Simple and Affordable Molecular Testing for
Tuberculosis
Request for Letters of Intent (LOI)
RULES AND GUIDELINES DOCUMENT
Bill & Melinda Gates Foundation
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INTRODUCTION
In the absence of an effective vaccine, the control of tuberculosis depends on detecting and treating
cases to limit disease transmission. Despite recent significant progress in development of new tools, the
diagnosis of tuberculosis remains problematic. Microscopy, which is poorly sensitive and cumbersome
to perform, remains the only widely-available test in most settings. As such, many cases are missed and
delayed detection is commonplace. Few patients in low-income settings have access to reference
laboratories where culture (which is slow) or conventional nucleic-acid amplification testing (NAAT)
(which is technically complex) might be performed.
Appropriate platforms and assays are needed which greatly increase access of high-sensitivity molecular
technologies, including reducing the cost and increasing the ability of these platforms to be used at
lower-level laboratories, or, ideally, outside of the laboratory setting in health centers.
PCR and other detection methods have been developed and commercialized to detect M. tuberculosis
sequences in processed clinical materials from which nucleic acids have been extracted. Though
commercial nucleic acid tests for tuberculosis have been available for nearly 20 years, they have had
little impact in settings where the prevalence of disease is high, primarily because of the cost of the test
and the technical complexity of processing the specimen and performing the assay. The operational
utility of recently-launched automated tuberculosis nucleic acid assay test with integrated sample
processing proved the feasibility of implementing molecular assays with appropriate design in peripheral
laboratories of disease-endemic countries. The Bill and Melinda Gates Foundation now seeks to support
the development of additional platforms and assays that have specific design characteristics that will
make them implementable in developing countries at low cost.
GOALS
We seek to support the creation of a validated, low-cost, nucleic-acid assay for clinical TB detection on
platforms capable of operation in rudimentary laboratories in low-resource settings. It is our intention
for these assays to be to created and validated for use within 24-36 months.
APPROACH
Program Structure:
The Gates Foundation provides funding to organizations and companies for the creation of products that
will support our global health goals. The goal of this funding is not to create profit for the foundation,
but rather to develop products and markets that will benefit our target populations and geographies.
Though we not fund or invest in companies with the intention of profiting, the Foundation does
structure agreements for project success, and does reserve rights to ensure products are available in the
market to our target populations at low cost. Further detail is provided in the Rules and Guidelines
section below.
This request will make use of a two-step application process:
Step 1: Interested parties will submit of a Letter of Intent to the Bill & Melinda Gates Foundation. A
“Letter of Intent” or LOI, is a short outline of the approach companies are proposing to address the
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problem, along with a proposed budget, and a description of institutional capabilities. There is a seven
(7) page limit on the LOI. A template will be provided for your institution to complete. Bill & Melinda
Gates Foundation staff and other experts will evaluate the LOIs. Those applicants who are eligible and
have projects of interest to the Foundation will be contacted directly and will be invited to submit a full
proposal. Letters of intent must be submitted electronically, using the forms and process described at
the following address:
http://zhenduan.gongyi.qq.com
Step 2: Institutions with successful LOIs will be invited by the Foundation to submit a full proposal.
Further details and instructions will be provided at that time.
Due to expected high volumes, the Bill & Melinda Gates Foundation will not provide individual critiques
or feedback on why LOIs were not selected;
It is our intention to solicit proposals from diagnostic developers to develop a TB assay on their platform
for use in low-resource laboratories. Low resource laboratories, such as those found in Health Centers,
have a limited amount of infrastructure available. The requirements listed in Table 1 reflect these
limitations. Additional detail on our target laboratories can be found in the Maputo declaration
(http://www.who.int/diagnostics_laboratory/Maputo-Declaration_2008.pdf), where we are targeting
the level 1 health clinic.
