Current Initiatives and Next-Generation Leads | 1

REPORT TO CONGRESS

The USAID Strategic Plan for 

Microbicide Research and Development: 

Current Initiatives and Next-Generation Leads

SEPTEMBER 2009
The USAID Strategic Plan for Microbicide Research and Development
Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .i

Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1

I. The Need for a Microbicide for Women in Developing Countries . . . . .5

II. Microbicides and Health Product Research at USAID . . . . . . . . . . . . . .5

III. The Coordination of the USAID Microbicide Program 

and Collaborations with Other USG Agencies and Stakeholders . . . . . .7

IV. The Milestones and Progress to Date of the USAID Program . . . . . . . .8

V. The Current Priorities of the USAID Microbicide Program . . . . . . . . . .9

VI. The Review, Selection, and Management of Activities Funded 

by the USAID Microbicide Program . . . . . . . . . . . . . . . . . . . . . . . . . . . .10

VII. The Strategic Plan for Continuing Progress 

with Current Initiatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12

VIII. The Strategic Plan for Advancing the Best Next-Generation 

Microbicide Leads . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

IX. The Strategic Plan and Accomplishments to Support Introduction, 

Distribution, and Use of Microbicides . . . . . . . . . . . . . . . . . . . . . . . . . . .18

X. Looking Forward Programmatically . . . . . . . . . . . . . . . . . . . . . . . . . . . .21

Current Initiatives and Next-Generation Leads

Table of Contents
The USAID Strategic Plan for Microbicide Research and Development
Current Initiatives and Next-Generation Leads | i

API Active Pharmaceutical Ingredients

ARV Antiretroviral 

CA Cooperating Agency

CAPRISA Centre for the AIDS Programme of Research in South Africa

CDC Centers for Disease Control and Prevention

DSMB Data Safety Monitoring Board

FDA Food and Drug Administration

FY Fiscal Year

IND Investigational New Drug Application 

IPM International Partnership for Microbicides 

NDA New Drug Approval

NGO Nongovernmental Organization

NIH National Institutes of Health

OGAC Office of the Global AIDS Coordinator

PEPFAR U.S. President’s Emergency Plan for AIDS Relief

R&D Research and Development

STI Sexually Transmitted Infection

USAID U.S. Agency for International Development

USG United States Government

USG Plan U.S. Government Strategic Plan for Microbicide Development 

Acronyms
ii | The USAID Strategic Plan for Microbicide Research and Development
Health research is integral to cost, have appropriate characteristhe ability of the U.S. tics for use in developing

Agency for International countries, and can be provided

Development (USAID) to achieve through public-sector programs. 

its development objectives worldwide. Past USAID research USAID’s strategy for microbicide

investments have led to products R&D focuses on moving the most

that today reach millions of people, promising and appropriate candisaving lives throughout the devel- date products available into

oping world. As a key implementer advanced testing. Clinical trials

of the U.S. President’s Emergency demonstrating the safety and effecPlan for AIDS Relief (PEPFAR), tiveness of these products must be

USAID plays a critical role in shap- completed in order for them to be

ing the strategic and technical approved by appropriate regulatodirection of microbicide research ry agencies and introduced into

and development (R&D) to meet prevention programs. USAID’s

developing-country needs. extensive field presence and experience in collaboration and

Although effective treatment pro- research in developing countries,

grams will help, the greatest impact including in populations with very

in mitigating and eventually revers- high rates of HIV incidence (where

ing the HIV/AIDS pandemic will clinical trials of microbicides must

ultimately be through the develop- be conducted), are highly instrument and introduction of new mental in this effort. USAID is also

prevention technologies. uniquely positioned to leverage

Microbicides are entirely new and coordinate the intellectual,

products that, when available, will proprietary, and financial resources

provide women with an effective of a wide range of contributors,

barrier to sexually transmitted HIV including other public-sector agenand possibly other sexually trans- cies, private foundations, and

mitted infections (STIs). An commercial partners.

effective microbicide will help fill

the enormous need for a new pre- To date, the USAID microbicide

vention option for women and program has made significant

complement other existing or new progress built on rigorous precliniprevention approaches. For more cal evaluations, selection of the

than a decade, the USAID has sup- most appropriate active agents, and

ported the research needed to formulation of the best leads for

develop safe, effective, and accept- clinical testing in humans. Since

able microbicides that are low in 2004, USAID has moved five promCurrent Initiatives and Next-Generation Leads | 1

Executive Summary
ising candidates – SavvyTM (C31G), While completion of these ongoing • Behavioral and social science

UshercellTM (cellulose sulfate), clinical trials is the highest USAID research

CarraguardTM, Tenofovir 1% Vaginal priority, there are additional

Gel, and oral TruvadaTM in women research priorities that are also • Provision of training and 

– through the early stages of clini- critical in addressing technical and infrastructure

cal testing for safety in humans other needs in the microbicide

(Phase I and II trials) and into the field. These include: novel delivery For the microbicide field, this coladvanced stages of clinical testing methods, combination products laborative approach has been both

to evaluate the candidate’s effec- including multiple-mechanism and productive and successful in coortiveness in reducing the risk of HIV multiple-purpose agents, develop- dinating protocols for preclinical

infection as well as to assess its ment of new and existing leads, testing, prioritizing promising canacceptability to users and provide optimized clinical trial design and didates, designing clinical trials,

additional safety data (Phase IIb management, clinical trial site coor- building local research capacity, and

and III trials). Although three of dination, alternative trial designs, preparing communities for clinical

these trials have now been either and post-trial access issues. These studies, as well as learning about

completed (Carraguard) or stopped research priorities are reviewed each other’s progress, the state of

(Savvy, due to low HIV incidence at and updated at least annually and the art, and best practices, includtrial sites, and Ushercell due to an shared with USAID partners and ing standards of care. This

unexpected indication of potential the field to stimulate creative coordination fosters the strategic

harm) without detecting protective approaches to meet needs and implementation of all research,

effects, these trials have demon- solve problems in microbicide R&D. ensures the best use of federal

strated for the microbicide field resources, and prevents unnecesthe feasibility and best practices of To ensure the coordination of fed- sary duplication of effort.

conducting large trials with exten- erally-sponsored microbicide R&D,

sive community involvement in USAID consults frequently with In the review and funding of microdeveloping countries. other U.S. Government (USG) bicide activities, USAID strives for

agencies, including the National clarity and transparency and seeks

The Phase IIb and III trials current- Institutes of Health (NIH), Centers stakeholder participation at every

ly underway with Tenofovir 1% for Disease Control and stage of R&D. Microbicide funds

Vaginal Gel (in the CAPRISA 004 Prevention (CDC), and Food and are generally provided through

trial) and Oral Truvada (a combina- Drug Administration (FDA). five-year cooperative agreements

tion of Tenofovir and emtricitibine USAID partners with these other that include substantial involvein the FemPrEP trial) will continue USG agencies in developing and ment of USAID technical staff to

with fiscal year (FY) 2009 support implementing the U.S. Government ensure appropriate use of funds

as part of the USAID strategic plan Strategic Plan for Microbicide and timely progress. Activities are

for microbicide R&D. These trials, Development (the USG Plan), and funded for only one year at a time

which will be completed in 2010 contributes to the following gov- and require an annual review of

and 2012, respectively, employ spe- ernment-wide objectives: progress, future work plans, and

cific antiviral agents and unique budget to receive additional funddelivery regimens that should • Preclinical development and ing. Partners are usually selected

increase both user compliance and evaluation of potential microbi- through competitive procurements,

product effectiveness. These large cide candidates but may be selected noncompeticlinical studies are conducted in tively when justified by their

collaboration with other agencies • Formulation and delivery of predominant technical capability,

and donors to share costs and potential microbicides proprietary products, or other

maximize the speed and efficiency unique intellectual property. 

