went up because
> people respond to having choice.
>
> So I think that what we do know is that when you are offering one
> thing to one group of people and two things, or four options of how
> they might combine those things, to another group of people, we are
> likely to have large and probably more than 10 percent difference in
> behaviors.
>
> So I think that the issues is real. We need a second generation of
> studies to answer that other question. We first have to convince
> ourselves, though, that what we can actually say to women that, \"If
> you use this, there will be some reduction in risk.\"
>
> DR. GULICK: Okay. I have Dr.\--
>
> DR. FLEMING: If I could very briefly respond, because she was\--
>
> DR. GULICK: Actually, let me stick to the list because a lot of people
> have been waiting to speak, so let me stick to the list.
>
> DR. FLEMING: Okay.
>
> DR. GULICK: Dr. Haubrich, Englund, Bhore, and Paxton.
>
> Dr. Haubrich.
>
> DR. HAUBRICH: I have to agree with the assessment that the use of
> microbicide could potentially have a deleterious effect on the overall
> burden of worldwide HIV cases.
>
> I think that there is little evidence to suggest so far that the use
> of a microbicide is going to be as effective as condoms. So anything
> such as the availability of a microbicide in a trial or, even more so,
> once it is approved, could potentially lead to a reduction in the use
> of condoms which could have the untoward benefit or the untoward
> action of leading to a global increase in HIV transmission.
>
> Therefore, I think trials that assess in whatever way we have, no
> matter whether they are flawed or not, the impact of no treatment
> versus use of agents like this are critical.
>
> That being said, I think that the regulatory perspective of showing
> that a particular agent is better than placebo is really a separate
> question than understanding the more global impact of the scientific
> question of how do these agents affect change of behavior, which is
> really a different question than the efficacy of a particular agent.
>
> So in my view, the sort of two-pronged approach of ongoing studies
> like the 035 which are targeted to address the sort of clinical
> strategy, which is really a very different issue and has another whole
> set of confounders that we have all discussed today, and the
> regulatory issue of approving a drug should proceed.
>
> I am very concerned\--if the 035 and studies like it were not planned,
> I think that to simply charge ahead and say we need to find out
> whether microbicides work or not would be flawed, because once one is
> approved, the impetus and the funding to carry out these large studies
> like 035 would go away.
>
> So the only way I would be comfortable with the regulatory allowance
> of just a two-arm study is the ongoing study like the 035. We talk
> about allowing Phase 4 studies in this country to answer some of the
> unanswered questions about ongoing long-term safety and so on, and we
> talk about how hard these studies are. To blindly think that we are
> going to carry out Phase 4 studies to answer questions like this once
> something has been approved I think is a little bit naive.
>
> DR. GULICK: Dr. Englund.
>
> DR. ENGLUND: I just wanted to address two things. Number one, I think
> it is absolutely important, and some of my colleagues who have done
> studies\--and I have not done studies, but I have worked over in these
> countries\--have to absolutely emphasize is that this condom use is so
> population-dependent.
>
> In the countries that I have worked on, the women will be killed,
> stoned, or thrown out of their house if they suggest the condom. When
> you are dealing with multiple wives with a single husband, these women
> are totally powerless to use a condom.
>
> So for us to impose on all populations our ideas of what the control
> group should be is actually a problematic. So I think first of all,
> the highest-risk people are the ones that many times are unable to use
> a condom in a clinical study, or they wouldn\'t be in a clinical
> study, and they probably won\'t be able to use one in practice.
>
> Having said that, I think that makes us forced\--and the one thing the
> FDA can help us do is to make sure that our Phase 2 safety is
> absolutely flawlessly done. And if that means that in Phase 2, we even
> have to have a placebo and a non-treatment arm so that we can
> absolutely assess the colposcopy and all these values before we go on
> to a Phase 2B or extended thing, that\'s where we really need to
> emphasize the safety, because I don\'t think we can do a 2B or a large
> study in some of the areas that need us most with condom usage.
>
> I think South Africa might be a great place to do it, but Tanzania is
> not. It is just going to be very population-dependent.
>
> DR. GULICK: Dr. Bhore.
>
> DR. BHORE: Thank you for the opportunity, finally.
>
> I just want to remind the panel, as I said in my presentation\--and I
> am hearing a number of opinions from a number of people that dropping
> the no-treatment or the condom-only arm would be the easiest approach
> to take\--but I just want to remind people that this assumes all along
> that the placebo\--which I put in quotes in my presentation \"assuming
> this is inert\"\--and the biggest concern is if the placebo is a
> harmful placebo. And showing superiority of a product over a harmful
> placebo is not going to be sufficient in showing that it is effective,
> because at worst, if a placebo is harmful, a product that is superior
> to placebo can at worst be harmful itself.
>
> So I would just like to remind you about that possibility.
>
> Then, second, I have a question for maybe the statisticians or whoever
> wants to try to answer this. That is, we have heard a number of people
> say that one of the reasons for dropping the condom-only or
> no-treatment arm is the differential compliance of condom use in the
> three different arms.
>
> My question is are there statistical methods out there that can
> address this issue of differential compliance rates and so still be
> able to analyze and interpret the data.
>
> DR. GULICK: Dr. De Gruttola, do you want to tackle that one?
>
> DR. DE GRUTTOLA: Yes. I would say that there are two issues. One, Tom
> has made the point that in fact the difference in condom use is one of
> the things that is important to find out about and the impact of that
> on the endpoints.
>
> Ms. Heise also made the point that behaviors are going to change once
> information is actually available regarding the efficacy of the
> product. But nonetheless I think the information about what happens in
> the trial with the current state of knowledge is of interest. That is
> the first point.
>
> The second point is that if you want to ask the question what would
> have happened had compliance with condoms been the same across
> different arms even though it wasn\'t the same, I think that\'s a hard
> question to try to formulate because the use of condoms is associated
> with all sorts of other personal characteristics that may themselves
> have an impact.
>
> So I think it is a little bit difficult for me to think even exactly
> about how you might formulate that question. Assuming that you can,
> there is a whole area of statistics, causal inference, where people
> try to address questions like that to try to make adjustments for
> differences in behaviors in different groups, to try to make some
> inference about a kind of ideal setting that didn\'t actually exist,
> and I think that\'s an interesting research question, but I wouldn\'t
> put a lot of emphasis on it as something that is going to be useful
> for regulatory purposes right now.
>
> DR. GULICK: Thanks.
>
> Yes?
>
> DR. SUN: This is Greg Sun \[phonetic\] from the FDA, Environmental
> Team Leader.
>
> I echo what Victor just said. Essentially, the question of adjusting
> for compliance may not be relevant for the FDA in the sense that if
> the drug use is going to modify the behavior of the patients\--and I
> think that is a reality\--then there is no sense to look for
> adjustment, because if by introducing drugs on the market is going to
> reduce condom use, if that\'s a reality, then it doesn\'t
> matter\--even if a drug is active, whatever the benefits may be offset
> by this less use of condom. Then we\'re not interested in answering
> the question if they have the same use of condoms.
>
> DR. GULICK: Thanks.
>
> Dr. Fleming, to add?
>
> DR. FLEMING: Yes. I would just add that I agree with both comments,
> that if one wanted to try to step back and make some kind of
> retrospective adjustments, of course, one of the real problems that we
> have heard many people state is that the self-reported risk-taking
> behavior is already just a surrogate for the true risk-taking
> behavior, and the true risk-taking behavior is in fact also a
> surrogate for what the actual true risk of transmission is.
>
> So even if we had good statistical methods, it would be
> extraordinarily difficult to apply them. But I agree with what you are
> saying here. Ultimately, my interest in comparing to the open label is
> to look at what is the comparison against a standard of care where it
> is based on condoms alone, and if that\'s a different level of
> exposure to use of condoms, I don\'t want to adjust that out.
>
> Lori, you make an important point, and your point was is there
> something a bit artificial about this trial, because we have just gone
> through an informed consent process and told people that our best
> understanding here is that there is equipoise\--we don\'t know for a
> fact that these interventions, and specifically the microbicide, will
> be protective.
