U.S. FOOD AND DRUG ADMINISTRATION

Center for Drug Evaluation and Research (CDER)

ANTIVIRAL DRUGS ADVISORY COMMITTEE (AVAC) MEETING

Clinical Trial Design Issues in the Development of Topical Microbicides

for the Reduction of HIV Transmission

20 August 2003

Holiday Inn - Versailles Ballroom - 8120 Wisconsin Avenue -Bethesda, MD
20914

PRESENTATION TO THE

OPEN PUBLIC HEARING

on behalf of the

*Ad Hoc* Subcommittee of the Alliance for Microbicide Development

*(submitted* a priori *as written public comment)*

*Alliance for Microbicide Development*

*8484 Georgia Avenue, Suite 940 - Silver Spring, MD 20910, USA*

*TEL 301-588-8091; FAX --8390; pharrison@microbicide.org*

*www.microbicide.org*

Introduction

**This presentation addresses core issues in microbicide clinical trial
design that have been under consideration by an *Ad Hoc* Subcommittee of
the Alliance for Microbicide Development since the Alliance "Mini-Summit
on Clinical Trials" held in March in Washington, DC *(see Appendix A for
Subcommittee roster)*. The Subcommittee does not presume to speak for
"the microbicide field" as some sort of organized whole, but finds that
it represents substantial consensus across that field. Some of that
consensus will be reiterated in other individual formal presentations
and written comments provided to the Antiviral Drugs Advisory Committee,
as will, of course, any significant divergence of opinion.**

**We wish to note that the discussions that led to the writing and
subsequent review of this document were completed before the FDA's
*Briefing Information* document was posted on the agency's web site.
However, the two documents do correspond in their overall focus and
emphases on the major components of microbicide clinical trial design.**

**The Fundamental Issue: The Need for Microbicides**

***A Large Global Population at Particular Risk.*** The increasing
intensity of focus on topical microbicides emerged largely from the
recognition that HIV/AIDS increasingly has a "woman's face"[^1].
Worldwide, almost half of the 37.2 million adults living with HIV/AIDS
at end-2002 were female and, of the 5 million new infections in that
year, 40% were in women. Those percentages are even higher in
sub-Saharan Africa, where for every 10 African men, 12-13 African women
are infected.[^2] In the United States, the proportion of AIDS cases
among women has more than tripled since 1986, rising from 7% to 23% by
2002.[^3] In sum, HIV transmission is now overwhelmingly heterosexual,
such that the greatest source of risk of HIV for a woman in a developing
country is likely to be her husband.[^4] Women---especially young
women---are further vulnerable, since they are biologically far more
susceptible than men to sexually transmitted infections other than HIV,
many of which enhance the sexual transmission and progression of HIV, in
some instances by a factor of up to 10.[^5]

Yet research indicates that many women in many geographic and
sociocultural settings are reluctant or unable to talk with their
partners about use of condoms, the one existing preventive technology
offering reasonable protection against sexually transmitted infections
(STIs). This is true in both developed- and developing-country settings,
and notably true for women disadvantaged by economic dependence,
poverty, and gender discrimination who cannot risk their relationships
by questioning partner fidelity.[^6] Consistent condom use has been
found universally hard to achieve in stable relationships, and there are
few examples over 20%; even individuals willing to use condoms with
"outside" partners appear unwilling or unable to use them with a
primary, stable partner. Further, in cultures where childbearing is
linked to self-worth and societal position, the prospect of
childlessness often outweighs considerations of risk.[^7]