of this work. • Clinical testing of microbicides

2 | The USAID Strategic Plan for Microbicide Research and Development
For FY 2008, USAID funding for technology at the individual and

microbicide R&D totaled community levels, and will require

$44,636,000 and was distributed strategic planning to promote servstrategically to each of the USG ice delivery, marketing, and

objectives as follows: preclinical programmatic impact. USAID will

development and evaluation – also support efforts to ensure that

$9,757,000 (22%), formulation and future access to microbicides is

delivery – $7,847,000 (18%), clini- sustainable by optimizing microbical testing – $17,731,000 (39%), cide manufacturing capacity in

behavioral and social science – developing countries, thereby

$2,933,000 (7%), research infra- decreasing the costs of production

structure – 6,368,000 (14%). The and distribution.

supported activities target the discovery, characterization, and Looking forward, greater resources

development of new active agents; will be needed to support ongoing

the development of new formula- and future clinical trials and to

tions and delivery systems to develop and implement the prodenhance product acceptability and uct introduction and HIV

use; the advancement of clinical prevention programs that will protesting of the most promising vide microbicides to the people

leads; behavioral studies of accept- who need them most. Long-term

ability and product use in trials; and studies on the impact of microbithe capacity building needed to cides on reducing HIV incidence

strengthen investigators and trial and prevalence in developing counsites in developing countries. tries will also be needed. 

The USAID strategic plan for The promising product leads,

developing the best next genera- sound strategies, and expanding

tion microbicides includes these research capacity currently funded

objectives combined with efforts by USAID are generating the

to reduce product cost, understand progress in microbicide developand avoid the risk of viral resist- ment that will enable and expedite

ance to active agents, broaden the success in this field. USAID has

range of active agents with alterna- demonstrated that it has the

tive and complementary know-how to undertake all of the

mechanisms of action, and sustain steps required to develop and

capacity for characterizing promis- introduce safe, effective, acceptable,

ing early-stage leads. and affordable microbicides, and

that it collaborates effectively and

USAID is simultaneously addressing efficiently with other USG agenpolicy and logistical issues that will cies, donors, and partners. The

be critical to the successful intro- results of USAID-supported actividuction of microbicides in ties continue to be both impressive

developing countries. These issues and promising and justify a susinclude the multiple factors that tained commitment to this effort.

will influence the acceptance and

use of this new HIV prevention

Current Initiatives and Next-Generation Leads | 3
4 | The USAID Strategic Plan for Microbicide Research and Development
Nearly three decades after the dis- An estimated 33 million people women with an effective barrier to

covery of HIV/AIDS, the pandemic worldwide are infected with HIV, sexually transmitted HIV and poscontinues to spread and threaten and in sub-Saharan Africa, almost sibly other STIs. The R&D of an

the prosperity, stability, and devel- 60 percent of those infected are effective microbicide, therefore, will

opment of nations around the women. The current strategies for help fill the enormous need for a

world. An estimated 2.7 million preventing HIV infection, including new prevention option for women

new infections occur every year, delay of sexual debut, partner and will complement other existing

infection rates continue to increase reduction, use of condoms, and or new prevention approaches.

in many developing countries, and male circumcision, are not options For more than a decade, USAID

no cure is available or expected in that can be successfully negotiated has supported the biomedical and

the near future. Although wide- by many women in developing behavioral research needed for the

spread treatment will help, the countries with concentrated or successful development of safe,

greatest impact in mitigating and general HIV epidemics. effective, and acceptable microbieventually reversing the pandemic cides with low cost and appropriate

will ultimately be through the Microbicides are an entirely new product characteristics for use in

development and introduction of class of HIV prevention products developing countries and through

new prevention technologies. that, when available, will provide public-sector programs. 

Current Initiatives and Next-Generation Leads | 5

I. The Need for a Microbicide for Women in Developing Countries

Health research is integral to the family planning methods, among microbicides to protect against HIV

ability of USAID to achieve its others. In 2005, Congress noted infection and mitigate its spread,

development objectives worldwide. this unique strength of USAID: especially in regions that are highly

In partnerships with key public and “With its experience in the devel- affected by this epidemic such as

private sector agencies and non- oping world, USAID does and should sub-Saharan Africa, India and other

governmental organizations play a valuable role in facilitating parts of Asia, and Latin America.

(NGOs), USAID applies a cycle of international clinical trials, consoliassessment, development, pilot test- dating markets, and finding new USAID’s strategy for microbicide

ing, and introduction of products, opportunities to speed the discov- R&D is to focus support on moving

policies, and practices that tackle ery, development, and delivery of the most promising and appropriate

high-priority disease and health products to improve the lives of candidate products available into

issues in developing countries. This those in the developing world.” advanced testing. Clinical trials

enables USAID to implement effec- demonstrating the safety and effective and sustainable programs that As a key implementer of PEPFAR, tiveness of these products must be

improve health worldwide. Past USAID also plays a critical role in completed in order for them to

USAID research investments have shaping the strategic and technical receive approval by the appropriate

led to products that today reach direction of microbicide R&D to regulatory agencies. Proof of

millions, saving lives throughout the meet developing-country needs. concept (i.e., demonstrating effecdeveloping world – including oral In concert with the Office of the tiveness in reducing the risk of HIV

rehydration salts, vitamin A, auto- Global AIDS Coordinator (OGAC), acquisition) will speed up the availdisable syringes, vaccine vial USAID will continue the develop- ability of the best product, stimulate

monitors, and a number of new ment and eventual introduction of the future development of alternaII. Microbicides and Health Product Research at USAID
tive or even better products, help nificantly in FY 2001 when developing countries, including in

identify the most appropriate pre- Congress allocated $12 million for populations with very high rates of

clinical models for evaluating future this purpose. Determined annually, HIV incidence (where clinical trials

candidate products, and attract congressional allocations reached of microbicides must be conductadditional resources, investigators, $45 million in FY 2009. USAID cur- ed), are highly instrumental in this

and donors to this field. The stages rently implements its microbicide effort. USAID is also uniquely posiinvolved in the extensive product R&D program through cooperative tioned to leverage and coordinate

R&D process are shown for micro- agreements that use subawards as the intellectual, proprietary, and

bicides in the table below. needed to accomplish their financial capital of a host of contribresearch objectives. USAID’s exten- utors, including other public-sector

Financial support for microbicide sive field presence and experience agencies, private foundations, and

R&D through USAID increased sig- in collaboration and research in commercial partners.

6 | The USAID Strategic Plan for Microbicide Research and Development

PRECLINICAL STUDIES

Purpose: Screening and testing in laboratory and animal studies

to evaluate the activity and toxicity of promising active agents.

Includes formulation for testing in humans.

Approximate Timeframe: 1-10 years

PHASE I CLINICAL TRIALS

Purpose: Early testing in small groups of 10-20 human 

volunteers to confirm the lack of toxicity and the delivery 

of effective doses. May include early acceptability studies.

Approximate Timeframe: 2-3 years

PHASE II CLINICAL TRIALS

Purpose: Testing to provide expanded safety and acceptability

data in up to several hundred human volunteers. For most 

non-microbicide products, provides early effectiveness data. Since

the only endpoint for microbicide effectiveness is prevention of

HIV infection, larger Phase IIb trials are sometimes done in many

hundreds or up to a few thousands of volunteers to obtain early

effectiveness data for very promising product candidates.