>
> That in a certain sense is artificial, because once the study is done,
> if it is proven efficacy, that could lead\--you are correct\--to a
> different level of commitment to implement that intervention.
>
> The reality is that that same argument applies to the assessment of
> the comparison with the placebo as well. That issue that you are
> raising that could in fact cast some doubt into the generalizability
> of your conclusion when you are comparing the active microbicide
> against the open label, in fact I make that same argument all the time
> about our own placebo control trials.
>
> My answer to that argument is that what we are hoping here is that
> what you have in a clinical trial setting is actually an artificial
> intensive oversight of participants to ensure adherence, so that level
> of oversight is going to offset what you correctly point out could be
> a level of intrinsic commitment to use an intervention once you have
> already shown that it is effective.
>
> But the fundamental bottom line to this is that if you are worried
> about this point, and hence you are as a result worried about the
> interpretation of the comparison with the open label, unblinded arm, I
> can make the same criticism about the interpretation of the comparison
> with placebo.
>
> DR. GULICK: Dr. Paxton.
>
> DR. PAXTON: Actually, one of the major points I was going to bring up
> was brought up by Lori. But one more minor thing is that I think your
> contention about whether we can say that the condom-only arm really
> does approximate the real world, because in no sense actually is this
> the real world in that these women will be getting intensive condom
> counseling repeatedly each time they come in, which doesn\'t happen in
> the real world. And then we have that other confounding thing about
> when you have somebody coming in and getting condom counseling and you
> ask them, \"How are you using the condoms?\" they might tell you what
> you want to hear, or they might be telling you the truth, and we have
> no way of knowing that given our present assessment measures for this.
>
> So I just would not say that in any sense this approximates the real
> world. It might be of interest, and I do think it is of interest, to
> look at these things, but I don\'t in any way in my mind consider it a
> proxy for the real world.
>
> DR. FLEMING: But Lynn, these issues are very parallel. The extent to
> which you are legitimately recognizing that our intent to do a real
> world comparison can\'t be fully achieved, you have got to look at the
> comparison against placebo in the same way. The blinding issue
> doesn\'t get rid of that particular concern\--that is, what you can
> state is the generalizability of the efficacy that you get from a
> blinded comparison is also sensitive to issues of how well was there
> adherence in that specific setting to the condoms, how well was there
> adherence to the intervention.
>
> DR. PAXTON: Can I respond?
>
> DR. GULICK: Sure. Response.
>
> DR. PAXTON: Just in response, I do think that when you are looking at
> two arms that are both using a gel, you are going to have less
> variability between those two arms in terms of behavior.
>
> DR. FLEMING: But that\'s okay. The fact of the matter is that the
> adherence to the microbicide gel in the placebo arm isn\'t my issue. I
> assume that is inert; I am hoping that is inert. My concern is what is
> the adherence. My biggest concern with microbicides, my biggest
> uncertainty of their efficacy is that unlike a vaccine that I can
> deliver once or on a periodic basis and be assured I have continuing,
> sustained adherence, I have got to use this microbicide on a regular
> basis to achieve the full essence of the benefit.
>
> And Lori is right\--if in fact I don\'t have the same commitment to
> that implementation when I haven\'t already been aware that it has
> proven efficacy, then, randomization hasn\'t protected me against that
> level of underestimation of efficacy as well, even in my comparison
> against placebo.
>
> DR. GULICK: Okay. We are going to need to draw this important
> discussion to a close, but Dr. Stanley, you have the last word.
>
> DR. STANLEY: Well, good, because that\'s about what I was going to
> say. That is, what we are really doing is dancing around the ethical
> conundrum that microbicides bring to us.
>
> There are two populations of folks out there at a minimum. One is
> folks who are going to use condoms, who have the authority, if you
> will, to mandate that their partners use condoms, and they don\'t
> necessarily need microbicides to the level that we are talking about.
>
> But then you have the other disempowered population that cannot
> mandate condoms, and those are the ones we feel an urgency to have an
> effective microbicide out there\--and it doesn\'t matter if it is only
> 20 or 30 percent effective, because they don\'t have another option.
>
> The problem is that once you approve one of these and put it on the
> market, the group that has been able to use condoms will alter their
> behavior or some subset of that group will, and that\'s where you
> stand the risk of doing harm.
>
> So, while you have done good for one population, you run the risk of
> doing harm to the other, and it is that ethical conundrum that then
> causes us\--we are trying to design clinical trial designs that
> aren\'t going to answer that.
>
> DR. GULICK: Okay.
>
> Dr. Fletcher, you have the last-last word.
>
> DR. FLETCHER: Mine is just a quick question for the FDA in terms of
> where we really are with a microbicide placebo. Is there a candidate
> product? Is there one in testing? Just give me some sense of where
> that universal placebo development is at.
>
> DR. WU: That so-called universal placebo is going to undertake a Phase
> 1 14-day trial as a safety assessment initially.
>
> DR. GULICK: And is there a plan\--this is a bit of a funny
> question\--to go to a Phase 2-type design with the universal placebo
> versus no intervention?
>
> DR. WU: Not at the present. At the present, once after that 14-day
> trial, the placebo will be used concurrently with a candidate
> microbicide into whatever the design, the next step will take them. If
> this is Phase 2 running to Phase 3, this placebo will be in use.
>
> DR. GULICK: Okay. Let me try to summarize what we are thinking here.
>
> Clearly, we have differences of opinion around the table. Dr. Fleming
> put it best to say there is no one right answer here as well. We are
> dealing, of course, with different cultures, different countries,
> where there is lots of different condom use, and that complicates our
> discussion of what the standard is even from population to population.
>
> We recognize again the inherent issues about clinical trials and how
> they are different from life, and specifically here that making an
> intervention may change behavior, that a commitment to an intervention
> may also change behavior, and that intensive counseling which is
> critical for these studies actually is not often a part of what
> happens in the \"real world.\"
>
> These are all issues of generalizability and how you take one study
> and apply it to the whole world, but that\'s really what we are
> talking about here. Also, the recognition that sexual behavior is
> difficult to assess in a clinical trial or really in any setting at
> all.
>
> We took some comfort in knowing that our recommendation for which
> design is optimal now may be the most appropriate for the initial
> studies, but then, when information is generated in these studies,
> other design could be considered, particularly simpler or, if some of
> the questions that we have been struggling with are answered, then a
> more complicated design would not necessarily need to be continued.
>
> There was some debate about that, though, whether it is more
> appropriate to try to answer these questions up front or limit the
> questions up front and then answer other questions in Phase 4 or down
> the road, and there were some differences of opinion on that.
>
> And clearly, everything changes when one microbicide shows safety and
> efficacy, because then that would be the standard to compare all
> future microbicides to. So a lot of our discussion becomes less
> important when that event occurs.
>
> As we heard earlier today, a requirement versus allowing a
> design\--there was a lot of support for flexibility in both
> approaches, really.
>
> So what did we say in all? The most attractive thing about the
> three-arm design is really that it gives you an overall net benefit.
> We are looking for benefit versus risk, antiviral effect versus the
> possibility that an intervention could actually change behavior or
> reduce condom use, and both of those are important in assessing the
> overall risk versus benefit.
>
> As Dr. Fleming reminded us, the amount of effect that we are looking
> for here is quite different than we are looking for in, for instance,
> a vaccine study, so that small benefits in antiviral effect actually
> could be offset by changes in behavior on the order of what we have
> been talking about. So that is a big concern, I think, around the
> table.
>
> Using this three-arm study, the comparisons of the two arms actually
> give you different information, which was stated again and again.
> There are really two questions\--how does a microbicide compare to the
> placebo asks a very different question than how does a microbicide
> compare to no intervention at all.
>
> Safety was something that we had not talked a lot about, but Dr.
> Englund reminded us that safety is important here, both of the
> microbicide and the placebo itself, and we need to keep that in mind.
>
> So people had concerns actually about all three of these designs.
