2020 NCATS ASPIRE Reduction-to-Practice Challenge

• SUBJECT OF THE CHALLENGE
• SUMMARY OF NCATS ASPIRE CHALLENGES
• SUMMARY OF NCATS ASPIRE REDUCTION-TO-PRACTICE CHALLENGE
• DATES AND DEADLINES
• THE IC'S STATUTORY AUTHORITY TO CONDUCT THE CHALLENGE
• RULES FOR PARTICIPATING IN THE CHALLENGE
• SUBMISSION REQUIREMENTS AND TEMPLATE
• THE PRIZE
• BASIS UPON WHICH SUBMISSIONS WILL BE EVALUATED AND WINNERS WILL BE SELECTED

SUBJECT OF THE CHALLENGE

NCATS has recently established the development of A Specialized Platform for Innovative Research Exploration (ASPIRE) to aid in the discovery and development of novel and effective treatments, while at the same time making the process faster and more cost-effective, with a particular focus on pain, OUD and overdose as part of the the Helping to End Addiction Long-term^SM Initiative, or NIH HEAL Initiative^SM.  The NCATS ASPIRE Program aims to develop and integrate automated synthetic chemistry, biological screening and artificial intelligence approaches in order to significantly advance our understanding of the relationship between chemical and biological space and enable further access into biologically-relevant chemical space. The ASPIRE platform will utilize currently available knowledge to develop innovative algorithms and predict and synthesize novel structures capable of interacting with specific targets; enable small-scale synthesis of the predicted molecules; and incorporate in-line, rapid biological testing of the molecules. Any new data obtained through this process would then be fed back into the system to further improve design, synthesis and biological characteristics of molecules.

Over 25 million people in the United States experience pain every day (2012 National Health Interview Survey data) and need safe, addiction-free treatments to alleviate their suffering.  This clinical demand is of tremendous importance given that overprescribing of opioids for managing acute and chronic pain has fueled the current epidemic of opioid use disorder and overdose deaths, and the effectiveness of opioids for long-term pain management is being questioned.  Safe, effective, and non-addictive drugs (small molecules and biologics) to treat pain, mitigate addiction and reverse overdose are key to addressing the opioid crisis.  Given failures and limitations of previous drug development efforts, drugs that recognize novel targets, have novel structures, and can be identified in human-based, physiologically relevant in vitro systems are needed.  To further advance the NCATS ASPIRE Program and build on the innovations of the ASPIRE Design Challenges, and reward and spur innovative solutions to the development of new drugs for pain, addiction, and overdose, NCATS is issuing this Reduction-to-Practice Challenge to highly collaborative innovators interested in developing working prototypes of novel approaches that would lead to efficacious and non-addictive pain treatments and/or novel treatments for addiction and overdose.

The ultimate goal of the NCATS ASPIRE Program under the HEAL Initiative is the development of a platform that a wide spectrum of scientists can use to advance their translational science relevant to development and preclinical testing of new and safer treatments of pain, OUD, and overdose. Further, it is essential that the approach developed in this phase is applicable to any translational problem.

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SUMMARY OF NCATS ASPIRE CHALLENGES

The National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH), is inviting novel solutions for the Reduction-to-Practice Challenge for the NCATS A Specialized Platform for Innovative Research Exploration (ASPIRE) Program. The overall goal of the NCATS ASPIRE Challenges is to reward and spur innovative and catalytic approaches towards solving the opioid crisis through development of: (1) novel chemistries; (2) data-mining and analysis tools and technologies; and (3) biological assays that will revolutionize discovery, development and preclinical testing of next generation, safer and non-addictive analgesics to treat pain, as well as new treatments for opioid use disorder (OUD) and overdose. The first phase of these prize competitions was implemented through a suite of concurrent companion design challenges that comprised a separate challenge in each of four areas: chemistry database, electronic laboratory knowledge portal for synthetic chemistry, algorithms, and biological assays; and an additional challenge for a combined solution to at least two challenge areas. For this first phase, innovators submitted designs, not final products or prototypes. Details about the winning submissions to the 2018 ASPIRE Design Challenges can be found at https://ncats.nih.gov/aspire/challenges.