Approximate Timeframe: 2-5 years

PHASE III CLINICAL TRIALS

Purpose: Large-scale testing to demonstrate effectiveness, safety,

and acceptability in thousands of human volunteers. Large trials

are needed to provide statistically significant data for review by

regulatory agencies (e.g., the U.S. FDA or others) before new

products can be approved for marketing and use. The drug

regulatory agencies require two independent and confirmatory

large trials for the approval of many products.

Approximate Timeframe: 2-6 years

PHASE IV STUDIES

Purpose: Long-term surveillance is essential, even after a product

becomes available to the public, to identify any very rare adverse

effects that could not be foreseen. For microbicides, this postmarketing surveillance might also include any long-term effects

on HIV disease progression and treatment (including possible

selection of drug-resistant HIV when relevant), HIV risk behaviors,

and interactions with other diseases, therapies, or products.

Approximate Timeframe: Indefinitely

OTHER PRE-APPROVAL STUDIES

Purpose: Data from additional studies are often required by 

regulatory agencies for the approval of new products. Such

studies may, for example, include testing to demonstrate that 

the product is safe for use by pregnant women, or to identify any

possible effects on the risk of cancer or cardiovascular disease.

Regulatory agencies also require information regarding product

manufacturing methods and quality control measures to ensure

that the marketed product is the same as the tested product.

Approximate Timeframe: 2-6 years. 

Note that many of these studies can be done concurrently with others.

PRODUCT INTRODUCTION AND SUPPORTING STUDIES

Purpose: Addressing policy and logistical issues is often critical

for the introduction of new health products. For microbicides,

many countries will require pre-introductory studies in their own

populations before allowing the importation and distribution 

of a new product. Scale up of manufacturing and transfer of

technology may be needed to produce adequate product supplies.

Operations and program research on the provision of a new

microbicide through public and private-sector programs will 

be needed to ensure that this new HIV prevention technology

reaches the individuals who need it most.

Approximate Timeframe: up to 10 years

Stages of Product Research and Development for Microbicides

Note: The timeframes indicated are illustrative and based on typical experience. Some activities in the same or different product development stages can be

undertaken simultaneously to expedite progress. As for many other health products, a realistic estimate for the minimum time required for the development

of an individual microbicide would be 10-15 years from preclinical testing through product approval by regulatory agencies.
To ensure coordination of federally chemical, pharmaceutical, physical, The effective coordination of

sponsored microbicide R&D, bioengineering, and social sciences. effort among the USG agencies is

USAID is in frequent consultation strengthened not only by extensive

with other USG agencies, including • Clinical testing of microbicides – to consultation, but also by the reprethe NIH, CDC, and FDA. This assess the human safety, effec- sentation and active contributions

coordination allows the strategic tiveness, and acceptability of of each agency in the technical and

implementation of all preclinical potential microbicides in reduc- programmatic planning and reviews

and clinical research, including the ing the transmission of HIV and of the other agencies. USAID and

prioritization of candidates in the other STIs and, in the case of a variety of other stakeholders

product pipeline. USAID partners products that are also contra- have also collaborated in an effort

with these other USG agencies in ceptive, in preventing pregnancy led by the Alliance for Microbicide

developing the U.S. Government in developing countries and the Development to complete The

Strategic Plan for Microbicide United States. Microbicide Development Strategy.

Development (USG Plan), which is This is a very extensive and comcurrently being updated for 2009 • Behavioral and social science prehensive framework for future

(under the coordination of the research – to enhance microbi- activities of all stakeholders in the

NIH Office of AIDS Research). cide development and testing microbicide field, including investiThese joint efforts ensure the best and to better understand factors gators, donors, and community

use of federal resources and prevent that will affect future microbi- representatives, and complements

unnecessary duplication of effort. cide use and acceptability in the USG Plan. For the microbicide

developing countries. field, this collaborative approach

USAID collaborates in implement- has been both productive and sucing the USG Plan by contributing • Provision of training and cessful in coordinating protocols

to the following government-wide infrastructure – to establish, for preclinical testing, prioritizing

objectives: maintain, and strengthen the promising microbicide candidates,

appropriate training and infra- designing clinical trial protocols,

• Preclinical development and structure needed to conduct building local research capacity, and

evaluation of potential microbicide microbicide research interna- preparing communities for clinical

candidates – to support the dis- tionally and to accelerate future studies. These collaborations also

covery, characterization, and access to microbicides in diverse allow the participating agencies to

early-stage development of populations and settings. learn from each other about

potential new active agents for progress, the state of the art, and

use as microbicides. The one objective of this USG Plan best practices, including opportunithat USAID’s development assistance ties to expand standards of care. 

• Formulation and delivery of potential funding does not support is the

microbicides – to develop and conduct of basic biological and

assess safe, effective, and accept- physiological research related 

able formulations and modes of to microbicides.

delivery for microbicides, applying knowledge from the

Current Initiatives and Next-Generation Leads | 7

III. The Coordination of the USAID Microbicide Program and

Collaborations with Other USG Agencies and Stakeholders
8 | The USAID Strategic Plan for Microbicide Research and Development

IV. The Milestones and Progress to Date of the USAID Program

Preclinical evaluation of potential for potentially unknown harmful described under Objective 4 of the

active agents and the effective effects of a test product. These USAID Strategic Plan (see Section

formulation of those that merit reasons for stopping were not VII). Despite the disappointing

clinical testing in humans have expected and only became appar- outcome, the Carraguard trial

allowed the USAID microbicide ent in the advanced stages of demonstrates for the microbicide

program to make very significant testing when sufficient data were field the feasibility and best practices

progress. Since 2004, USAID has available. Appropriate follow-up of conducting large trials with

moved five promising candidates – investigations are underway to extensive community involvement

SavvyTM (C31G), UshercellTM (cel- inform future efforts. In both of in developing countries. The findings

lulose sulfate), CarraguardTM, these cases, the respective Data of this trial are also important

Tenofovir 1% Vaginal Gel, and oral Safety Monitoring Boards (DSMBs) because Carraguard may be a key

TruvadaTM in women – through the had conducted an interim analysis component of some next-generation

early stages of clinical testing for of the unblinded trial results (in microbicide formulations. Moreover,

safety in humans (Phase I and II such a trial, the study personnel do it should be noted that important

trials) and into the advanced stages not know if an individual partici- lessons were learned and capacity

of clinical testing to evaluate the pant receives the test product or built as a result of this trial, as well

test product’s effectiveness in the control) while the trial was the trials that were stopped before

reducing the risk of HIV infection ongoing and recommended that being completed.

as well as assessing the acceptabili- the trial be stopped. This analysis

ty of the product to users and and the resulting recommendation In FY 2009, USAID continues to

providing additional safety data are in accord with the intended support the international and

(Phase IIb and III trials). function and authority of the multi-year Phase IIb and III trials

DSMB and ensure that trials are currently underway to evaluate the

As in the development of other appropriately monitored and meet safety and effectiveness of

pharmaceutical products (for which high scientific and ethical standards. Tenofovir 1% Vaginal Gel (in the

it is customarily necessary to test CAPRISA 004 trial) and of Oral

many leads to find an effective The Phase III trial with Carraguard, Truvada (a combination of

product), the evaluation of two however, is a milestone: It is the Tenofovir and emtricitibine in the

of these candidates, Savvy and first large clinical trial for a micro- FemPrEP trial) in thousands of

Ushercell, was stopped before bide’s effectiveness to be volunteers (see Objective 3 of the

completion of the respective trials. successfully completed, although USAID Strategic Plan in Section