> There were concerns voiced. On the two-arm versus the placebo, which
> you might think of as the efficacy comparison in that you are looking
> for antiviral effect above and beyond behaviors which we would like to
> think would be randomly distributed between two arms, is attractive;
> however, we are not convinced that the placebo is inert. It could have
> beneficial properties such as barrier or lubrication, or on the other
> hand, it could actually be harmful, and we may not know enough about
> the placebo\--I think that is what prompted Dr. Fletcher\'s late
> question\--how much do we know about the placebo before we go into
> this.
>
> Then, there is a big concern that just the use of any intervention
> here could decrease the use of condoms, and how do we evaluate that,
> and then, conversely, that\'s an important part of evaluating this
> kind of intervention in and of itself.
>
> There were lots of concerns about the no-treatment arm. This is more
> of an effectiveness evaluation, in a sense. This is real world\--or is
> it? There was a lot of debate about that, and I won\'t review that,
> but there is controversy about how real world this really is.
>
> People noted again that it is difficult to evaluate behaviors or
> changes in behaviors. And there was a big concern that
> post-randomization, there would be different behaviors in the
> different arms, and condom use could go up or down and you really
> can\'t guess which might occur in each of the three arms, and that
> there might be a significant enough difference that it could actually
> affect the overall interpretation of the study. There were lots of
> concerns about that.
>
> So in summary, we\'re not sure.
>
> \[Laughter.\]
>
> DR. GULICK: But all approaches have value, and I guess\--we talked
> about taking a vote on this before. I think that would go down in
> flames, so I don\'t think we\'ll do that. You heard our pros and cons,
> and I guess if I had to reach consensus from the vibes I am feeling
> right now, generally, I think that what people liked was a broader
> approach earlier on and then a quick answering of some of these
> questions and then focusing on a two-arm design may be more
> appropriate after some initial information. And I know there are
> differences of opinion about that.
>
> Okay. How are we doing?
>
> DR. BIRNKRANT: Okay. That was helpful.
>
> Well, Question 3 is specific to the three-arm trial design, and even
> though not everyone favors that, perhaps we could get some opinions on
> FDA\'s definition of a \"win\"\--that is, the microbicide arm has to
> show significantly better reduction in seroconversion rates compared
> to both placebo and the no-treatment arms. However, if Dr. Fleming
> could reiterate his proposal from this morning, and that is having
> different P values for the various comparisons, that may also help the
> discussion here.
>
> DR. FLEMING: As I mentioned this morning, I think the FDA has given a
> great amount of consideration in recent times to this concept of
> recognizing the importance for flexibility in certain settings to
> allow approvals on single trials. And as we were saying, this setting
> that we are in here certainly does seem to be within the mainstream of
> what the FDA has considered in the past to be such a setting\--a
> setting where you have a compelling endpoint in settings where it is
> very resource-intensive to be able to do multiple trials.
>
> What I have noted through numerous discussions across the wide array
> of situations with FDA is that there seems to be a very common aspect
> of how they characterize this. The results must be \"robust and
> compelling.\"
>
> I also respect why the FDA is reluctant to say what that P value is
> because any assessment of strength of evidence has to be a global
> assessment and has to factor in all issues that are relevant to
> understanding benefit to risk.
>
> My general sense that I tried to characterize this morning, and I
> think it seems consistent with what I have heard from the FDA, is
> something that is basically a middle ground between the strength of
> evidence of one trial and the strength of evidence of two trials in
> such settings where you have such a compelling unmet need and very
> significant clinical endpoints would be an appropriate target, and
> that would be, then, something, as we have said, on the order of
> one-sided .0025 to .05 or a two-sided P value slightly lower than .01.
> But again, obviously, that will then depend on the nature of the
> totality of the data.
>
> What I had mentioned this morning is in this two-arm trial, one
> strategy that I would think would be very consistent with that FDA
> philosophy would be to require that robust and compelling set of
> evidence against one of these two comparisons, so that one of them
> would have to be compelling, the other would have to be supportive,
> specifically being that if there were compelling evidence of the
> difference against the placebo, it wouldn\'t have to also be
> compelling. It would just have to be supportive that the comparison
> against the open label was suggestive also of favorable effects\--and
> vice versa, I would also think.
>
> So essentially, my own sense is that that would incorporate basically
> what has been an FDA philosophy in other settings, I think, in a
> manner that would be consistently implemented in this setting.
>
> DR. GULICK: Dr. Paxton.
>
> DR. PAXTON: A question for clarification. Does the FDA\'s definition
> of \"robust and compelling evidence\" also include things like animal
> studies or a stand-alone Phase 2 that looked very promising?
>
> DR. BIRNKRANT: It would be less likely to include the animal studies.
> We actually need the clinical data to make our decision in this
> setting.
>
> DR. GULICK: Other comments on this point?
>
> Dr. Mathews.
>
> DR. MATHEWS: The rationale for requiring a more rigid P value for the
> single trial as I understand it is to minimize the chance in a single
> trial that the outcome would be observed by chance alone. But the
> problem that we have been dealing with all day has not a lot to do
> with random events or chance. It is differential effects of behavior
> that could trump any statistical variation between the arms due to
> chance alone.
>
> So in some ways, I don\'t understand the agency\'s rationale. It is
> almost as though you are saying that if the effect size is above a
> certain threshold, you think that any systematic biases that might be
> in that trial would be trumped by the higher precision of the
> estimate. And I think somebody earlier this morning, I think even Tom,
> made this point, that if you have a systematic bias, and you estimate
> it more precisely, you still have that bias. And if condoms are so
> much more effective than a microbicide which is actually being
> developed because people are not using condoms, then I\'m not sure
> that requiring a smaller P value addresses that limitation,
> post-randomization changes.
>
> DR. GULICK: Dr. Haubrich.
>
> DR. HAUBRICH: Just to follow up on Chris\' point, I think there may be
> a couple of issues here that we are combining. One is the need for one
> trial versus two, and the other is the statistical comparisons of the
> three-arm study. I am going to just comment on the three-arm study.
>
> I would be a little afraid of requiring rigorous comparisons of both
> the placebo arm and the no-treatment arm, and I would agree with
> something where if you were clearly better than the placebo arm and
> not worse than the no-treatment arm, that would be acceptable; but to
> require the hurdle of being highly statistically significantly better
> than both would be unreasonable.
>
> To some extent, then, if you are not worse than the no-treatment arm,
> you have gotten rid of the problem of what is the effect of reducing
> condom use having on it, so if you are better than placebo and nor
> worse than the no-treatment arm, that in my mind would satisfy the
> requirements.
>
> DR. GULICK: Ms. Heise.
>
> MS. HEISE: I guess I just want to go on record and say that this is
> actually the most important decision that is being discussed today,
> and I fundamentally disagree with the concept of having to be better
> than both.
>
> I think that that is a standard that, one, I think is uninterpretable,
> and I think that also again, this issue of how it is going to act\--as
> a health advocate, I would give up the possibility of having a single
> trial to avoid this, because I am actually more concerned that we are
> never going to be able to generalize to all of the settings. Behavior
> is so driving of how this is going to operate in different settings
> that if you showed me a trial with convincing evidence for sex
> workers, I would not be convinced of how that is going to operate in
> Tanzania with married women. I would want to see, if I were a
> regulator, even if it is a smaller trial, or it is an introduction
> study, or it is something\--I think we cannot generalize to many of
> the settings that we want to generalize in, so I almost think we want
> more trials. And I think our hope that we are going to get it in a
> single answer is the chimera that is going to drive us crazy.
>
> And I fundamentally think that the issue of how this operates and
> combines with behavior in real life settings, as well as underlying
> STD and HIV rates\--you know, depending on whether or not this
> microbicide is also effective against certain STDs, will interact in
> different settings with the effectiveness achieved.
>
> So I think that we are kidding ourselves in terms of thinking that
> adding this one arm in one study in one population is going to really
> address the use-effectiveness questions that are very real and we need
> to deal with, but I think we are setting up a standard that stops us
> from being able to mount those next phase trials because we don\'t
> even have anything that we can say works to start to do the behavioral
> work and figure out how to introduce it so those things do not happen.