We intend to evaluate LOIs based on the capability of each institution, according to the criteria listed in
Table 1, and in the Selection Process section. We plan to select a sub-set of proposers for further
discussions, including on-site visits. Selection of a final awardee(s) will be subject to negotiation at the
end of the selection process. The foundation may select none, one, or more proposers as a result of
this request.
Selection Timeline:
Please note that all dates are subject to change.
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Wednesday, September 26, 2012: Final Request for Letters of Intent (LOI) released
Friday, December 14, 2012 Letters of Intent (LOI) due
February, 2013: Invitations for Full Proposals sent
April, 2013: Application deadline for full proposal
Project Activities/Proposal content
Letters of Intent (LOIs) submitted for consideration must clearly state the key challenges, technical and
otherwise, to the successful development of a diagnostic that meet the criteria in Table 1. The extent of
these activities should be appropriate to the level of development of your platform and your assay. A
brief work plan should be included which defines the activities envisioned to develop a tuberculosis
assay, the number and type of staff that could be dedicated to the work, and timelines and milestones.
To aid in our understanding and evaluation of your proposal, please budget for each objective for your
project separately. A regulatory plan is not required at this stage, however we would encourage you to
present your approach.
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A full description of your company and its institutional capacities should be included in the LOI, including
annual revenues, number of employees, physical assets, and brief corporate history. The status of
development of other assays developed or in development for the platform should be described. Please
also provide an overview of your company’s relevant background intellectual property, as well as
freedom to operate in the diagnostics space.
Some examples of projects that would be considered within the scope of this Program:
 Improvement of an existing assay for tuberculosis
 Development of a tuberculosis assay on an existing platform
 Development of sputum processing methods or automation to complement a platform
or assay
 Clinical trials for tuberculosis assays
Projects that would be considered outside the scope of this Program:
 Development of a new molecular platform
Applicants should indicate areas in which they do or do not have tuberculosis relevant capacity that is
likely to be required, including access to bacterial strains and types of well-characterized clinical
specimens. Please note that BL-2/3 capability may be required for TB sample processing and analysis;
this capability should be considered as part of your proposed team. Capacities to conduct appropriate
diagnostics clinical trials should also be noted. Proposals should include costs and plans for clinical trials.
The program is currently intended to complete within 24-36 months from start. We are interested in
accelerating the development of the product and will factor ability to accommodate this in with other
selection characteristics.
PLATFORM AND ASSAY CHARACTERISTICS
The envisioned product is primarily intended to be a case detection tool at lower peripheral level
laboratories. Expected cost of goods is critical, and work on a platform with expected consumable costs
above those listed in the minimal column will not be supported. Assay specifications will depend on the
specific technology, but some indicative characteristics are noted below. Applicants are not expected to
provide data addressing each of these features, but should do so when preliminary data exist. Where
data do not exist, please provide a rationale for how your platform or assay might perform for that
characteristic.
A detailed description of the technology should be included in the LOI that would allow estimation of
the likelihood of meeting many of these targets. Another section that details known or potential
obstacles should address any areas in which it is expected that the minimal criteria below will not be
met. In particular, we would like detailed descriptions of the following areas:
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Description of platform and assay technologies proposed for this application
Performance data for platform and related assays
Description of regulatory status of platform
Nucleic acid prep technologies utilized, and specific plans for sputum processing
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We would encourage you to provide data on your assay and platform in a manner that could be easily
compared with Table 1 below.
Table 1: Optimal and Minimal Product Characteristics for proposed tuberculosis diagnostic.
Characteristic
Optimal
Minimal
Cost of consumables (all) FOB
< 4 USD
< 8 USD
Diagnostic specificity
> 99 %
>97%
Reagent Kit stability
24m at 40oC, 70% humidity, incl.
transport stress (48h at 50oC)
12m at 30oC, 70% humidity, incl.