The Savvy trial was stopped the results (publicly announced in VII). These trials will be completed

because of concerns about the fea- February 2008) indicate that the in 2010 and 2012, respectively, and

sibility of successfully completing product, while safe and acceptable, will employ specific antiviral agents

the trial since the incidence of HIV did not significantly prevent infec- and unique delivery regimens, which

at the trial sites was lower than tion in this trial. This result may should increase both user compliexpected. The Ushercell trial was have been due in part to low com- ance and product effectiveness.

stopped because the number of pliance (or adherence) by some These large clinical studies are

new infections in the group using trial participants to the instructions being conducted in collaboration

the test product exceeded the for product use. Efforts to improve with other agencies and donors to

number of new infections in the compliance in the future are being the greatest extent possible to

control group to a degree that met addressed as part of the behavioral share costs and maximize the

the pre-defined stopping criteria and social science research speed and efficiency of this work.
Current Initiatives and Next-Generation Leads | 9

While completion of ongoing clini- reviewed and updated at least these priorities into consideration

cal trials with the most promising annually and then shared with and address them with their

and advanced product candidates is USAID partners and the field. USAID funding whenever possible.

the highest USAID priority, there These priorities are intended to Subsequent funding and program

are simultaneously other strategic stimulate, not limit, creative management decisions can then be

research priorities that are critical approaches to meet needs and made accordingly.

in addressing technical and other solve problems in microbicide

needs in the microbicide field. The R&D. Investigators requesting The USAID strategic research priresearch priorities identified in the USAID funds for microbicide orities for 2009 are shown in the

USAID Microbicide Program are research are expected to take following table.

V. The Current Priorities of the USAID Microbicide Program

Priority Area Description

Research is needed on novel delivery methods, including coitally independent methods.

Novel Delivery Methods These may include a vaginal ring delivery system, sponges, diaphragms, oral formulations,

long-acting gels, or other innovative technologies.

Combination Products

a. Dual Mechanism

b. Dual purpose – 

microbicide/contraceptive/other

Research is needed for a potential next generation with one or more active agents in a 

single product that prevent infection through a variety of mechanisms. Microbicides that 

confer additional reproductive or health benefits are also an objective 

(e.g., contraceptive microbicides).

In an effort to maintain a full development pipeline, and as the virology and transmission

Development of New 

and Existing Leads

mechanisms of HIV are further understood, research is needed on novel mechanisms for

prevention of HIV infection and the application of those technologies to microbicide

development. New or existing leads (or products) that can be quickly moved to Phase III

trials are of particular interest.

Optimized Clinical Trial Design 

and Management

Creative solutions are needed for:

• Accurate and predictive methods of measuring incidence

• Improving product compliance/adherence by participants in trials

• Prevention of unintended pregnancies in trial participants

• Provision and referral for reproductive and/or other health care

• Effective preclinical models and biomarkers that accurately predict 

clinical performance and safety

Given the limited number of appropriate clinical trial sites, creative solutions that enable

Clinical Trial Site Coordination cooperation and coordination are needed to ensure that viable sites are developed and

used to their maximum potential and downtime is minimized. 

Alternative Trial Designs

a. Phase I/II trials with 

higher predictive value

b. Alternative Phase III trial designs 

Innovation is needed to validate Phase I & II trial models, as well as preclinical models, with

higher predictive abilities in order to determine if a particular product warrants the investment required for a Phase III trial. Additionally, emphasis should be placed on designing

clinical trials that provide legitimate, verifiable data that show the safety and effectiveness of

microbicide products while reducing the investment of time, human capital, and resources. 

Post-Trial Access Issues Ensuring the broad and equitable distribution of the first generation of emerging microbicide

products will require plans for access, uptake, regulatory approval, and supply.
10 | The USAID Strategic Plan for Microbicide Research and Development

USAID strives for clarity and trans- external review mechanisms, often level of review that is consistent

parency about how microbicide including a scientific advisory with the relatively large commitactivities are reviewed and funded, group. These requests are then ment of resources involved. Such

and it seeks to enhance stakeholder evaluated by a review team in the review includes consideration of

participation in this process. Bureau for Global Health that the participants, clinical sites, invesincludes staff with extensive expe- tigators, funds, and other resources

Microbicide funds are generally rience in the R&D of microbicides needed, as well as any potential

provided to implementing partners and other health products and risks to volunteers and the lost

(known as Cooperating Agencies, expertise, as needed, in HIV pre- opportunity to support alternative

or CAs) through cooperative vention and reproductive health studies. Prior to requesting support

agreements that are usually estab- programs, public health, virology, for a Phase IIb or III clinical trial to

lished for five years and include clinical trial design and manage- confirm safety and evaluate effecsubstantial involvement of USAID ment, social science, regulatory tiveness in preventing HIV infection,

technical staff to ensure appropriate affairs, ethics, community the CA must have obtained and

use of funds and timely progress. involvement, gender issues, presented sufficient evidence to

All activities are funded for only and international development. justify the advanced clinical trial,

one year at a time and require an including extensive preclinical,

annual review of their progress, USAID reviews the progress of pharmacokinetic, animal model,

future work plan, and budget to ongoing activities and assesses the human safety, and other data. 

receive additional funding. technical and programmatic merits Peer-reviewed publication of the

Following USAID and federal regu- of the proposed work plans and available evidence and open dislations, CAs are usually selected budgets of all of the activities cussion of its implications among

through competitive procurements, submitted. External reviewers are all experts and stakeholders is

but they can also be selected non- included when additional expertise preferred, but proprietary product

competitively when justified by the in a particular area is needed, information is also considered

CA’s predominant technical capa- another informed perspective can whenever necessary to protect

bility, proprietary products, or help address relevant programmatic intellectual property and future

other unique intellectual property. and budgetary issues, or clinical product development interests.

Extensive opportunities for USAID trials beyond small Phase I safety

support are also available to other trials are under consideration. This At this stage, independent external

implementing partners through annual review often entails an iter- reviewers with relevant technical

subagreements with current CAs. ative process between USAID and and clinical-trial expertise are

In all cases, CAs and their subpart- the CAs to ensure that the funded engaged to review thoroughly the

ners are selected to provide activities reflect both the priorities proposed study rationale and the

appropriate technical expertise as of USAID and the needs of the clinical protocol with objectivity

part of a sound research plan to broader microbicide field. This and rigor. Technical, strategic,

meet USAID objectives in microbi- allows consideration of all R&D budgetary, and ethical issues are

cide research. options, including promising considered in this review. Efforts

alternative leads, across the are made to ensure the independCAs submit annual requests to entire microbicide field. ence of the external reviewers and

USAID for support of ongoing and to minimize any real or perceived

new activities after they have been When advanced clinical trials are conflicts of interest. The

vetted by their own internal and proposed, they merit an expanded Microbicide Working Group being

VI. The Review, Selection, and Management of Activities 

Funded by the USAID Microbicide Program
Current Initiatives and Next-Generation Leads | 11

established in the NIH Office of New Drug Application (IND), the

AIDS Research may be a useful New Drug Approval (NDA)

resource for future reviews. process, or equivalent procedures

of other drug regulatory authoriPrior to trial initiation, the pro- ties. These generally include the

posed clinical protocols are subject regulatory review of all preclinical

to a substantial number of addi- and existing clinical evidence for

tional reviews, including those by safety and effectiveness, as well as

other independent advisory com- the study rationale, clinical protomittees, the principal investigators col, and any amendments to the

at each clinical site, the institutional protocol that occur during a trial.

or ethical review boards for each Non-U.S. drug regulatory authoriengaged institution, and the inde- ties may be involved as well. 

pendent DSMBs when established.