>
> The last thing I want to say is that I think this issue of condom
> migration is very important. I suggest, though, that people look at
> some work that the London School of Hygiene has done that has been
> published in AIDS about modeling of these various different scenarios.
> What they have done is looked at the tradeoffs\--because condoms are
> very, very efficacious; they reduce risk very well if they are used.
> But we have tons and tons and tons of studies around the world showing
> that inconsistent condom use confers very little protection in many
> populations, and we have tons and tons and tons of studies showing
> that most people use condoms inconsistently.
>
> So this notion that the condom is so great\--we also have to think
> about the number of people we are recruiting who are doing nothing to
> doing something, and when you look at those tradeoffs even on the
> individual risk level in these models, what you see is that you don\'t
> even have to worry about migration unless you are at the level of 80
> percent consistent condom use. Then, you have to worry about how good
> your microbicide is or whatever. But up to there, you could almost
> have total migration. If you could have something that is 30 percent
> efficacious used 60 percent of the time, it buys you more protection
> on an individual basis, not even on a population basis, than something
> that is 90 percent effective that is used 30 percent of the time.
>
> So I think we have to be really careful when we make these judgments
> about tradeoffs even at an individual level.
>
> DR. GULICK: Dr. Bhore.
>
> DR. BHORE: I\'d like to address the point about this win against both
> arms. In my presentation, I mentioned the alternative possibility of
> showing evidence of a single trial with evidence worth less than two
> trials\--for example, evidence worth one-and-a-half trials. So that is
> an example where, as Dr. Fleming mentioned, one could have two
> different types of criteria for a win against the two control arm.
>
> One arm, for example, could show compelling evidence, and the other
> arm could show less than compelling evidence.
>
> So in the example of the evidence worth one-and-a-half trials, a P
> value would be less than .008, which is slightly higher than what I
> mentioned, .001, but in that case, you could have two
> possibilities\--both arms show an equal amount of evidence, or one arm
> shows more compelling than the other one.
>
> So there are these kinds of alternative possibilities that one can
> look at.
>
> And then, secondly, the topic of condom migration keeps coming back
> again and again, and if one were to have just two arms, the
> microbicide and the placebo, and here, supposedly, Lori mentioned that
> if such a trial is designed, then a participant would be strongly
> informed that we don\'t know anything about the activity of the gel
> right now, so condom use is very, very strongly encouraged.
>
> If that kind of message is given to a participant, then that raises a
> question in my mind: Would that affect the enrollment? Would the
> participant just run away and say, \"You just cannot tell me anything
> about the activity of whichever product I am getting, so why should I
> be staying in this trial?\"
>
> So again, this issue also ties in with the three-arm design issue. I
> just wanted to bring that up.
>
> DR. GULICK: Let me try to focus us because the hour is getting late,
> and these are important points, but I\'d like to get us back to the
> question at hand.
>
> So we have covered a lot of ground, and clearly there are differences
> of opinion around the table that we have not resolved, so they are
> going to continue to be. But the question that we are being
> specifically asked is if we accept the three-arm studies\--and we have
> to take that as a given\--how do we compare the two arms, and what
> kind of reductions are we looking at for both pair-wise comparisons.
>
> And Dr. Fleming proposed \"compelling\" for one of the comparisons and
> \"supportive\" for the other comparison, and then Dr. Haubrich got
> more specific and said \"compelling against the placebo,\" meaning a
> high degree of statistical significance, and \"supportive\" being
> defined as \"not worse than the no-treatment arm at all.\"
>
> Is that a consensus?
>
> Dr. Sherman.
>
> DR. SHERMAN: I just want to say that I don\'t think you can answer
> this question in a vacuum without taking into account is there going
> to be a separate and highly supportive Phase 2 trial and what are the
> P values that you accept. They are all tied to the same thing. If
> there was a very supportive Phase 2 trial, then you could be more
> generous in your P values and be more allowing in terms of the
> comparisons in your groups here.
>
> If you are going with a single trial, then you might go with higher P
> values and be stricter in the requirements that are going to be used
> here. And on the front end, a sponsor might discuss this and negotiate
> what set of conditions would be acceptable to the agency, because this
> question really cannot be separated from those other things.
>
> DR. GULICK: I think that\'s a good point, but we are not asked to come
> up with specific P values in this question\--and you are right, it
> could be different at different times, but we use the word
> \"compelling\" to say some high degree of statistical significance,
> Richard\'s suggestion, versus the placebo arm versus not worse than
> the no-treatment arm. That seems to be what we are migrating toward.
>
> Dr. Flores.
>
> DR. FLORES: I think in addition to this \[inaudible\] P value that has
> been discussed, the other worry that I\'m sure is in the minds of
> everyone and that hasn\'t been mentioned is the issue of compliance,
> because it is truly going to be much harder to ascertain compliance in
> that third arm.
>
> Therefore, perhaps not just because of the comparison level that we
> are trying to establish here, but because of the potential for that
> arm not to have the same level of compliance, that might sink the
> entire study.
>
> Now, if you determine at the end of the day that, yes, the two active
> arms, meaning two placebo or other two study arms, versus the
> non-intervention arm, they might be okay in terms of compliance,
> because women may be more enticed, if they think they are receiving
> some benefit, to continue on, but that third arm where they are
> getting nothing is going to be a challenge to maintain at the same
> level.
>
> DR. GULICK: Well, again, I would say a priori you cannot predict which
> way adherence would go in that arm. It could go down or it could go up
> because women are not receiving something and they know they are not
> receiving something. But let\'s not revisit that at this point.
>
> Have we addressed this question to your satisfaction?
>
> DR. BIRNKRANT: I think so, but I also think that we have rolled in
> Question 5 with regard to discussion of the P value\--
>
> DR. GULICK: We have.
>
> DR. BIRNKRANT: \--so that\'s good; I don\'t think we have to spent
> more time on that.
>
> But what I\'d like to spend more time on and get the Committee\'s
> input is in the area of what other supportive evidence should we have.
> It is part of Question 5\--but if we go with the approach where we
> have compelling evidence against one arm, that is, against the
> placebo, and it is not worse than no treatment, what other data should
> we have along with this approach?
>
> DR. GULICK: Okay. So essentially, we have lumped Questions 3 and 5
> together in our discussion.
>
> DR. BIRNKRANT: Right.
>
> DR. GULICK: And you would like us to focus on the last part of
> Question 5.
>
> DR. BIRNKRANT: Right, and specifically but not limited to are there
> other STIs that could serve\--that is, reduction of transmission of
> other STIs that could serve as supportive evidence, because we are
> frequently asked this question.
>
> DR. GULICK: Dr. Paxton.
>
> DR. PAXTON: It seems that that would be highly dependent on what
> product you are testing. For example, if you are looking at a highly
> specific product like an NNRTI, you wouldn\'t expect it would have any
> efficacy against STIs; whereas if you are looking at something that is
> more broad-based, yes, again, I think this is going to be a highly
> product-dependent decision.
>
> DR. GULICK: Other suggestions about other supportive evidence in this
> case?
>
> DR. HAUBRICH: I guess it does raise the conundrum that if you have a
> product that theoretically has broad activity, and it shows reduction
> in HIV but fails to show reduction of other STIs, that might fall in
> the category of being negative supportive evidence, because
> theoretically, if the combination of biologic plus behavioral things
> leads to a reduction in HIV, you would suppose that you would have
> reductions in others as well. So that might be a bit of a conundrum.
>
> DR. GULICK: Although I suppose it depends on the mechanism of action,
> if it is a physical barrier, or is this something specific to viruses?
>
> Dr. Paxton.
>
> DR. PAXTON: I just wanted to respond. I think, yes, it wouldn\'t be as
> desirable to have something that is useful against both, but frankly,
> if you offered me something that was effective against HIV and said,
> \"but it\'s not going to be effective against gonorrhea,\" I would say
> fine, give me penicillin.