***The Potential Value of Microbicides.*** Microbicides, as an
innovative preventive technology whose use need not depend on partner
cooperation or even knowledge, would offer women for the first time the
ability to determine their own protection. A major modeling exercise by
the London School of Tropical Medicine and Hygiene found that a 60%
efficacious microbicide used by 20% of women in 73 lower-income
countries (including all of sub-Saharan Africa) in 50% of sex acts where
condoms were not used would avert 2.5 million HIV infections over three
years in women, men, and children, saving \$2.7 billion in health care
costs and \$1 billion in lost productivity.[^8] These savings estimates
are probably modest: according to the recently-issued UNDP *Human
Development Report*, 54 countries are now poorer, 21 countries have
worse hunger problems, and 34 have experienced declines in life
expectancy since 1990, primarily because of HIV/AIDS.[^9]

The potential of microbicides as a new preventive technology is further
promoted by the fact that the search for an HIV vaccine, which would
theoretically protect both males and females, is proving far more
complex than anticipated, and remains a distant possibility.[^10] This
means that microbicides could be, at a minimum, a critical preventive
technology for what may be a long interim period until an HIV vaccine
materializes. Even after that, since microbicides and vaccines will each
provide only partial protection, a strong argument can be made for them
both as complementary preventive technologies, particularly in the case
of microbicides offering a broader spectrum of protection against
different HIV clades and any non-HIV STIs or vaginal infections acting
as co-factors for HIV transmission.[^11] It may well be, in fact, that
microbicides and/or vaccines that could elicit durable mucosal immunity,
thus targeting the earliest stages of HIV infection, might offer the
best prospects for preventing or containing HIV infection.[^12]

**Background Issues**

The Subcommittee recognizes and honors the FDA's mandate to protect the
health and safety of the US population. However, that mandate is
challenged in several ways by drug products---with microbicides the
present case in point---whose main objective is to combat
life-threatening diseases whose predominant weight falls on populations
beyond US borders. These diseases include not only HIV/AIDS but the
other major global killers, malaria and tuberculosis, as well as "other
neglected diseases" primarily affecting developing countries and
"emerging infectious diseases" that may or may not represent direct
risks for US populations.[^13]

First, such products typically fail to attract the involvement of "Big
Pharma", so that their development becomes a patchwork effort across the
public, nonprofit, and biotechnology sectors which can generate
inefficiencies that may confound, or be especially confounded by,
regulatory processes.

Second, the bulk of clinical testing of these products must by
definition take place outside the United States in putative "countries
of use", at the same time that, for epidemiological, ethical, and/or
regulatory reasons, at least some trials may need to take place among
at-risk populations in the United States as the "country of
origin."[^14] This "globalization of clinical trials"[^15] raises
ethical and practical dilemmas for product sponsors, protocol designers,
trial implementers, and regulators, in the United States and in
countries of use. At the top of the list of practical dilemmas may be
the demand that the growing number and size of clinical trials of
preventive technologies will place on the capacity of low- and
middle-income countries to support the conduct of such trials according
to Good Clinical, Laboratory, and Manufacturing Practice standards.[^16]

Third, FDA approval may be construed as the "gold standard" by
regulatory authorities outside the United States, such that the agency
acts as a gatekeeper for licensure in some countries even though its
mandate is officially "US only" and even though, in some instances, the
United States may be an uncertain market.[^17]

Cutting across these factors are two others: (1) the urgency imposed on
all areas of relevant research by the rapid escalation and expansion of
the HIV/AIDS pandemic, and (2) the divergence between epidemiological
risk-benefit ratios in countries of origin and those in countries of
use.[^18] The need for urgency should be obvious and has been
acknowledged operationally by the FDA, whose pace of approval of new HIV
therapeutics has accelerated dramatically; however, whether the
mechanisms used to speed development of HIV therapeutics might fit the
case of microbicides is unclear.[^19] As a product category intended for
continued use over time by "healthy" people for disease prevention,
microbicides, like HIV vaccines, raise challenges for testing unlike the
testing of products intended for those who are already ill.

What is also unclear yet utterly central is how regulatory processes can
take into account the differences between the enormous volume of risk in
the countries which, in the case of HIV/AIDS, bear roughly 95% of the
burden of disease and corresponding risk, and the volume of risk in
countries where the burden of the epidemic is considerably less.[^20]
The question here, for the FDA and the microbicide field, is how to act
expeditiously while striking an appropriate balance among consummate
scientific rigor, ethical treatment of human subjects, and what is
realistically feasible and truly informative.