The progress of the trial is then USAID also subscribes fully to the

regularly evaluated in the following USG “Common Rule” for the proways: through the tracking of mile- tection of human subjects in

stones built into the study research. All recipients of microbiprotocol, by the annual work plan, cide funding must comply with

budget, and management reviews, these requirements, which ensure

and by the DSMBs. The progress review and approval of all research

of the trial is then regularly evalu- involving human subjects by the

ated by the DSMBs and appropriate domestic and internamanagement reviews and also tional institutional and ethical

against the annual work plan, the review boards. 

budget, and milestones built into

the study protocol. When possi- Finally, USAID and other stakeholdble, these trials are also used to ers have an important interest in

investigate and/or validate more reviewing any proprietary or intelsensitive and predictive preclinical lectual property rights, licenses,

assays for safety and effectiveness, sub-licenses, or other relevant

as well as to conduct behavioral or agreements that are involved in

social science studies to under- microbicide R&D supported by the

stand acceptability and compliance Agency. The effect of these on coissues and thereby contribute to funding, product development

better clinical testing and better timelines, marketing, and publicprovision and use of microbicides sector pricing or any other aspect

in the future. When these activi- of providing microbicides to the

ties occur, they are also reviewed women who need them most is

prior to the approval of a study. also subject to discussion and

negotiation by the appropriate

For new product research and concerned parties, with confidenapproval, the FDA is typically tiality and non-disclosure

involved through the Investigational agreements as necessary. 
12 | The USAID Strategic Plan for Microbicide Research and Development

The USAID strategic plan for

microbicide R&D specifically seeks

and funds activities that address

the current research priorities

(stated in Section V) within each of

the USAID Objectives in the USG

Plan (in Section III). As noted previously, USAID targets the

development of products that will

be most suitable for use in developing countries and that are feasible

for procurement and provision

through public-sector programs.

The activities and funding levels

that are described below by objective and level of funding illustrate

the implementation of the USAID

strategic plan for FY 2008.

Specific activities that address the

USAID strategic research priorities

within each objective of the USG

Plan are described below.

Objective 1: Preclinical development

and evaluation of potential microbicide candidates 

The USAID strategic plan for

microbicide R&D supports the

discovery, characterization, and

early-stage development of potential

new active agents (i.e., active pharmaceutical ingredients or APIs) for

use in microbicides, as well as the

application and development of

improved testing methods. 

• As some microbicide candidates

using large-molecule non-specific

HIV attachment blockers (sulfated

polyanions) that moved into

advanced clinical trials had disappointing results, more specific

antiviral agents, largely with a HIV attachment, fusion, and/or

single mechanism of action, have entry into human target cells.

been sought as an alternative These activities include ongoing

approach by the field. Current work with Tenofovir, MIV-150,

USAID activities include agents UC 781, Pyrimidinediones, and

that are reverse transcriptase inhibitors of gp41, NCp7, and

inhibitors (that block HIV repli- CCR5 binding, among others.

cation in cells) or that inhibit

VII. The Strategic Plan for Continuing Progress with Current Initiatives

7% 14%

22%

18%

39%

Research

Infrastructure

Behavioral and

Social Science

Research Preclinical

Development 

and Evaluation

Formulations and

Modes of Delivery

Clinical

Testing

FY 2008 Funding Distribution by USAID 

Microbicides Research Objectives

USAID Microbicides Research Objectives FY08 Funding (in thousands)

Preclinical Development and Evaluation 9,757

Formulations and Modes of Delivery 7,847

Clinical Testing 17,731

Behavioral and Social Science Research 2,933

Research Infrastructure 6,368

TOTAL 44,636
• Small animal models are being

optimized and applied to characterize the activity and safety of

product leads. Transgenic rabbits, for example, are being

developed as a more readily

available and cost-effective animal model for the study of

vaginal infection.

• A variety of biomarkers for safety

and effectiveness are being tested

and used to assess new leads.

Objective 2: Formulation and delivery

of potential microbicides 

The USAID strategic plan supports

development of new formulations

and modes of delivery for microbicides. These are intended to be

not only safe and effective, but also

more acceptable to potential users.

Greater acceptability may enhance

product use in future prevention

programs as well as in the clinical

trials of these products. Chemical,

pharmaceutical, physical, bioengineering, and social sciences are all

contributing to these activities. 

• As new active agents proceed in

development, optimized gel formulations are needed for further

characterization in animal models and for future products that

would be topically applied. 

• Vaginal rings that would release

one or more anti-HIV agents, or

agents that would simultaneously

protect against HIV and other STIs

or pregnancy, are being rapidly

and collaboratively developed.

• The feasibility of products that

prevent HIV, protect the vaginal

flora, and are delivered in beneficial and self-sustaining bacterial • USAID will continue to support

formulations is advancing. the advanced Phase IIb and III

clinical trials that are currently

• Support is essential for the man- underway with Tenofovir 1%

ufacturing of active agents and Vaginal Gel and with oral

formulations to be used in pre- TruvadaTM in women. These

clinical studies and clinical trials. multi-year international trials are

Novel production technologies evaluating the safety, effectivefor active agents may also be the ness, and acceptability of these

key to minimizing microbicide products in thousands of voluncosts and transferring manufac- teers and will demonstrate

turing technologies to whether these products can

developing countries. meaningfully reduce or prevent

the sexual transmission of HIV.

• Existing or novel barrier devices Additional information regarding

are also being developed and these trials is shown above. 

tested as possible microbicide

delivery devices. These include • The data from these trials will

diaphragms, female condoms, and allow the FDA and/or European

vaginal sponges. and African regulatory agencies

to determine if these products

Objective 3: Clinical testing of can be approved for marketing

microbicides and introduction. The initiation

The USAID plan continues to place and progress of these landmark

high priority on support for clinical trials confirm the strength of

trials of the most promising micro- USAID’s collaborations with

bicide candidates to assess their other agencies and donors to

safety, effectiveness, and acceptability accomplish this work.

in a variety of populations in

reducing the transmission of HIV • Pharmacokinetic studies are

and other STIs, and in preventing powerful tools to determine if

pregnancy for products that are effective levels of active agents

also contraceptive. are reaching the tissues and cells

Current Initiatives and Next-Generation Leads | 13

CAPRISA 004 Study FemPrEP Study with Oral

with Tenofovir 1% Vaginal Gel Truvada for Women

USAID Partner 

Conducting Trial

Family Health International, 

CONRAD, CAPRISA Family Health International

Location 

(# of Sites) South Africa (2) Kenya (2); Tanzania (1); 

South Africa (2); Malawi (2)

Dates of Initiation

and Expected 

Final Report

May 2007 and

December 2010

July 2008 and

June 2012

No. of Volunteers 

to be Enrolled

980

(Enrollment completed 

in December 2008)

3,900
that need to be protected from for prioritizing development of Objective 5: Provision of training and

infection as well as how these design alternatives. infrastructure 

levels change with time. These To expedite the development and

studies are instrumental in opti- • In clinical trials of microbicides, a testing of microbicides at the highmizing microbicide formulations meaningful assessment of effec- est scientific and ethical standards,

and delivery systems and in tiveness and safety depends on the USAID strategic plan includes

defining the regimen needed for accurate reporting of product activities to establish, maintain, and

effective product use. These use and risk behaviors by the strengthen the appropriate training

studies are currently underway participants. Studies on how and infrastructure needed to confor gel formulations of Tenofovir and when products are used, and duct this research internationally.

and UC 781. on better methods for collecting These activities will also accelerate

sensitive information (including future access to microbicides in

• Other clinical studies to evaluate computer-assisted and new diverse populations and settings

potential biomarkers for safety communication technologies) relevant to USAID programs.