>
> DR. HAUBRICH: No. What I meant was if the agent theoretically had
> activity against the STD, so it was broadly in the test tube active
> against all of the agents or several agents yet failed to protect
> against the some but did protect against HIV, I think that would make
> me scratch my head.
>
> DR. GULICK: Well, and interesting\--the COL 1492 study, as you
> mentioned earlier, showed no differences among secondary endpoints
> which were STI occurrences.
>
> One thing that seems obvious for supportive evidence is behavioral
> information, although fraught with peril, and how do you collect this
> most effectively, and those conversations came up earlier today. But I
> would suppose that some data is better than nothing, at least to try
> to get a handle on what condom use is doing on the three arms, for
> example.
>
> Other supportive information that we would suggest?
>
> \[Pause.\]
>
> DR. GULICK: Okay. So we\'ll turn to our last\--yes, Dr. Fleming.
>
> DR. FLEMING: I wanted to wait to make sure there weren\'t any more
> comments on that. Since I didn\'t realize we were actually fully
> addressing Question 5 when we answered Question 3, I would at least
> like to make a brief comment about the second-to-last sentence in
> Question 5, which was specifically asking us about a strength of
> evidence issue.
>
> I think it is worth at least pointing out that since in the open
> session, there was a comment made about the ethics are appalling, that
> we could consider a necessary strength of evidence on the order of two
> adequate and well-controlled trials or .025 squared is to say that the
> FDA has enormous experience, and through that experience, there have
> been a plethora of examples where an initial trial that might provide
> evidence at roughly a one-sided .025 level in fact has not been
> confirmed, i.e., the concept of the value of replication in clinical
> trials science I think has strongly been established by the
> experiences that FDA has seen, and as a result, that does need to be
> considered seriously if we are going to go with a single trial; what
> is that strength of evidence.
>
> It is worthy of at least just reiterating why this is important, and
> that is it surely is true we want to get timely access to promising
> interventions, but it is also important to avoid an unacceptable level
> of false-positive conclusions. It was once said it isn\'t so much what
> we don\'t know that can get us into trouble; it\'s what we think we
> know that isn\'t so.
>
> I just gave an example this morning of the 5-FU levamisole and
> levamisole alone experiences in a trial in a very compelling
> situation, a life-threatening disease situation, that talked about
> reducing mortality by 33 percent. Was it proper to do a confirmatory
> trial there? If there hadn\'t been 5-FU levamisole and levamisole
> would be out there, levamisole might be a very attractive regimen
> because it is much less toxic. Yet it provided no benefit, a
> false-positive conclusion. If we have multiple microbicides out there,
> we want to protect women. It is important for us not to put a
> microbicide out on the market if one that is out there is highly
> effective and another one is not effective.
>
> Furthermore, to in fact be using an ineffective microbicide that might
> in fact even lead to or be associated with reduced condom adherence
> would also be very negative.
>
> So I think the balancing issue that has to be kept in mind here is
> that it is a serious problem to be in fact judging something to have
> been established when in fact it hasn\'t been reliably established.
> And I won\'t go into a lot of examples that I have written down here,
> but there are many examples where a single positive trial at just the
> strength of evidence of one-sided .025 hasn\'t been validated.
>
> So I think there is real wisdom in the FDA asking for \"robust and
> compelling\" evidence if it is based on a single trial.
>
> DR. GULICK: Yes, Dr. Mathews.
>
> DR. MATHEWS: I think this discussion is framed around an assumption
> that Dr. Birnkrant made in her opening remarks that the risk-benefit
> ratio should be the same across the world, if I understood you
> correctly, and I don\'t think I agree with that, because we are
> dealing with vastly different incidence rates of disease in this
> country compared to the countries where the need is greatest.
>
> If I were a decisionmaker in a country where one out of three people
> had HIV infection, I would be willing to take more risk in terms of
> the levels of confidence and the effectiveness of a particular
> intervention than I might be in a country like this one, where the
> risks are lower.
>
> I mean, ideally, what you are saying is true, but the urgency of the
> threat is very different. In some ways, it is kind of odd that we are
> even talking about this in an American setting, because this is not
> where most of the need is, and whatever guidelines we set up for this
> country surely\--I mean, the people from WHO who have been dealing in
> these other countries have a very different perspective on what the
> needs are.
>
> What does it really mean if a product gets licensed in the United
> States for this indication in terms of what will be done in
> Sub-Saharan Africa?
>
> DR. BIRNKRANT: That\'s the sponsor\'s choice, though, whether or not
> to submit the marketing application to the United States or not. Once
> it is submitted to the United States, it has to meet the Code of
> Federal Regulations, and if it is approved, then clearly, American
> women will be entitled to use the product, so therefore the standards
> are what the standards are.
>
> DR. MATHEWS: Right, but we are making recommendations based on our
> conditions in this country, and I\'m not sure that they necessarily
> apply, particularly if the standard set by the FDA is expected to be
> implemented in the developing world, as you implied it should be.
>
> DR. GULICK: Isn\'t it true, though, that many countries around the
> world actually look to the FDA and their decisions in evaluating this
> and then take those recommendations back to their own countries in
> terms of accessing drugs, so the standards and the approval of the FDA
> really does carry a lot of weight all over the world.
>
> DR. BIRNKRANT: And we are also told that some countries rely solely on
> an FDA approval, that they don\'t have the regulatory bodies to do the
> type of work that we do.
>
> But I understand what you are saying. We are having data come in that
> are generated outside the United States and may likely have a greater
> benefit there, but nonetheless it is subject to U.S. regulations.
>
> DR. GULICK: Dr. Haubrich.
>
> DR. HAUBRICH: Although I agree completely with Chris\' assessment that
> the risk-benefit ratio is very different from country to country and
> that some countries might be willing to accept a greater risk
> potentially, I think that here, we are talking about the likelihood of
> finding a false-positive. And if we are willing to accept a single
> study versus two studies, I think the bar has to be higher, because if
> we accepted something as being efficacious, and it was truly a
> false-positive, we wouldn\'t be helping anybody.
>
> DR. GULICK: Okay. Other comments?
>
> Yes, Dr. Stek.
>
> DR. STEK: In the discussion, there was mention made of what if we find
> that there is some efficacy of the microbicide intervention, but it is
> actually less than regular condom use. I don\'t think that is an
> appropriate thing to actually discuss. Our goal here is to determine
> whether the microbicides are safe and effective, not which is the most
> effective intervention. That is information that should be made
> available to everybody here and internationally to make the decisions
> that are appropriate for the local setting.
>
> So I was a little disturbed by the thought of the ethical issue of
> perhaps approving something that might not be as effective as
> something else that is already available. I think the goal should be
> to increase the options.
>
> DR. GULICK: Well, and as we have been reminded by the agency before,
> it is to demonstrate safety and activity, not necessarily better than
> something else in many cases, but in this case, the standard of care
> is condoms are the best you can do essentially, isn\'t it.
>
> Okay. Let\'s move to Question 4, back to Question 4, which talks about
> duration of follow-up.
>
> DR. BIRNKRANT: Both on-treatment and off-treatment.
>
> We have received proposals that either call for 12 months for every
> participant, and that\'s it, they are finished; or the other approach
> is 12 to 24 months when the last participant is enrolled.
>
> Now, for treatment trials, although we look at 24-week data, we also
> look at longer-term data, that is, 24 weeks from when the last patient
> is enrolled in the clinical trial, and that is for treatment of HIV.
>
> This is prevention, and we were wondering what the committee thought
> about having a fixed period of time\--for example, 12 months\--versus
> 12 to 24 months when the last patient is enrolled. That would give us
> extensive data with the product, both for efficacy, safety, and
> durability of effect.
>
> DR. GULICK: So let\'s consider duration of follow-up generally, and
> then we can see if we like one of these choices more than the other.
>
> Dr. Stanley.
>
> DR. STANLEY: Well, I think we have to be realistic with where these
> studies are going to be done, and the comparison with the American MSM
> population having intensive behavior modification intervention is not
> a valid comparison in any way, shape, or form in my view. These
> populations are migratory, transient to some extent. Getting them to
> stick for a year is going to be a challenge and probably a target that
> we ought to target, and if you can keep them longer, that\'s great,
> but I think it is unrealistic to set the bar that high.