**Need for a Paradigm Shift**

If we accept the foregoing issues as valid, then it becomes evident that
some sort of "paradigm shift" is needed in the testing and approval of
certain product categories for certain populations. Indeed, the
dimensions of such a shift with respect to HIV vaccines are already
under active consideration by the World Health Organization and the EMEA
(European Agency for the Evaluation of Medicinal Products) in a process
that includes representation from the FDA's Center for Biologics.[^21]

**The position of the FDA to date with respect to microbicides has been
to maintain flexibility and consider the new products in this new field
on a case-by-case basis. We vigorously urge continuance of this
position. The very fact of an evolving technology, the intrinsic
differences between traditional therapeutic trials and trials of
preventive technologies, continued limits on understanding of the
correlates of protective immunity in HIV infection,**[^22] **lack of
validated surrogates for product efficacy, and the dominance of needs
for offshore testing together recommend a regulatory posture that is
persistently flexible. We applaud the agency in its search for clarity
and its ongoing and present efforts to involve the wider community of
microbicide research and advocacy in that search. At the same time, we
respectfully submit that a regulatory strategy for Phase II/III studies
that is unduly complex, demanding, and rigid may not be feasible in
developing-country settings and could, in fact, compromise safety, data
quality, ethical integrity, and research specificity. We argue for
simpler studies that successively substitute data from multiple sources
for what are presently assumptions, address only the major issues for
worldwide regulatory approval, provide a sound** **basis for Phase IV
and/or post-market monitoring, and are doable at a reasonable level of
confidence. Finally, we urge the leadership of the FDA and CDER to
become active participants in the advancing dialogue on the particular
challenges of developing pharmaceutical products for developing-country
populations.**

In the spirit of this argument, we offer the following observations,
presented according to what we agree to be the strengths and limitations
of each major element in the design of clinical trials to evaluate
product effectiveness. We agree that trials must be large enough to
ensure sufficient HIV end-points to provide a robust, statistically
significant result; that enrollment must occur at various sites where
there is a high incidence of new HIV infections; that bridging studies
in US populations will in some cases make sense; and that the recruited
populations should share the main characteristics of the eventual target
groups for Phase 3 and beyond. Thus, we will focus only on the main
components of trial design, which will, of course, be affected by HIV
incidence and will, in turn, affect and be affected by trial sample
size. These components are (1) control arms, (2) trial duration/duration
of follow-up, (3) strength of evidence and level of effectiveness, and
(4) adherence and its measurement.[^23]

**Control Arms**

Randomized controlled trials of new drugs are classically blinded and
commonly include randomization of participants to either drug or
inactive product (placebo) to control for observer bias and differential
behavior. In the case of microbicides, a completely inactive or "inert"
placebo remains to be identified. For example, a placebo might contain
antimicrobial components in the form of preservatives or charged jelling
agents, have an acidic pH disfavoring infection, provide lubrication
reducing physical trauma to the mucosa, or act as a physical barrier to
infection by coating the mucosa, thus producing some kind of protective
effect in itself. Considerable work has been done to develop a placebo
that would minimize the potential for protective effect, as reported in
regulatory submissions in preparation for HPTN 035. Alternatively, a
placebo might have some harmful effect, though this is speculative and
believed highly unlikely for the hydroxyethyl and methyl cellulose gels
that have been specially developed for trial use as part of ongoing
efforts to minimize any possible protective effect. Some trial designers
propose that this "placebo problem" can be circumvented by using a
condom-only (no-treatment/no-product) arm so that the HIV rate in the
microbicide arm may be compared directly with the baseline rate in that
population.