and effectiveness, distribution are underway.

and coating properties of gels in • The USAID program includes

women, and tolerance of new • Recruitment of appropriate par- site identification activities in

formulations in men are also ticipants is essential for trials to selected communities that, based

underway. assess safety and effectiveness of on the presence of clinical

new products. New techniques resources and high-risk populaObjective 4: Behavioral and social for identifying and reaching com- tions, might be appropriate sites

science research munities and individuals where for future clinical trials. A sysAs part of the USAID strategic trials can be most effectively tematic and multidisciplinary

plan, behavioral and social science conducted and where the bene- approach is used to involve local

studies provide unique data on the fit of conducting trials will be stakeholders in assessing and

factors that affect microbicide use greatest, are being investigated. preparing these potential sites

and acceptability, especially in and provides targeted training in

developing countries, and thus con- • Informed consent of participants research methods, laboratory

tribute to the better understanding is a cornerstone of conducting techniques, ethical review, data

of these products and their future clinical research. Achieving and analysis, and communications.

use in prevention programs. They maintaining informed consent in The intent is to build research

also provide key information to microbicide trials, however, is capacity (for example, to conduct

improve the clinical testing of challenging since trial participa- local HIV incidence studies) that

microbicides and to understand tion may continue for 12–24 can be successfully sustained in

the results of clinical trials. months, the intervals between the future to support microbiclinic visits may vary, and some cide and other health research

• Compliance with the recom- participants may be unduly moti- that benefits the community. 

mended regimen for product vated to participate by the

use is important if new microbi- increased access to health care • It is increasingly evident that

cides, regardless of their or the locally required level of there are many community and

inherent potency, are to be compensation. Both prospective national-level stakeholders who

effective in preventing HIV infec- and retrospective studies com- are not involved in microbicide

tion. Acceptability studies and paring different approaches and development in a technical

compliance/adherence data from materials are revealing what capacity but have significant

clinical trials are useful for works best. roles as community leaders,

improving product design and media specialists, policy makers,

14 | The USAID Strategic Plan for Microbicide Research and Development
and regulators. USAID supports

targeted training and development of information resources

in collaboration with the World

Health Organization and advocacy

groups to enhance community

awareness and stakeholder

input, and to strengthen clinical

studies and future microbicide

introduction. 

• USAID also supports activities

to ensure that after testing is

completed, introduction and

distribution of microbicides will

be expedited in the developingcountry populations where the

studies were conducted and

where the need is greatest. This

includes preparing for pre-introduction studies, manufacturing,

and procurement, as well as

addressing the policy and regulatory requirements for approval

and introduction of these products (see Section IX). 

Current Initiatives and Next-Generation Leads | 15

The USAID strategic plan for microbicide R&D is currently being 

implemented through cooperative agreements and/or technical collaboration

with a number of partners. These partners include, among others, the 

following organizations.

• Alliance for Microbicide Development

• CONRAD 

• Family Health International

• Global Campaign for Microbicides

• International Partnership for Microbicides

• PATH

• Population Council

• Centers for Disease Control and Prevention

• World Health Organization

These partners and collaborators also have a large number of subawardees

that are instrumental in the progress of these activities.
16 | The USAID Strategic Plan for Microbicide Research and Development

As part of the USAID strategic to be effective in preventing infec- product with complementary

plan for microbicide R&D, advanc- tion, and cellulose sulfate may mechanisms of action – for example,

ing the best next-generation leads actually have slightly enhanced one with a specific ARV and a

merits special attention, with con- infection. Because the reasons for more broadly acting attachment

sideration of the following goals. these disappointing results are still blocker such as a polyanion.

uncertain, they are being investigat- Polyanions are now less promising,

Pursuing new active agents ed with USAID support. They may so other potential combinations

Consistent with the USAID strategic include a lack of significant protective are under consideration. 

plan, which gives highest priority to activity in real use, a countervailing

supporting the most promising negative effect that obscured or In accord with the USAID research

microbicide leads, a large part of exceeded any protective effects, or priorities (see Section V) the current

the USAID microbicide budget has insufficient adherence to product USAID strategic plan is to continue

supported Phase IIb and III clinical use by trial participants to allow formulating and characterizing ARVs

studies in recent years. In contrast detection of a protective effect. that could be combined to yield

to the potential products that pre- Although a number of relevant more effective prevention, and

viously reached this stage of clinical inflammatory and other immuno- simultaneously be less susceptible

testing (e.g., Carraguard, cellulose logical responses have been to the selection or development of

sulfate, Savvy), the two trials that examined and not found to be viral resistance. Of most interest

are now ongoing (the CAPRISA problematic, it remains possible are single or combination ARVs

004 study with Tenofovir 1% gel that there are other parameters, that do not select for resistance to

and the FemPrEP study with such as those related to immune any ARVs currently used as theraTruvada) with support from USAID cell function, that are still unknown peutic drugs. Other reproductive

and others use specific antiviral but significant. health benefits are also desirable

agents (Tenofovir alone or in com- (e.g., preventing other STIs or

bination with emtricitibine) and As reflected by the ongoing USAID pregnancy), but these attributes may

unique delivery regimens (vaginally trials with Tenofovir gel and be less achievable with the specific

applied gel before and/or after Truvada, the next-generation focus ARVs alone and may require concoitus or an oral tablet) that are of USAID and others in the field is sideration of other classes of

intended to increase user accept- now largely on more-specific anti- agents to be used in combination

ability and compliance as well as retroviral (ARV) agents, including with ARVs if the latter are shown

product effectiveness. Tenofovir, a nucleoside reverse to be effective.

transcriptase inhibitor. Other

The earlier leads, including ARVs under investigation include Each USAID partner involved in

Carraguard and cellulose sulfate, UC 781 and MIV-150, which are the selection of preclinical and clinwere large-molecule, negatively- both non-nucleoside reverse tran- ical candidates has developed an

charged sulfated polysaccharides scriptase inhibitors, as well as algorithm for rationally evaluating

(polyanions) that blocked HIV other agents that prevent viral what is known about particular

attachment. Despite preclinical attachment and/or entry, e.g., by agents and for choosing the most

evidence of strong anti-HIV activity blocking key molecules such as promising candidates. In addition

and both preclinical and clinical evi- gp41, NCp7, or CCR5 receptors. to antiviral activity and inflammatodence of safety, in advanced clinical Initially, the USAID strategic plan ry or other safety parameters,

trials, Carraguard was not shown was to develop a combination there are many other relevant

VIII. The Strategic Plan for Advancing 

the Best Next-Generation Microbicide Leads
parameters to be considered in and retains drugs are also instru- Considering other 

these choices, including physico- mental for improving product non-ARV options

chemical properties that limit the design, dosing, and delivery, and for Given the challenges of current

possible options for product for- defining the instructions for prod- ARV-based leads, the possibility of

mulation, costs that will determine uct use. a microbicide that inactivates HIV

whether a product is viable for before attachment, or that blocks

USAID and other donor-assisted Reducing product cost attachment through a non-specific

programs, and access to the intel- The USAID strategic plan also pri- effect that is not subject to resistlectual property rights needed to oritizes next-generation microbicides ance, for example, remains

complete product development that will be inexpensive to manu- attractive and would merit investand ensure access. The selection facture and purchase, and whose ment if sufficiently promising. A

protocols in use by microbicide manufacturing can be transferred product in which resistance was

development researchers are simi- to developing-country settings. not a concern and that would be

lar but not identical, and efforts to This will enable the provision of a suitable for over-the-counter and

harmonize the resulting decisions, cost-effective and accessible micro- other wide-scale distribution withwhile fostering legitimate and use- bicide. Collection of data about out HIV testing would be

ful scientific debate, will continue. potential manufacturers and pre- significantly easier to provide and

liminary discussions regarding their protect more users. PRO 2000 (a

Developing new interest in microbicide production naphthalene sulfonate) gel, for

formulations for delivery are underway. which USAID supported some of

The USAID strategic plan also the preclinical characterization, is

prioritizes the development of Understanding and avoiding now the most advanced candidate

alternative delivery systems for the risk of resistance in this category. There are now

next-generation products. The significant challenges entailed clinical indications that PRO 2000