>
> We have to look at the examples that we have had, and in the N-9
> experience, it was 48 weeks, and there was 81 percent follow-up, which
> means that you had almost 20 percent who dropped out. That is real
> life experience, and that is with experienced researchers who know
> what they are doing in this setting.
>
> So I think you can be permissive in trying to get longer follow-up and
> trying to allow for that, but if you set the bar too high, you are not
> going to be able to enroll folks.
>
> I think the other issue is that even if people have enrolled, and as
> the comment has been made, they tend to drop off in the first few
> months, and then they stick it out\--if you came to me and said, \"I
> want you to enroll in this study, and I\'m going to follow you for 2
> or 3 years,\" that\'s a disincentive to me to even enroll to start
> with, and I think it would be a real disincentive for some of the
> populations we are looking at in Sub-Saharan Africa because they
> can\'t guarantee to you that\--if they enroll, they may be doing it
> with the knowledge that they are misleading you, because they probably
> won\'t be there in the same place possibly.
>
> So I think you can\'t set the bar too high here, or you are going to
> hurt yourself and hurt the ability of sponsors to conduct the studies.
>
> DR. GULICK: Can I just clarify this point again? The follow-up 81
> percent actually refers to the COL-1492 study, but it\'s not that
> those patients were lost to follow-up; it\'s that they came off drug.
> Is that right? They discontinued\--well, let me not guess. Can you
> tell us again, Dr. Van Damme?
>
> DR. VAN DAMME: In COL-1492, the study done and finished, the retention
> after one year was indeed 81 percent, and that\'s indeed people who
> were still in the study after one year. That is not all the other
> people who were not lost. But that was also open, so people could come
> into the study and stay as long as they wanted. But based on
> experience, I would recommend a short follow-up.
>
> DR. GULICK: Okay. Again, I\'m not sure I understood. Let me ask you
> one more time. So those are people who were lost to follow-up after
> one year, 19 percent, or simply discontinued study treatment and were
> continuing in follow-up?
>
> DR. VAN DAMME: Yes, that could also be.
>
> DR. GULICK: Which one?
>
> DR. VAN DAMME: Well, both. I mean, there were people that we really
> lost, and there were people that discontinued.
>
> DR. GULICK: Do you know the exact figure of people who were actually
> completely lost to follow-up after one year? I think that would be
> helpful for us, because someone who reaches an endpoint or becomes
> pregnant but is still being actively followed doesn\'t\--they are not
> really lost to follow-up. They are still in study follow-up even
> though they have completed their participation.
>
> Dr. Haubrich.
>
> DR. HAUBRICH: We have heard proposals today to have studies that have
> very short follow-up because of retention issues, and there is always
> a balance in clinical trial between what is going to happen with
> differential dropout and how that affects the interpretation of your
> results and wanting to have more data, to collect more endpoints, and
> to have better safety data.
>
> I would argue that if we approve something based on 6 months\'
> follow-up which we are asking hundreds of millions of people to take
> for the rest of their lives, I would be a little concerned about that.
>
> In fact, if people are dropping out, it may be telling you something.
> Of course, you may not be able to discern what it is telling you, but
> I think we should have trials that are of adequate duration to
> evaluate safety concerns as well as efficacy. So anything shorter than
> 12 months I think would be problematic, and the longer, the better, as
> far as I\'m concerned, although arguably, that then increases the risk
> of having dropouts\--although I think we did hear that in other trials
> that looked at these, many of the dropouts did occur early, and that
> once you had crossed a certain threshold, the follow-up was good. So
> that would actually argue for at least 12 months if not longer
> follow-up which I would advocate.
>
> DR. GULICK: Dr. Paxton and then Dr. Wood.
>
> DR. PAXTON: I Just wanted to follow up again. I can\'t remember\--I
> think, Tom, you were talking about that study\--was that again an MSM?
> I think it is an important thing that we are talking about an African
> population of heterosexual women, and I don\'t know that we can say
> that the ones who stay are going to have the same number of events. I
> think it has been our experience in some of the trials that we have
> done at CDC that the people who stay tend to be the ones who are more
> compliant, are more interested in their health, they use the condoms
> and all that.
>
> That would factor into my recommendation because I think we are trying
> to balance the effort that goes into keeping somebody, because it is
> an enormous thing to follow someone for 2 or 3 years, and if they
> aren\'t going to really contribute much in terms of events, then I
> think that might argue for having a shorter follow-up time.
>
> DR. GULICK: Dr. Fleming.
>
> DR. FLEMING: Yes. I was giving that .015 example just specifically to
> refer to a prevention trial setting where it came up in the context of
> we don\'t have data on whether or not an open arm could be followed,
> and it is just intriguing to see in that 4,000-person prevention study
> for HIV prevention that we actually had a higher retention rate in the
> open-label control arm.
>
> I would certainly agree that what I\'d like to do most specifically is
> look at settings as close as possible to the settings that we have
> here. And we were given data that was reported in JAMA \'02 for the
> Cameroon study of N-9 gel against a no-treatment condom where there
> were very high levels of retention.
>
> The 012 trial conducted in Uganda I think is another very relevant
> experience. In Uganda, before we launched that trial for prevention of
> transmission from mother to child, we were told things that you might
> hear now\--it\'s just not realistic to think you\'re going to retain
> 80 percent. We were told it\'s just not going to be possible. Women go
> up-country; they are just not going to be able to be tracked with
> their infants.
>
> Efforts were made to have high levels of retention in that trial, and
> at the primary endpoint of 3 months, there was 98 percent retention.
> At 18 months, at the final analysis, there was 95 percent retention.
> We were told that we couldn\'t do better than 80 percent; there was 95
> percent retention.
>
> Somebody said earlier that \"quality trumps quantity,\" and I would
> agree with that. I think it comes back to a question that Victor had
> asked earlier about what is the risk of bias when you have more people
> missing than you specifically have events.
>
> I would actually rather have a study that was somewhat smaller where
> intensive efforts were made to obtain reliable, interpretable results
> because we have high levels of retention.
>
> It is possible\--it is possible\--to do better than one might think by
> putting specific energies and efforts into achieving high levels of
> retention, and it is extremely important to do so.
>
> I would like to jump on, though, and reinforce something that I think
> Richard had said, and that is what drives me to think more than
> anything else about what is the right duration of follow-up is what is
> the clinical question; is this an acute setting or is it a chronic
> setting?
>
> To my knowledge, this is a chronic setting. This is not a situation
> where we have to identify an intervention that is going to get a woman
> through a 2- or 3-month at-risk period, and then she\'s going to be
> risk-free.
>
> When in fact you envision delivering an intervention in a chronic
> setting, it becomes even more important to obtain results that in fact
> are as relevant as possible in a practical fashion for that overall
> time period.
>
> My own view is that participation in clinical trials, whether you are
> in a control arm or the active arm, generally provides benefit to
> people, not just because of the altruistic aspect of contributing to
> understanding benefit to risk, but because overall level of care
> generally is at the highest level of what would be achievable.
>
> People are getting very high levels of attention compared to normal
> care. So if somebody in fact is followed for an extra period, let\'s
> say, 24 months, is that a burden or is that in fact a privilege that
> this person is in fact in a circumstance where they are going to be
> getting just that much more attention to their care and to their needs
> over a longer period of time?
>
> And as Richard pointed out, I do want to know about safety issues, I
> do want to know about efficacy issues. Some people have said maybe
> adherence wanes. If adherence wanes, isn\'t that relevant to
> understanding what the actual protection of the intervention is going
> to be over a chronic risk period?
>
> There has to be a practical tradeoff here, but surely I would strongly
> support the point that some people have made that quality trumps
> quantity. I would rather see a high-quality study that achieves
> interpretable, unbiased results, minimize loss to follow-up. At a
> minimum, I would like to see 12 months of follow-up, although I would
> be delighted to see trials run to 24 months of follow-up if in fact we
> could achieve that.