The question here is whether a condom only/no-product arm is essential
in effectiveness trials of topical microbicides. Further questions would
have to do with the circumstances under which such a control arm could
be dropped in the course of a given trial and whether such a control
would be necessary for every tested product.

***STRENGTHS.*** Comparison of placebo (P) and condom-only (C) can
provide a valid estimate of the effects of a placebo, assuming that
behavior (i.e., condom use and other risk-taking behavior) remains
independent of group assignment. Comparison of active treatment (T) and
condom-only (C) can provide an estimate of the combined effect of
microbicide use plus behavioral changes due to availability of
microbicides, i.e., an estimate of "real world" or "use-effectiveness".

***LIMITATIONS.*** By definition, a condom-only arm cannot be blinded.
This means that differences in HIV rates, in whichever direction
(protection or potentiation), may be due as much to different risk
behaviors as to the direct biological effect of the product, even though
participants are told that the effectiveness of the microbicide is
unknown. Some have argued that it is not necessary to understand the
basis of any observed difference in HIV rates between arms as long as
the situation reflects "real life". But a comparative study of treatment
against condom-only does not reflect real life: when the microbicide
comes to market, there will be no informed consent procedure, no regular
safer sex counseling, and no clinical trial ethos to influence user risk
behavior. The arguments laid down under "Strengths" above can be seen as
essentially contradictory and requiring of contradictory assumptions.
Comparing P to C requires the assumption that the associated behaviors
do not differ, whereas in comparing T to C ("use-effectiveness"), we are
allowing for the fact that behaviors might, in fact, differ.

It is also not certain that enough women can be motivated to possible
randomization to a condom-only arm and comply with the protocol for the
full length of the trial, including regular clinic visits for blood
tests, etc., since the inducement of receiving product/placebo would not
pertain. The differential in inducement raises an ancillary question:
those who advocate for inclusion of a condom-only control have alluded
to use of self-reported data to compare risk-taking behaviors across
groups although, as observed later in this document *(see section on
Adherence)*, our methods for assessing such behaviors remain limited. An
unblinded control arm for which a core incentive to participants (i.e.,
access to test product) is lacking imposes further complexity on
behavioral assessment that is now---and may remain---imponderable.
Finally, the possibility of heavy losses to follow-up in a no-product
arm could introduce significant bias if, for example, dropouts tended to
be those who found condom use difficult or thought themselves more or
less likely to have been infected.

***RECOMMENDATION:*** **The Subcommittee believes that the additional
data a condom-only arm might furnish are likely to include more noise
than useful information, may be uninterpretable, and could lead to
erroneous conclusions about the products being evaluated. While there is
no intent to imply that cost savings should take precedence over good
science, we contend that cost savings resulting from the elimination of
a condom-only arm might be better invested in increasing the power of
the product and placebo arms and, possibly, Phase IV studies as more
accurately reflective of "real-world" effectiveness. Still, we
understand that there is considerable commitment to including a
condom-only/no-treatment arm in the forthcoming HPTN 035 trial of
PRO2000/5 and BufferGel. We recognize that the findings from the HPTN
035 trial could influence future regulatory policy, but argue that until
those findings become available, which could be several years away, it
would be unwise to lock in a regulatory requirement for a no-treatment
arm. Given the implications of such an arm for sample size, recruitment,
follow-up, costs in time and resources, and questions about
generalizability to other candidate products, we therefore urge a highly
flexible position with respect to inclusion of a condom-only arm in
future effectiveness trials.**

**Trial Duration/Duration of Follow-up**

The question here is: how long should participants be followed in Phase
II and III trials of microbicides? Our understanding is that the FDA is
looking for periods of on-treatment evaluation of 12-24 months, with all
participants treated until the last recruit enrolled has completed 12-24
months of treatment. We do not know FDA's thoughts about duration of
off-treatment follow-up.