Although coitally-dependent gel in delivering ARV-based products might be at least partially effective,

application may be preferred by for HIV prevention also need to be and the results of further clinical

some users, options that are not clarified and addressed in much trials with this product are expectcoitally dependent and may or may greater detail. At present it is not ed in late 2009. Microbicides that

not be topical gels may be pre- clear how the use of these prod- simultaneously protect against

ferred by others. ARVs and other ucts, and particular active agents, other STIs, such as herpes simplex

drugs released from vaginal rings may increase the risk of selecting virus (HSV) and human papilloand barrier devices are being resistant virus, especially if infection mavirus (HPV) among others,

actively explored. Oral drugs, as has already occurred. This risk and/or against pregnancy may also

used in the FemPrEP trial with may require frequent testing of be attractive for many users. 

Truvada, are also of interest in the product users for infection status

context of preventing sexual trans- and highly provider-controlled or Supporting the 

mission of HIV. Especially when prescription-only distribution of next-generation pipeline

using ARVs for prevention of infec- these products. There are also Until a microbicide that is proven

tion, it is relevant to know what implications regarding the level of to be safe, effective, and acceptable

levels of drug are achieved in key adherence to proper use that will is available for regulatory approval

tissues and for what length of time. be needed for product safety. and introduction in developing

Agents and formulations that create These factors may significantly countries, it will be necessary to

a persistent barrier that protects impact the design of products, trials, continue supporting research and

between dosing or if a dose is and provision programs. Strategic development of the most promismissed could greatly enhance effec- combinations of agents that yield ing next-generation leads. There

tiveness. Pharmacokinetic data the highest barrier to resistance are promising candidates in the

indicating how the body absorbs merit more intense investigation. pipeline now, especially given the

Current Initiatives and Next-Generation Leads | 17
18 | The USAID Strategic Plan for Microbicide Research and Development

possibility of combinations and Continued and strategic targeting first microbicide product is shown

new delivery options, and a range of funds is essential to advance to be safe and effective enough to

of alternative leads is needed to these existing and potential leads be used in prevention programs,

ensure robust and cost-effective through clinical testing and the there will still be the need to

opportunities for microbicide subsequent product development develop more effective products

development in the future. steps if merited. Even when the and broaden the range of options.

As the necessary microbicide R&D microbicide introduction, distribu- Family Health International, the

continues, USAID is simultaneously tion, and implementation are Population Council, and the World

addressing critical policy and logis- reflected in the activities described Health Organization. The expertise

tical issues to introduce successfully below. Many of these initiatives of USAID and its partners is critical

a microbicide product in developing contribute to the success of ongo- for understanding the key issues

countries once a product has been ing preclinical and clinical product and cultural contexts that are

shown to be safe and effective. The R&D activities as well as strategi- involved in these developingmultiple social, cultural, economic, cally ensure access to these country settings. 

and political factors that will influ- products once they are available.

ence acceptance and use of this Targeting and engaging hidden or

new HIV prevention technology at Understanding behavior that hard-to-reach populations will be

the individual and community levels determines microbicide essential to plan introduction activare also being studied. USAID will acceptability and use ities effectively when a product is

continue to support behavioral and A microbicide will not prevent or available and to impact the epidemic

social science research on the spe- reduce HIV infection if it is not significantly. This research, including

cific factors that could encourage used. To have an impact on the the acceptability of different possior inhibit acceptance and use in HIV epidemic, it is essential to ble product characteristics (e.g.,

order to guide message develop- develop a microbicide that potential formulation, mode of delivery,

ment, product promotion, and users find acceptable and easy to duration of action, effects on other

uptake in the context of behavioral use. This is also a relevant factor STIs or pregnancy) also informs

choices made by individuals in rele- in the successful testing of microbi- the product R&D process. Results

vant communities. Other studies cides in clinical effectiveness trials. of this research are already conwill identify the necessary adjust- If participants are not willing to use tributing strategically to what a

ments in the service delivery the test product, the trial will be a successful microbicide will look like

environment, assess future marketing failure regardless of the inherent and how it will be introduced in

potential, and plan for programmatic effectiveness of the product. the future.

impact. USAID funding will also be Behavioral research studies that

used to optimize manufacturing address the circumstances in which Involving local communities

capacity in developing countries, a microbicide would be useful for in clinical research and

ensure the lowest possible costs HIV prevention, and the reasons an future introduction

for production, and support tech- individual would or would not use Involving civil society and local

nology transfer where possible. a microbicide in those circumstances, communities will be essential for

The breadth of these USAID are being conducted by a number the successful introduction of a

initiatives that are preparing for of USAID recipients, including microbicide. Even before the start

IX. The Strategic Plan and Accomplishments to Support

Introduction, Distribution, and Use of Microbicides
of clinical trials, significant community ent levels of microbicide use, in dif- Learning lessons from the

consultation and education about ferent personal circumstances, and introduction of other health

test products and procedures are with different levels of product products

needed to ensure that the potential effectiveness, as well as in combina- Given the extensive historical

value of the product being tested, tion with other prevention experience of USAID in the develand hopefully introduced in the behavior or with other prevention opment and introduction of health

future, is understood and supported technologies. Strategically, microbi- products and intervention programs

in the community. Local capacity cides may be most effective as part in developing countries, it is critical

building at trial sites is often needed of a “prevention package” of inter- to apply the lessons learned from

to conduct product testing, which ventions, and modeling is these experiences to microbicide

has broader beneficial impacts on a instrumental in understanding what introduction. To this end, the

community and significantly con- packages may work best in various Population Council, a key impletributes to the preparation for circumstances. These modeling menter with USAID of past

product introduction when possible. activities are also very important introduction programs for 

Community-level activities with for planning research and program reproductive health products, 

local media and with prevention investments, leveraging support has already convened a group of

advocacy groups (e.g., public health from other donors, and motivating experts in the fields of product

workers, women at risk, persons other stakeholders and efforts introduction and social marketing,

with HIV, or others) also contribute that will be needed for product clinical trials and product developto future introduction. USAID introduction. ment, and reproductive health and

recipients that conduct clinical HIV/AIDS to identify key features

testing of new microbicides must Developing regulatory that can guide microbicide introengage civil society and engender policies needed for product duction efforts. A future effort is

local community involvement as approval and distribution being planned to focus specifically

part of their efforts. With USAID With USAID support, the World on how microbicide introduction

support, the Global Campaign for Health Organization has conducted could be implemented in the conMicrobides works at this level to four international workshops in text of “prevention packages” that

create and conduct workshops and India, South Africa, and China that include other prevention interventraining and to develop educational have engaged national and local tions, and how to integrate

materials to ensure that both regulatory officials and other microbicide introduction with

research and future product intro- stakeholders from the region in existing HIV prevention and health

duction are conducted as ethically considering how a microbicide for programs (especially those that are

and equitably as possible. HIV prevention will need to be supported through PEPFAR), in

evaluated, approved, and intro- order to maximize impact on

Modeling the use and duced in their respective countries. reducing the epidemic overall. Also

impact of microbicides These workshops, which focus on planned is the development of a

Realistic and predictive models for the regulatory and policy require- logistical framework to define disthe potential impact of microbicides ments, organizational capacities, cretely the steps and timing of

on the HIV epidemic have been and logistical demands that will activities that need to take place

developed and refined as part of need to be addressed, have been once an effective microbicide is

USAID-supported activities with very productive to date. The out- available for introduction. This will

the Global Campaign for comes of these workshops are include the required activities and

Microbicides in collaboration with being organized for publication to timelines for regulatory approval,

the London School of Hygiene and ensure the maximum contribution pre-introduction studies, and 

Tropical Medicine. These models to future product introduction. mobilization of production and 

evaluate the effectiveness of differ- distribution capacity, as well as

Current Initiatives and Next-Generation Leads | 19
appropriate identification and messaging that is both consistent different types of microbicides was

preparation of communities for and appropriate for different coun- developed and distributed to

microbicide introduction and access. try-level stakeholders. developing-country manufacturers.