transport stress (48h at 50oC)
Sample preparation and Assay
processing (total steps)
Integrated
Thermal Tolerance of
Platform/Assay
Operation between 15°C and 40°C
Minimal sample processing; no
more than 3 – 5 steps (requiring
operator intervention )
Operation between 15°C and 35°C
Time to Market
≤ 24 Months
≤ 36 Months
Time-to-result
< 1 hour
<2 hours
Additional equipment required
None
Minimal (e.g. Heat block)
Analytic sensitivity
< 102 cfu/ml
< 103 cfu/ml
Analytic specificity
No cross reactivity with other
organisms including nontuberculous mycobacteria(NTM)
No cross reactivity with other
organisms including nontuberculous mycobacteria(NTM)
Biosafety
No need for biosafety cabinet, and
direct disposal of consumable
No need for biosafety cabinet, and
autoclaved consumable
Controls
Internal full-process positive
control and negative controls
External controls
Cost of instrumentation
< 5,000 USD
< 10,000 USD
Diagnostic sensitivity
> 98% smear-positive and 80%
smear-negative patients
95% of smear-positive and 65%
smear-negative patients
Drug resistance screening
Rifampin drug resistance testing
via a separate cartridge with
additional consumable cost (Reflex
Testing)
Electronics and data analysis
Detection of rifampin, isoniazid,
and fluoroquinolone resistance
testing via a separate cartridge
with additional consumable cost
(Reflex Testing)
Integrated
Instrumentation
Single device
Sample prep + amp/detection
Power
None, optional battery or solar
operation
110-220V AC current; DC power
with rechargeable battery lasting
Separate computer required
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Quantitation
Semi-quantitative
up to 8 hours of testing
Qualitative
Reagent integration
All reagents in consumable
< 4 external reagents
Result capturing &
documentation | Data display
Electronic and printed, wireless
transmission capable s).
Electronic
Sample type
Sputum
Sputum
Throughput
> 48 Samples per day,
asynchronously
12 tests per 8-hour day
Training & education needs
<1/2 day, healthcare worker
<1 day, trained laboratory
technician
Goal of Test
Diagnosis of active pulmonary TB
in adults and children for the
purpose of treatment initiation;
diagnosis of MDR TB by diagnosis
of drug resistance to rifampin,
isoniazid and fluoroquinolone;
Liquid culture
Diagnosis of active pulmonary TB
in adults for the purpose of
treatment initiation
Equipment
Small, portable or hand-held
device
Small, table-top device; portable
device optional
Additional 3rd party consumables
None
None, except for sample collection
Cold Chain
None required at any point in
supply chain or storage
None required at any point in
supply chain or storage
Clean Water Requirements
None
None
Duration of valid sample (time
from taking sample to insertion
into device)
2 hours without refrigeration
If running samples sequentially, 5
minutes; if batching without
random access, 2 hours
Waste/disposal requirements
Disposal by incineration of
infectious disease materials;
simple trash for other materials
Service/Maintenance
No annually scheduled preventive
maintenance required; device has
capability to send an alert or to be
detected remotely when it is not
functioning properly. Mean time
to failure of at least 12 months; 18
months preferred
Incineration of infectious disease
materials; recyclable or
compostable plastics and
consumables for other materials
No on-site service and
maintenance required; broken
devices can be swapped with
replacement device; device has
capability to send an alert or to be
detected remotely when it is not
functioning properly. Software
updates can be pushed out
remotely over GSM and data
networks. Mean time to failure of
Reference Test
Liquid culture
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18 months
Calibration
None required
Minimal user calibration required
Test/platform
size/footprint/Portability
Small, portable device (<2 kg) or
handheld analyzer
Small, table-top analyzer or
portable device (<5 kg)
Regulatory requirements
Manufactured pursuant to GMP,
ISO 13485:2003 certified and
authorized for use by a regulatory
authority that is a member of the
Global Harmonization Task Force
(GHTF); registered for in vitro
diagnostic use.
Simple test menu, integrated LCD
screen; simple key pad or touch
screen.
Full data export over mobile
phone network (data transmission
can automatically select between
GPRS or more advanced networks
and GSM, based on available
coverage). GPRS should be able to
utilize the internet File Transfer
Protocol (FTP) to transmit data.