***STRENGTHS.*** Longer duration of follow-up permits accumulation of
more person/years of safety data and efficacy endpoints in conjunction
with chronic use of product over time. This theoretically permits
smaller sample sizes, in itself a benefit in terms of costs and
logistics. Longer studies would also be advantageous if rates of
sero-conversion were uneven over time, since such variability would be
more likely to be captured; however, field experience to date has found
that such rates are steady, so that there would seem to be no particular
advantage to a longer period of follow-up if this is a desired
objective.

***LIMITATIONS.*** With longer periods of follow-up, adherence may
decrease with respect to both product use and clinic attendance, for a
variety of reasons, including real and perceived side effects,
withdrawals for pregnancy, and simply participant fatigue. Large loss to
follow-up compromises study power almost by definition, can erode data
quality as well as quantity, and may have an overall negative effect on
study reliability and consequent regulatory assessment. Large losses to
follow-up can also lead to bias if the reasons for the losses differ
between study arms; they might also lead to an amount of variability
across multiple trial sites that could be confounding.

***RECOMMENDATION:* The Subcommittee appreciates the desire of the FDA
to capture as much data on putative product toxicity as possible. There
is, nevertheless, no "magic time" that could unimpeachably predict
toxicity, particularly against the background of extremely high risk
that characterizes HIV-pandemic countries. Consideration is being given
to trial designs in which the required woman-years of participation are
achieved by enrolling a substantially larger number of women (perhaps
requiring more trial sites) who are followed for a shorter time, e.g., 6
months. The logistical and cost implications of a strategy requiring a
large overall number of recruits to get the same reliability would be
partially offset by the larger numbers needed for studies with longer
follow-up which need to compensate by "over-recruiting" to account for
drop-outs and withdrawals. Expectations from this temporal compression
are that losses to follow-up and any consequent biases would be
significantly smaller. Longer-term safety and acceptability data would
be derived from sites where longer follow-up of good quality proved
feasible.**

**We believe that such approaches offer a defensible balance between the
ideal and the practicable, and propose a period of on-treatment
evaluation of no more than 12 months per participant. We note that the
potential for advance understandings about post-licensure surveillance
studies has not been adequately explored and urge such exploration.
Finally, we suggest scrutiny of the strategies employed in studies of
contraceptive safety and effectiveness as a possibly informative
analogue.**

**Strength of Evidence and Level of Effectiveness**

The question here is: What minimum level of effectiveness should a Phase
III microbicide trial aim to demonstrate, and with what degree of
confidence? (We note parenthetically that in pursuing answers to that
question, it is important to define what we are talking about. A Phase
III microbicide trial does not measure the product's *efficacy*, i.e.,
its innate anti-infective potency, but rather its *effectiveness* in
reducing the infection rate when used *as it was in that particular
trial*. It may be that more consistent use in "real life" subsequent to
the trial might well result in even fewer infections.)

Results from two adequate and well-controlled Phase III trials, each
independently convincing (*p*: 0.05 x 0.05 = 0.0025), are generally
required by the FDA to establish product effectiveness for licensing
approval. Nonetheless, FDA has indicated that it would consider
approving a microbicide on the basis of a single, large, multi-center,
well-designed, and well-executed Phase III trial.[^24] For such a trial,
a one-sided *p* value of 0.000625 (0.025 x 0.025, 0.001 two-sided) has
been mooted, with the objective of showing significance at the same
level as from two independent studies. There are, however, indications
that the FDA might consider a value between 0.001 and 0.01, assuming
that key criteria for study quality were met.

***STRENGTHS:*** Obviously, the *p* value articulated above offers
greater likelihood of licensure based on the results of a single trial.
As for level of microbicide effectiveness, most product developers would
regard an effectiveness level of about 33% (one-third fewer infections
in the microbicide arm than in the control arm) as the minimum
acceptable, in the belief that anything lower would be of dubious
practical value. Furthermore, the number of women required, and hence
the trial's practicability and costs, would increase dramatically to
detect a lower effectiveness with the same degree of confidence. In any
event, if a trial designed to detect 33% effectiveness were to actually
show greater protection, say 50-60%, confidence in the result would be
correspondingly greater.