>
> DR. GULICK: Dr. Mathews.
>
> DR. MATHEWS: On the issue of whether there should be a fixed follow-up
> or until the trial ends, my sentiment is that it should be fixed,
> because the people who are continuing until the trial ends are
> probably going to be different than the ones that have dropped out,
> and the sample size in that group is going to be smaller, and if
> adherence wanes, that effect alone will just attenuate whatever the
> effect of the intervention is.
>
> And the point that Tom just made about wanting to know about whether
> adherence wanes, what\'s the long-term impact of this intervention,
> again, I think that\'s an effectiveness question, and if the purpose
> of the trial is to establish that you have an active intervention and
> to precisely estimate it, then I think the population study should be
> as similar as possible throughout the trial, and that implies that
> their duration of follow-up should be similar.
>
> DR. GULICK: Dr. De Gruttola.
>
> DR. DE GRUTTOLA: Yes, just to respond to that point, I think that
> there can be value in continuing to follow patients. Let\'s say you
> look at the options of doing a 12-month follow-up on each patient
> versus following them to the end of the study, where you have at least
> 12 months on each patient. Those studies are going to take the same
> amount of time. But if you follow all of the patients longer, you\'ll
> get additional information, and it can be safety information as well.
>
> I think the point you raise, that as time goes on, you are going to
> have more dropouts, so your population is in a sense increasingly
> self-selected, is true, but I think finding out about that dropout and
> about the acceptability is important as well.
>
> So I think if you are going to be taking the same amount of time to do
> two studies, you can only gain by having the additional information
> about safety, tolerability, and about efficacy, taking into account
> your point that you do have to be concerned about the dropout and
> selection issues.
>
> But I think that the implication of that is that a lot of effort has
> to be put into retaining patients for the longer haul, and whatever
> creative strategies can be developed would be important to avoid
> selection bias.
>
> DR. GULICK: Dr. Wood.
>
> DR. WOOD: In examining studies, the issue of duration, one of the
> reasons is not only to look for safety but efficacy as well. So your
> ability to detect event rates is either going to be determined not
> only by the duration of follow-up but also by the sample size.
>
> So on the one hand, I understand the need because of issues of
> retention and concerns about dropouts, the desire to have
> shorter-duration studies. I would maintain that if there were going to
> be shorter-duration studies that were less than 12 months that there
> would be an appropriate requirement for a larger sample size to allow
> you to have an adequate detection of events that you would lose since
> you are observing the population for a shorter period of time.
>
> On the other hand, I have got to agree with the fact that we are
> talking about potentially approving a product that would be used by
> women potentially by the rest of their lives. So the issue of
> longer-term safety and adverse events diminishing efficacy over time,
> whether that is behavioral, whether or not depending on the product it
> is related to the development resistance, but say with the NNRTI
> microbicide candidates, would be very critical to ascertain.
>
> The other point that I would like to raise in terms of Phase 4
> follow-up that is done post-marketing is that for the most part, what
> happens is that we always hear about what goes wrong and when
> something is bad in terms of safety. What we really hear from Phase 4
> marketing studies is that people\'s livers are being killed, they are
> dying from the drug, there are unanticipated toxicities.
>
> So anticipating to get additional information from that type of Phase
> 4 mechanism I think is unlikely.
>
> DR. GULICK: Dr. Stek.
>
> DR. STEK: Just to point out that continuing follow-up for a long time
> to assess adherence doesn\'t seem to make a lot of sense, because
> adherence to an experimental regimen that you don\'t know if it is
> efficacious or not, you wouldn\'t expect that to be comparable to
> adherence in real life to a product that was shown to be efficacious.
> So that would argue against following for a long time for that
> purpose.
>
> DR. GULICK: Do we want to entertain some of the specific choices that
> we have here? There was a proposal that anything less than 12 months
> would not be acceptable. Is there general agreement about that? We
> heard earlier suggestions about 6 and 9 months.
>
> Dr. Fletcher.
>
> DR. FLETCHER: On that, I think one of the themes that we have heard
> today is flexibility and what a sponsor may approach the agency with.
> And I guess on the issue, then, of duration, I wonder if there is not
> an opportunity for flexibility.
>
> Let me try floating this and see how it goes. What if a sponsor came
> to the agency and said, \"We are willing to do two pivotal studies,\"
> two traditional Phase 3 studies, \"but we would like the first one to
> be of 6 months\' duration to try to get an early answer of efficacy,
> and then, if that is present, we\'ll do a long-term Phase 3 study.
> Might that be an acceptable approach?\"
>
> In my mind, I could think about buying something like that, so
> therefore, walking in, everything has to be 12 months in some settings
> might be inflexible.
>
> DR. GULICK: Dr. Stanley.
>
> DR. STANLEY: I want to echo the flexibility issue, because I think
> again, we are trying to balance the sense of urgency to get something
> out to women who have nothing else, and every day, 16,000 people are
> getting infected. But we also have to balance that with a
> responsibility to first do no harm.
>
> So I think, as I said earlier, that 12 months is probably a good
> length, but I think there may be circumstances where a 6-month or
> 9-month trial might in fact be justifiable, particularly if the
> sponsor is willing to commit to a Phase 4 to look at longer-term use.
>
> Again, we talk about adherence, but this is going to be a product that
> clients can use at their own volition and their own choice and their
> own discretion and not like taking a drug regimen where they have to
> make sure they get their TID dose in.
>
> So I think there are some different considerations here, and I think
> \"flexibility\" is a key word.
>
> DR. GULICK: Dr. Fleming.
>
> DR. FLEMING: I agree with what one of my colleagues said earlier, and
> that is the Phase 4 post-marketing study is really not the venue or
> the approach that is going to give us reliable efficacy and safety
> data usually. I doubt we are going to do a proper no-treatment or
> placebo control in a Phase 4 environment.
>
> If the issue is urgency\--and it is certainly one of the key
> issues\--I would say it is urgency to get a reliable answer, not
> urgency to get a study done, but urgency to get a study done that will
> provide robust and compelling results, then actually, you do yourself
> a disservice by doing a 6-month study rather than a 12- or a 24-month
> study. And to be specific, let\'s even say you\'re doing just the
> intermediate-size trial with 100 events, and let\'s say you are
> targeting a population that has a 5 percent event rate. That\'s going
> to take 2,000 person-years of follow-up. If you follow those people
> for a year, that\'s the size of 2,000. If you follow them for 6
> months, that\'s 4,000.
>
> There\'s no way I am going to finish that 4,000-person enrolled trial
> until the last person is followed 6 months anywhere close to the time
> frame I can finish the 2,000-person enrolled trial where I follow that
> person for 12 months.
>
> So if you are going to drive this issue based on finishing the study
> sooner, you are clearly going to be doing a disservice by just doing a
> shorter-term follow-up study\--and that\'s just an approximation. But
> the bottom line here\--I guess I would go back to what you were saying
> earlier, Dr. Gulick\--is that I like the concept of flexibility, too,
> and if in fact you were saying that some experience could come from a
> trial with shorter duration as long as there was essential experience
> coming from at least a 12-month. But I like the guideline principle as
> you stated, that A, B, and C are fine in principle, that in essence
> there ought to be substantial data within this overall application
> that allows us to at least look over a 12-month period, and that will
> actually get us answers sooner in calendar time in almost all cases.
>
> DR. GULICK: Okay. I\'ll summarize what we thought of here.
>
> There were differences of opinion once again. Balancing length of time
> and sample size came up. I forget who said it, but we would like to
> follow patients, quote, \"as long as practical,\" which takes a lot of
> things into account\--the urgency of the question, the feasibility of
> doing long-term follow-up in these particular populations, the fact
> that safety is a big issue, a really big issue, and obviously efficacy
> as well, which is why we are doing this study in the first place.
>
> There was an assumption around the table that adherence would decrease
> over time, but we were challenged by Dr. Fleming over that. The HIVNET
> 012 and the results of the Cameroon study earlier suggested that there
> was actually pretty good follow-up there.