The responses were validated with

Facilitating communication Assessing and developing site visits and further assessment

between stakeholders in capacity for future manufac- of the most promising candidates.

microbicide introduction turing and distribution Additional information about 

and access Developing a microbicide that regulatory oversight and export

With support from USAID, an works will be fruitless if it cannot requirements was collected for

annual Microbicides Access Forum be manufactured and distributed the countries in which candidate

has been established by the for introduction and use in the manufacturers were located. The

International Partnership for countries where it is most needed. results of this successful activity

Microbicides (IPM). This Forum As part of USAID-funded activities are now being widely presented

facilitates information exchange conducted by IPM, Regulatory and published, and have not only

and planning for successful intro- Compliance Initiatives, Inc. assessed generated useful discussion, but

duction and scale-up of microbicides the worldwide capability for pro- also have stimulated the developfor use by women living in devel- duction of active agents and final ment and identification of

oping countries. IPM develops the microbicide products. The manu- additional manufacturing candidates

meeting agendas in consultation facturers of the microbicide as well. USAID has also supported

with other USAID-supported candidates and applicators that are the Population Council to conduct

partners (including the Population now in advanced clinical trials do intensive site visits and assessCouncil, the World Health not have the production capacity ments of manufacturing and

Organization, and the Global needed for introduction of these marketing candidates specifically

Campaign for Microbicides), as well products in developing countries. for the proprietary microbicide

as other stakeholders in this field. Moreover, the current manufactur- leads of the Population Council.

The most recent Forum in Mexico ing facilities for candidates being

City in August 2008 (1) provided tested are located in developed Focusing on the process and

an update on microbicide develop- countries and not in countries costs of future procurement

ment and timelines for access where the products are most and distribution

planning; (2) presented and dis- needed. Scaling up high-quality When the first microbicide

cussed recent activities and manufacturing capacity sufficient becomes available, who will pay for

research related to access, includ- for product launch will require it? Since there may not be a large

ing results from modeling studies; timely investment in process and highly profitable private-sector

and (3) created an opportunity to development and manufacturing market for microbicides that can

share information and facilitate col- facilities. Manufacturers in some subsidize products provided in

laboration among participants. developing countries, such as India, public-sector programs, the public

Participants identified several South Africa, and Brazil, could and not-for-profit sectors need to

important next steps including provide attractive options for low- be prepared to pay the full cost of

keeping country-level gatekeepers cost, high-volume manufacturing of buying and distributing this prodinformed of progress, identifying quality microbicides, and bringing uct. USAID has already organized

financing and technical cooperation production closer to demand may a major international conference

mechanisms, agreeing on realistic also reduce shipping and distribu- session to address this issue with

goals for introduction programs, tion costs, as well as regulatory representatives from multilateral

developing tools and guidance for burdens. To assess this potential donors (the World Bank and the

decision-makers to determine cri- capacity, a systematic survey that United Nations Population Fund),

teria for microbicide introduction detailed the technical specifications bilateral donors (the UK

in different settings, and developing required for the manufacture of Department for International

20 | The USAID Strategic Plan for Microbicide Research and Development
Development and USAID), and an ments, how their procurement ensure rapid purchase and distribuNGO (the International Planned contracts are managed, how the tion in public-sector programs

Parenthood Foundation), with addi- quantities purchased and shipped once a microbicide becomes availtional discussion by other donors are determined, how the recipients able. Some of the participants

(including the Joint United Nations are chosen, and finally, how the in- reported that the session provoked

Programme on HIV/AIDS and the country logistics are handled to important internal discussions that

Bill & Melinda Gates Foundation). ensure the intended distribution have already improved their readiEach participating organization and availability. The presentations ness to respond as soon as

addressed their decision-making illustrated the different approaches microbicides have regulatory

process for adding new products used by donors in selecting the approval and are requested for

to their portfolio, including their products in their portfolios as well country programs.

regulatory and registration require- as the critical steps needed to

Current Initiatives and Next-Generation Leads | 21

Once the research, development, tion is essential. In addition, the latory review procedures at global

and testing of a safe, effective, cost of the large, ongoing, multi-site and national levels that will miniacceptable, and affordable microbi- clinical trials will continue or mize the hurdles to licensing safe

cide are completed, it must be increase, especially in view of the and effective microbicides.

introduced in developing countries need to ensure that local HIV inci- Research and development of new

as quickly as possible. USAID’s dence rates are carefully evaluated and improved products may also

experience in pre-introductory before individual sites begin trials. continue since it is likely that addistudies, distribution and logistics Since it is very likely that additional tional and more effective products

management, capacity building, clinical testing of next-generation will be needed before a vaccine for

provider training, service delivery, product leads will be warranted, HIV becomes available.

community involvement, and social further investments will also be

marketing, positions the Agency necessary to ensure success in the With the regulatory approval of

to introduce microbicides and timely development and introduc- the first effective microbicide,

support their appropriate and tion of these products. greater resources will be needed

effective use. for product introduction activities

Beyond the next several years, and, eventually, for supporting the

USAID and its partners are uniquely USAID will continue to work with HIV prevention programs that will

able to undertake these essential partners to prepare for microbicide provide these products to the

multi-stakeholder efforts and will manufacturing and introduction in people who need them. The cost

work with the OGAC and other developing countries. Activities will of introducing and promoting the

USG agencies to introduce these focus on policies, procurement and use of effective new microbicides

new products into HIV/AIDS and financing, and logistics and distribu- in service delivery programs and in

reproductive health programs and tion networks within public and other delivery approaches outside

ensure their availability and use to private sectors. Countries will the health system will be substanreduce the risk of HIV infection need assistance to plan for the rel- tial – and critical to the success of

and AIDS in developing countries. evant information needs of diverse this new prevention option. In

audiences, including policymakers, addition, it is likely that some 

During the next several years, an service providers, community regulatory authorities will require

increased investment in activities members, and consumers. USAID post-marketing surveillance studies

to prepare for product introduc- funding will aid in developing regu- (Phase IV trials) to monitor side

X. Looking Forward Programmatically
effects that might only be seen To succeed in microbicide developafter thousands of women are ment, continued substantial funding

using these products. Long-term will be required until a safe and

studies on the impact of a micro- effective microbicide is discovered,

bicide on reducing HIV incidence tested, and introduced. The promand prevalence will also be needed. ising product leads, sound

strategies, and expanding research

capacity currently supported by

USAID will enable this success.

22 | The USAID Strategic Plan for Microbicide Research and Development
Current Initiatives and Next-Generation Leads | 23