***LIMITATIONS:*** We offer just one example of the potential
implications of the *p* value stipulated above, in association with a
33% effectiveness level. In a population with 2% annual HIV incidence, a
two-arm trial with 2 years of follow-up and 90% power to detect 33%
effectiveness at this significance level would require approximately
28,000 woman-years of data, or 7,000 women in each arm ─ a challenging
target with heavy budgetary implications if we accept prevailing
estimates of a per-volunteer cost of from US\$3,500 to \$5,000.
Arguments that have been made against attempting such a trial have been
predicated on feasibility, in turn predicated on implications for site
number and capacity, recruitment potential, and costs.

***RECOMMENDATIONS:* The consensus of the Subcommittee is that we are in
what is essentially a data-free zone with respect to decisions about the
intertwined variables of level of effectiveness, strength of evidence,
trial duration, and number of control arms. We respectfully ask the
Advisory Committee to examine the table of alternative design scenarios
prepared by the HPTN 035 protocol team, which is provided as an
*Appendix* to this document, and to scrutinize its various implications.
The table is based on a 33% effectiveness target, but consideration is
being given by some product sponsors to a 50% effectiveness level. Since
the 33% level is presently theoretical and there is as yet no basis for
arguing too hard one way or the other, we submit that this is**
**another area where regulatory flexibility would be appropriate. We
observe that elimination of the condom-only/no-treatment arm and
shortening the period of follow-up (even accounting for the concomitant
sample size increases mentioned earlier) could produce savings in time
and costs that need not compromise the essential quality of microbicide
effectiveness trials, particularly given the acute public health need
which motivates them. As the closest example, the HPTN 035 trial, we
vigorously urge that the AVAC question what is to be defined as a
"win"**[^25] **for the microbicides being tested. Is it essential that
the product in question "beat" both a placebo and a
no-treatment/condom-only arm, or might a victory over the former
(perhaps with the other going in "the right direction", assuming
interpretability), be sufficient, and how might "beating" and
"sufficient" be defined?**

**Adherence**

Admittedly limited experience in the trials of COL-1492 informs us that
within a multi-site microbicide trial, as noted above, any observed
differences in effectiveness among sites may be due, at least in part,
to different adherence levels.

***STRENGTHS.*** Trustworthy information about adherence during a trial
is relevant both to interpreting results and formulating claims about
the product's protectiveness, and high confirmed levels of product use
during Phase III will be critical to obtaining product registration. We
believe that it is useful for regulators to be aware that behavioral
research and trial experience have accumulated and advanced over the
last few years in quantity and quality. It is reasonable to expect
improvement in existing approaches (e.g., coital logs, diaries,
questionnaires, and in-depth interviews) and/or their replacement with
more rewarding techniques that could inspire greater confidence in trial
results.

***LIMITATIONS.*** Nonetheless, there is yet no "true" measure of
product adherence, since in microbicide trials it is understandably
difficult to obtain invariably reliable feedback from participants on
sexual behavior and microbicide and condom use.

***RECOMMENDATION:* This is not a recommendation to the Advisory
Committee but, rather, an acknowledgment for its information. Despite
deepening understanding about what behavioral research can produce in
the way of microbicide trial quality and reliability, the Subcommittee
agreed that the field has work to do with respect to learning from other
drug trials about protocol adherence, and that efforts dedicated to
promoting adherence to product use are as important and urgent as
research aimed at developing microbicides with greater potency.**

**HPTN 035 Design Scenarios, 33% Targeted Effectiveness**

  -------------- ---------- ----------- ----------- --------- ------------------ ------------ --------- -------- ------------
  **Option**     **Active   **Control   **Power**   **Final   **Non-US           **Non-US     **Yrs**   **No. of **Total
                 Product    Arms**                  2-sided p Person-Years\***   Sample                 Mos.**   Costs**
                 Arms**                             value**                      Size\*\***                      