>
> As Dr. Stek reminded us, adherence to a microbicide that is shown to
> be effective later may actually change over time, so future studies
> may actually have less of a problem with any kind of adherence issues
> than earlier studies.
>
> The basic principle, dropouts, missing data is hard to account for
> statistically, so we heard the phrase \"quality trumps quantity,\" but
> as Dr. Haubrich pointed out, dropouts can actually give you
> information if you are able to assess why they dropped out and may
> speak to the acceptability question as well.
>
> Good retention on a clinical study takes effort, and with limited
> resources, resources aimed toward that question or that issue are
> paramount in importance, so planning up front to have specific efforts
> that will allow people to continue follow-up on the study are
> key\--and it has to be culturally and setting-specific. Whether it is
> money or food or whatever it is that will keep people coming, those
> interventions are extremely important and may ultimately save the
> study and make it interpretable.
>
> On the issue of fixed versus rolling enrollment, we had some
> disagreement. In general, it was felt that you gain by following
> people longer, so that perhaps the rolling idea that you continue to
> follow people who are already enrolled rather than discontinuing after
> a fixed amount of time would increase the amount of safety,
> acceptability and efficacy data you get. But as Dr. Mathews pointed
> out, it makes the population somewhat less homogeneous when you do do
> that given differing lengths of follow-up; and selection bias for
> those people who don\'t drop out and continue.
>
> In terms of the length of time, flexibility, flexibility, flexibility
> is what people said, and feasibility as well.
>
> There was a general consensus that 12 months of data is necessary.
> Whether that could be coupled with some studies that went shorter
> period of time was something that should be entertained, and longer
> follow-up data again was felt to be really important, whether it is in
> the context of a Phase 2 run-in Phase 3, or a Phase 4 where less
> formal data is generated, but some data can be generated, was a
> subject of disagreement as well.
>
> How did we do?
>
> DR. BIRNKRANT: I think we have some ideas.
>
> Then, the other follow-up issue has to do with follow-up once the
> trial has stopped or once a participant has discontinued. We want to
> be able to capture seroconversions within the time frame when a
> patient stops the trial.
>
> So what is a feasible and scientifically sound time frame? Is it one
> month, or is it longer than one month?
>
> DR. GULICK: Is that clear to everybody? We want to capture late
> events\--the day the study participation stops is not the day you want
> to stop seeing the patient. So is 4 weeks a reasonable amount of time?
> Eight weeks?
>
> Dr. Fleming.
>
> DR. FLEMING: Could I seek clarification from Debra. There might be two
> different ways of interpreting this question.
>
> Let me be real specific. Let\'s suppose a sponsor plans to do a
> 12-month, fixed follow-up period on participants. If someone stops
> treatment at 6 months, it is imperative that that person be followed
> out to 12 months for an intention to treat for an unbiased assessment.
>
> So I think you are not referring to that issue, are you, or if you
> are, I would say that once you stop treatment, clearly you should
> continue to follow that person for the uniform period of follow-up
> that the study is designed to obtain so that you get an unbiased
> assessment of overall treatment effect, i.e., in the spirit of
> intention to treat.
>
> Now, a separate question that you might have been referring to is
> let\'s say you do say 12 months, and you are saying if the trial in
> fact specifically then indicates that treatment is stopped or that
> treatment can be continued and stopped at the participants\'
> discretion. Then, are you saying in that context beyond the time
> period of the formal analysis, should you continue to follow\--is that
> the context of your question?
>
> DR. GULICK: And also, you want to pick up\--it depends on how you
> assess seroconversion.
>
> DR. BIRNKRANT: Right. We were interested in the late seroconverters.
> However, if the trials are long enough\--let\'s say they are 24
> months\--we are not as concerned as if they are shorter, perhaps.
>
> DR. GULICK: So\--and I\'m sorry I don\'t know this\--but on most of
> the studies, it\'s true seroconversion that is the endpoint, so
> antibody-positive rather than using viral load levels, for instance,
> which probably are prohibitively expensive\--or are both being used in
> some of the trials?
>
> DR. BIRNKRANT: I don\'t know.
>
> DR. WU: So far, all the trials have been using seroconversion as the
> endpoint.
>
> DR. GULICK: So standard antibody testing.
>
> DR. WU: Correct.
>
> DR. BIRNKRANT: Right.
>
> DR. GULICK: So to avoid a window period, you would really want a
> three-month follow-up to capture most people who\--worst case scenario
> is that they seroconvert on the last day of the study, so 90 percent
> would be positive by three months later.
>
> Am I getting that right? Dr. Mathews?
>
> DR. BIRNKRANT: But suppose we use a different type of diagnostic test
> so that we wouldn\'t have to go that long.
>
> DR. MATHEWS: Right. I think, like if you were going to use viral load,
> a month would probably be fine. But if you stretch it out too long,
> and you are doing either modality, then you may be picking up
> endpoints that aren\'t attributable to the\--
>
> DR. GULICK: That\'s right.
>
> DR. MATHEWS: So we would need to know what the medium time to
> seroconversion is probably in the country or the region. I don\'t know
> if that\'s uniform.
>
> DR. GULICK: Does anybody know that information? So we all carry around
> 90 percent within three months in this country. Is that the same
> worldwide? Anybody?
>
> \[No response.\]
>
> DR. GULICK: Okay. We don\'t know.
>
> Dr. Bhore?
>
> DR. BHORE: Yes. We do want to know what should be the off-treatment
> follow-up of those participants who are not lost to follow-up but have
> discontinued the study drug. So this off-treatment question would
> apply to those who prematurely discontinue the study drug but not the
> study, as well as those who have completed the study.
>
> DR. GULICK: I think that\'s the point Dr. Fleming was addressing
> before. Strict intent to treat approach, they should be followed for
> the duration of the study.
>
> Okay. Dr. Birnkrant, did we do everything we needed to do today?
>
> DR. BIRNKRANT: Almost. I have one more question since we have an
> expert panel here, and that has to do with the population. Do you
> think we should be enrolling homogeneous subjects, or should we look
> at a more heterogeneous population given we may only be able to do one
> trial. Should that one trial be one particular type of subject\--for
> example, high-risk commercial sex workers\--or should we get a broad
> view of the population who will be exposed subsequent to marketing? In
> other words, once it\'s on the market, everyone is using it, so should
> we try to get some of that information ahead of time?
>
> DR. GULICK: I\'ll make a suggestion here and let others chime in. If
> we have one study that is our Phase 2/3 study for this compound, it
> should look at much like the world at-large as possible in order to be
> able to generalize the results to everyone.
>
> If you were going the traditional Phase 2 and then Phase 3, then I
> would choose a every homogeneous population for Phase 2 to get the
> proof of concept and then a much larger population in Phase 3.
>
> Dr. Haubrich, to add to that.
>
> DR. HAUBRICH: I partially agree with my colleague from the Democratic
> State of New York but would like to add that if you were going to do
> the 2A/3 lead-in type of study, you could accomplish both by picking
> the homogeneous population for your lead-in phase and then widening it
> out in the Phase 3.
>
> DR. GULICK: That\'s a good point from the Schwarzenegger State of
> California.
>
> \[Laughter.\]
>
> DR. GULICK: Okay.
>
> DR. BIRNKRANT: Now we have accomplished everything.
>
> DR. GULICK: Yes, including making it political right at the end.
>
> \[Laughter.\]
>
> DR. GULICK: I\'d like to thank everyone.
>
> I would like to thank our speakers from the morning for being
> available all day, for their excellent presentations and really
> setting the stage for the discussion.
>
> I would especially like to thank the people who presented at the open
> public hearing. We had a lot of you, and people were very nice to keep
> to the time limits, but also some very important points came out both
> in the oral and the written presentations that people gave. So thanks
> for doing that. That was extremely helpful to the Committee.
>
> Thanks to the agency, and thanks to the Committee, especially our
> retiring members; we are sad to see you go.
>
> Thanks.
>
> \[Whereupon, at 5 o\'clock p.m., the proceedings were concluded.\]
>
> \- - -