Data transfer should be initiated
every 6 to 12 hours automatically
by the analyzer. Data can be
exported in a format compatible
with HL7 standards, where
appropriate. Instrument tracks
and transmits QA data over time
(e.g. identify shifts or trends).
Manufactured pursuant to GMP,
ISO 13485:2003 certified and
authorized for use by a regulatory
authority that is a member of the
Global Harmonization Task Force
(GHTF); registered for in vitro
diagnostic use.
Simple test menu; integrated LCD
screen; simple key pad or touch
screen
Full data export over mobile
phone network
User Interface
Data Export (for External Quality
Assurance)
ELIGIBILITY
This request is intended to survey and engage with Chinese diagnostics companies. We encourage
sharing this document with other Chinese companies that may have relevant capabilities.
PROJECT SUPPORT
The terms of funding, amount, and payment schedule will be determined through negotiations with the
foundation. It is expected that each applicant would be able to demonstrate the amount of financial or
in-kind support that they would be able to commit toward the development process, determined not
only by the availability of existing resources but also by the potential commercial value of the resulting
product(s). The Gates Foundation intends to provide direct financial support for assay, and (to a limited
degree) platform development, analytic testing materials, clinical specimens, trial capacity, and
analytics. We understand that many commercial entities may not have internal expertise or resources
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for specimens and clinical trial capacity for TB, we would encourage you to identify partners, and are
willing to help identify partners in these areas, if required.
As the price of the assay and instrument platform will be critical to adoption and utilization by
developing countries, we are open to approaches to defer capital expenses and other investments as a
means to lower Cost of Goods Sold (COGS). We would therefore suggest inclusion of different options in
your proposal and how they may impact end-user costs or other critical parameters. This might include
options for the following:
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Advance market commitments
Capital investment to reduce manufacturing costs
Initial platform or assay subsidies
Proposers may also propose other approaches to lowering COGS.
SELECTION PROCESS
Awardees will be selected primarily on the overall likelihood of success, including:
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Strength and clarity of the proposal
Judged ability of the testing platform to conform with user requirements including, importantly,
estimated cost of goods of the envisioned product specification.
Stage of platform and test development, and expected times to market
Extent of preliminary data demonstrating the performance of hardware, reagents and
consumables
Financial and managerial soundness of the company and commercial attractiveness of the core
technology
Flexibility of the technology and capacity for menu expansion
Expertise of the applicant company, and quality and range of current product line
RULES AND GUIDELINES
A. Application Instructions and Review Process
Letters of Intent written in response to this request should be submitted no later than Friday, December
14, 2012. The Bill & Melinda Gates Foundation will evaluate each LOI using the criteria listed above. All
applicants will be contacted directly by the Foundation, and those who submitted proposals found to be
of specific interest will be invited to enter into further discussions by teleconference or face-to-face
meetings. All applicants will be notified by email in a timely manner of any change to the dates for
notification and proposal deadline. All dates are subject to change.
The foundation may use external reviewers to assess the merit of LOI; however, final selection decisions
will be made by the foundation.
An invitation to submit a proposal does not guarantee that the foundation will award a grant to the
applicant. The Foundation may amend or cancel this request at any time.
B. Allowable Costs
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Grant funds may be used for the following costs: personnel, necessary travel, supplies, contracted
services, sub-grants, and consultants. Please provide budget estimates according to these categories.
Partial or full support for equipment may be requested subject to the circumstances described below.
Please provide budget estimates according to these categories.
Equipment: Use of any equipment purchased with grant funds is limited by law to charitable purposes
for the depreciable life of the equipment. Please note that for many non- U.S. entities, U.S. tax law
considerations may affect whether the Bill & Melinda Gates Foundation will permit purchase of
equipment with a depreciable life that is greater than the grant period being requested. In such cases,
leasing would be preferable.
The Bill & Melinda Gates Foundation does not provide for indirect costs to for-profit organizations.