  1a             1          1           80%         0.05      4810               2749         1.75      21       23,088,000

  1b             1          1           80%         0.005     8158               4662         1.75      21       39,158,400

  1c             1          1           90%         0.05      6439               3679         1.75      21       30,907,200

  1d             1          1           90%         0.005     10244              5854         1.75      21       49,171,200

                                                                                                                  

  2a             1          2           80%         0.05      6764               3865         1.75      21       32,467,200

  2b             1          2           80%         0.005     11472              6555         1.75      21       55,065,600

  2c             1          2           90%         0.05      9054               5174         1.75      21       43,459,200

  2d             1          2           90%         0.005     14405              8231         1.75      21       69,144,000

                                                                                                                  

  3a             2          1           80%         0.05      7730               4417         1.75      21       37,104,000

  3b             2          1           80%         0.005     13111              7492         1.75      21       62,932,800

  3c             2          1           90%         0.05      10348              5913         1.75      21       49,670,400

  3d             2          1           90%         0.005     16463              9407         1.75      21       79,022,400

                                                                                                                  

  4a             2          2           80%         0.05      9620               5497         1.75      21       46,176,000

  4b             2          2           80%         0.005     16316              9323         1.75      21       78,316,800

  4c             2          2           90%         0.05      12878              7359         1.75      21       61,814,400

  4d             2          2           90%         0.005     20488              11707        1.75      21       98,342,400

                                                                                                                 

  \*Assuming                                                                                                     
  5.67% annual                                                                                                   
  HIV-1                                                                                                          
  incidence in                                                                                                   
  the placebo                                                                                                    
  and no                                                                                                         
  treatment arms                                                                                                 
  and 81% annual                                                                                                 
  retention                                                                                                      
  rate.                                                                                                          

  \*\*Assuming                                                                                                   
  average                                                                                                        
  follow-up time                                                                                                 
  of 21 months.                                                                                                  
  -------------- ---------- ----------- ----------- --------- ------------------ ------------ --------- -------- ------------

**ALLIANCE FOR MICROBICIDE DEVELOPMENT**

**Subcommittee Convened *Ad Hoc***

**To Prepare for FDA/CDER AVAC Meeting, 20 August 2003**

Sandra Arnold

Vice President, Corporate Affairs 

Population Council

New York, NY

Richard P. Bax, MD, FRCP, FFPM, MRCGP

Chief Scientific Officer

Biosyn, Inc.

Philadelphia, PA

Ward Cates, Jr. MD, MPH

President and CEO

Institute for Family Health

Family Health International

Research Triangle Park, NC

Anne Coletti

Senior Scientist

Family Health International

Reading, MA

Rosalie Dominik, DrPH

Director of Biostatistics

Family Health International

Research Triangle Park, NC

Tim Farley, PhD

Coordinator, Department of Reproductive Health and Research

World Health Organization

Geneva, Switzerland

Henry Gabelnick, PhD

Director

Contraceptive Research and Development Program

Arlington, VA

Caroline Galbreath

Senior Manager, Regulatory Affairs

Biosyn, Inc.

Philadelphia, PA

Polly F. Harrison, PhD

Director

Alliance for Microbicide Development

Silver Spring, MD

Sharon L. Hillier, PhD

Associate Professor

Magee-Women's Hospital

Pittsburgh, PA

Christine Mauck, MD, MPH

Senior Medical Advisor

Contraceptive Research and Development Program

Arlington, VA

Albert T. Profy, PhD

Vice President, Preclinical Development

Interneuron Pharmaceuticals, Inc.

Lexington, MA

Zeda Rosenberg, PhD

Chief Executive Officer

International Partnership for Microbicides

Silver Spring, MD

Jeffrey Spieler

Chief, Research, Technology and Utilization Division

USAID

Washington, DC

Alan Stone DPhil, MD

Medical Scientific Advisory Services Ltd.

London, UK

Don E. Waldron, PhD

Director, Clinical Research

Rockefeller University

New York, NY

Mark A. Weaver, PhD

Senior Biostatistician

Family Health Council

Research Triangle Park, NC

**REFERENCES**

[^1]: Annan KA. In Africa, AIDS has a woman's face. New York Times, 29
    December 2002, p. 9.

[^2]: Joint United Nations Programme on HIV/AIDS (UNAIDS). Report on the
    global HIV/AIDS epidemic. Geneva: UNAIDS, 2002.

[^3]: Kaiser Family Foundation. Women and HIV/AIDS fact sheet, July
    2002; World Health Organization. Department of HIV/AIDS/STI Report.
    Geneva: WHO, 2001.

[^4]: Centers for Disease Control and Prevention. Tracking the hidden
    epidemic: trends in STDs in the United States, 2002. Atlanta, GA:
    CDC, July 2002.

[^5]: Fleming DT, Wasserheit J. From epidemiological synergy to public
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[^6]: Bentley ME, Morrow KM, Fullem A, et al. Acceptability of a novel
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[^7]: Hearst N, Chen S. Condoms for AIDS prevention in the developing
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[^8]: Watts C, et al. The public health impact of microbicides: model
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[^9]: United Nations Development Programme. Human development report.
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[^10]: McMichael AJ, Hanke T. HIV vaccines 1983-2003. Nature Medicine
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[^11]: Gross M, Johnston MI. HIV vaccines and topical microbicides: a
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[^12]: Pope M, Haase AT. Transmission, acute HIV-1 infection and the
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[^13]: Feachem R. AIDS hasn't peaked yet---and that's not the worst of
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[^14]: This terminology originated in the 1993 CIOMS^?^ *International
    Ethical Guidelines for Biomedical Research Involving Human
    Subjects*, which stated that the first Phase I trial of any
    pharmaceutical product should be conducted in the country where that
    product was developed and manufactured, referred to as the "country
    of origin." The guideline was motivated by concerns about the
    exploitation of volunteers implicit in the testing in
    developing-country sites of drugs that would primarily benefit
    developed-country populations (termed "countries of use"). It was
    modified in the 2001

    revision of the *Guidelines*, largely in deference to the realities
    of HIV/AIDS and the disparities between developed and developing
    countries with respect to burden of disease.

[^15]: Institute for International Research. Phases: maximizing clinical
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[^16]: Godwin J. HIV vaccines, microbicides, and treatments: developing
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[^17]: The recommendation has been made that a compendium be developed
    of "listed countries" that look to the FDA, as well as to South
    Africa and India, for regulatory approvals, but this remains a work
    in progress (International Partnership for Microbicides. Notes from
    meeting of microbicide product developers, 8 April 2003, Silver
    Spring, MD).

[^18]: Fauci AS. HIV and AIDS: 20 years of science. Nature Medicine
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[^19]: Pomerantz RJ, Horn DL. Twenty years of therapy for HIV-1
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[^20]: Joint United Nations Programme on HIV/AIDS (UNAIDS). Report on
    the global HIV/AIDS epidemic. Geneva: UNAIDS, 2002.

[^21]: European Agency for the Evaluation of Medicinal Products (EMEA).
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    developing world, Seoul, Korea, 20 June 2003. Draft meeting minutes;
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    orphan medicines. Presentation at international meeting on a global
    framework for supporting health research and development in areas of
    market and public policy failure, Geneva, 29 April 2003. Brussels:
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[^22]: Fauci, 2003, *op. cit.*

[^23]: Stone A. Clinical trials of microbicides. The Microbicide
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[^24]: Bhore R. Regulatory preferences, expectations, and requirements.
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[^25]: Roddy R. Welcome presentation: hurdles in microbicide clinical
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