Please review the foundation’s indirect cost policy at
http://www.gatesfoundation.org/grantseeker/Documents/Indirect_Cost_Policy.pdf.
C. Privacy Notice
To help The Bill & Melinda Gates Foundation staff in their evaluation and analysis of projects, all
proposals, documents, communications, and associated materials submitted to the Bill & Melinda Gates
Foundation (collectively, “Submission Materials”) will become the property of the Bill & Melinda Gates
Foundation and may be subject to confidential external review by independent subject matter experts
and potential co-funders in addition to analysis by the Bill & Melinda Gates Foundation staff. Please
carefully consider the information included in the Submission Materials. If you have any doubts about
the wisdom of disclosure of confidential or proprietary information, the Bill & Melinda Gates Foundation
recommends you consult with your legal counsel and take any steps you deem necessary to protect your
intellectual property. You may wish to consider whether such information is critical for evaluating the
submission, and whether more general, non-confidential information may be adequate as an alternative
for these purposes.
We respect confidential information we receive. Nonetheless, notwithstanding your characterization of
any information as being confidential, the Bill & Melinda Gates Foundation may publicly disclose all
information contained in Submission Materials to the extent as may be required by law and as is
necessary for potential co-funders and external reviewers, such as government entities, to evaluate
them and the manner and scope of potential funding consistent with appropriate regulations and their
internal guidelines and policies.
D. Warranty
By providing any Submission Materials, the sender warrants the Bill & Melinda Gates Foundation that
they have the right to provide the information submitted. Applicants with questions concerning the
contents of their Submission Materials may contact the Bill & Melinda Gates Foundation at:
Chinadx@gatesfoundation.org.
E. Intellectual Property
The Bill & Melinda Gates Foundation requires that you agree to use good faith efforts to conduct and
manage the research, technologies, information and innovations involved in the Project in a manner
that enables (a) the knowledge gained during the Project to be promptly and broadly disseminated, and
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(b) the intended product(s) to be made available and accessible at reasonable cost to the developing
countries of the world. The foundation refers to this as “Global Access.”
As part of the foundation’s review and evaluation of each full proposal, due diligence will be conducted
with respect to each participant’s ability and commitment to manage intellectual property in a manner
consistent with the stated scientific and charitable goals of the Bill & Melinda Gates Foundation. Due
diligence activities may include inquiry into an applicant’s:
1) Freedom to operate (FTO) and ability to freely use and acquire needed background technology;
2) Commitment to promote the utilization, commercialization and availability of inventions for
public benefit in developing countries
In order to facilitate this due diligence process applicants are encouraged to provide information with
respect to the items above in their submission materials.
Applicants are also expected to make new information and materials known to the research and medical
communities in a timely manner through publications, web announcements, progress reports to the
foundation, and other appropriate mechanisms. Moreover, a condition for the award of a grant may be
the grant of certain sub-licensable intellectual property rights to the Bill & Melinda Gates Foundation.
Such a requirement may be made if it is determined that such rights are the best way to ensure that the
Global Access requirements will be met. These concepts may be discussed at some length with the
applicants invited for further discussions, and will be addressed (to the extent appropriate) within each
final grant agreement. The Global Access Strategy will also include provisions defining these concepts.
RESEARCH ASSURANCES
The Bill & Melinda Gates Foundation will require that for each venue in which any part of the project is
conducted (either by your organization or a subgrantee or subcontractor) all legal and regulatory
approvals for the activities being conducted will be obtained in advance of commencing the regulated
activity. The foundation will further require you to agree that no funds will be expended to enroll human
subjects until the necessary regulatory and ethical bodies’ approvals are obtained.
A. Research Involving Human Subjects.
You agree that no funds will be expended to enroll human subjects in any research project subject to
Institution Review Board (IRB) or independent ethics committee (IEC) approval until such approval has
been obtained for each site.
B. Clinical Trials
A condition of this grant is your agreement that the appropriate Institutional Review Boards (“IRBs”) and
ethical committees will review and approve the clinical protocols prior to trial initiation. You further
agree to conduct clinical trials associated with the project under the generally accepted principles of
“Good Clinical Practices” as defined by the International Conference on Harmonization (ICH) E-6
Standard, the United States Food and Drug Administration (FDA) or the European Agency for the
Evaluation of Medicinal Products (EMEA), as applicable. You acknowledge and agree that, as between
you and the foundation, you take and will have full responsibility for all compliance, data safety,
monitoring, and audit requirements of the relevant regulatory agencies, both for yourself and all other
sites included in the project, including those activities conducted through subgrants, subcontracts or
other collaborative efforts. You acknowledge and agree that any activities by the foundation as the
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grantor funding the Project, including its review of the Proposal or suggested modifications to the
Project, does not modify the provisions of this paragraph or constitute the basis for any claim by you
against the foundation.
C. Coverage for all Sites
You agree that for each venue in which any part of the Project is conducted (either by your organization
or a subgrantee or subcontractor) all legal and regulatory approvals for the activities being conducted
will be obtained in advance of commencing the regulated activity. You further specifically agree that no
funds will be expended to enroll human subjects until the necessary regulatory and ethical bodies’
approvals are obtained.
D. Regulated Activities
The coverage requirements set forth in the preceding paragraph include but are not limited to
regulations relating to: research involving human subjects; clinical trials, including management of data
confidentiality; research involving animals; research using substances or organisms classified as Select
Agents by the U.S. Government; use or release of genetically modified organisms; research use of
recombinant DNA; and/or use of any organism, substance or material considered to be a biohazard,
including adherence to all applicable standards for transport of specimens, both locally and
internationally, as appropriate. As applicable, regulated activities and their documentation are to be
conducted under the applicable international, national, and local standards. Documentation of research
results should be consistent with regulations and the need to establish corroborated dates of invention
and reduction to practice with respect to inventions where this is relevant.
E. Institutional Review Board (IRB) Approval
You agree to obtain the review and approval of all final protocols by the appropriate IRBs and ethical
committees prior to enrollment of the first human subject and when using human material. A similar
provision applies to Institutional Animal Care and Use Committee approval of studies involving animals,
and Institutional Biosafety Committee for biohazards and recombinant DNA. You agree to provide
prompt notice to the foundation if the facts and circumstances change regarding the approval status of
the IRBs or ethical committees for any final protocol(s).
F. Provision of Care for Human Subjects Research
In keeping with “Good Clinical Practice” standards, you will disclose to subjects and the IRBs what care
and/or referrals will be available through participation in the study. Institutional policies regarding what
care will be provided to personnel who are injured as a result of their work on the Project should
similarly be developed, approved and implemented with notice to the employees.
G. Use of Animals in Research
You agree to be responsible for the humane care and treatment of animals in projects supported in part
or whole by Gates Foundation funds; and to adhere to the official guidelines for animal research
applicable in the country and locality where the trial is being conducted. No grant funds may be
expended on studies involving animals until all requisite approvals are in place, and notification to that
effect has been provided to the foundation. For purposes of this provision, an “animal” is defined as any
live, vertebrate animal used or intended for use in research, research training, experimentation,
biological testing or for related purposes. In the case of multi-national collaborations, the standards of
each country may be followed, as long as (i) differences do not interfere with the design and analysis of
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the Project, and (ii) regulations in your institution and host country do not conflict with the management
of the Project.
You agree to take responsibility for compliance of all subgrantees or subcontractors (if any) with the
appropriate animal welfare laws, rules and regulations. You must report annually as a part of your
progress report that the activities are being conducted in accordance with applicable laws in each
respective venue (e.g., U.S. grantees must use the U.S. Public Health Service standards. Non-U.S.
grantees may cite national laws or the CIOMS International Guiding Principles for Biomedical Research
Involving Animals (see http://www.cioms.ch/publications/guidelines/1985_texts_of_guidelines.htm) if
there is not a relevant national standard.
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