In this second phase, the follow-up reduction-to-practice challenge, the goal is for an open competition to integrate the best designs for a chemistry database, electronic laboratory knowledge portal for synthetic chemistry, algorithms, and biological assays into a single comprehensive platform. Innovators should invoke further scientific and technological development of a comprehensive and integrated solution for the development of new treatments for pain, opioid use disorder and overdose. Innovators design and then demonstrate their integrated solutions and working prototypes, from which winners will be selected.

The NCATS ASPIRE Challenges are part of the of the the Helping to End Addiction Long-term^SM Initiative, or NIH HEAL Initiative^SM to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative will bolster research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the the initiative is available at: https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative.

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SUMMARY OF NCATS ASPIRE REDUCTION-TO-PRACTICE CHALLENGE: Development of a Comprehensive Integrated Platform for Translational Innovation in Pain, Opioid Use Disorder and Overdose

The goal of this Challenge is to combine the best solutions and develop a working platform that integrates four component areas: Integrated Database, Electronic Synthetic Chemistry Portal, Predictive Algorithms and Biological Assays. The first stage of this Challenge requires submission of a plan for the reduction-to-practice of a platform that integrates the four component areas into a comprehensive solution. The second stage of this Challenge requires the construction and development of a working prototype of this integrated platform. The third stage of this Challenge involves independent testing of the working prototype. In this Challenge, the functionality and degree of integration of the components in the integrated platform/solution will be evaluated. It is anticipated that successful teams for this Challenge will consist of large, multi-disciplinary groups with expertise in all four component areas.

Component Area 1 relates to the development of an open source, controlled access database that incorporates all currently available chemical, biological and clinical data of known opioid and non-opioid based analgesics, drugs of abuse, and drugs used to treat drug abuse.

Component Area 2 relates to the development of a next-generation open source electronic lab notebook (eLN) that collects, organizes and analyzes data relevant to the chemical synthesis and analyses of known opioid and non-opioid-based analgesics, drugs of abuse and molecules used to treat drug abuse into an electronic laboratory knowledge portal for synthetic chemistry (electronic synthetic chemistry portal; eSCP). 

Component Area 3 relates to the development of open source, advanced machine learning algorithms that would facilitate the discovery of novel, efficacious and non-addictive analgesics and/or treatments for drug abuse by utilizing the data collected in open source databases (Component Area 1), eSCPs (Component Area 2), and biological assays (Component Area 4).

Component Area 4 relates to the development of novel, physiologically relevant biological assays that accurately replicate the safety profile and effectiveness of existing drugs to treat addiction and/or overdose, and that can be reliably used in predictive risk assessments of new analgesics or drugs to treat addiction and/or overdose; and/or be able to anticipate the degree of addictiveness of an analgesic prior to clinical testing.

It is anticipated that this Challenge would require large, multi-expert teams. These teams may be assembled from the innovators from the 2018 Design Challenge areas and others who did not participate in the 2018 Design Challenges. All winners of the 2018 ASPIRE Design Challenges are highly encouraged to participate in this ASPIRE Reduction-to-Practice Challenge. Winners of the 2018 ASPIRE Design Challenges may choose to work with other winners from other Challenge areas or to find additional, new collaborators. All submissions, including those from the winners of Challenge 5 from the ASPIRE Design Challenges must propose plans for a solution that integrates all four challenge areas into a comprehensive platform.

Evaluation criteria that judges and technical reviewers will be asked to address are specified below.

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DATES AND DEADLINES

Stage 1: Planning Comprehensive Integrated Platforms

Challenge begins: November 30, 2020 
Submission period: November 30, 2020-February 28, 2021 
Judging period: March 1-31, 2021 
Winners announced: April 2021

Plans for Integrated Platforms must be submitted to NCATSASPIREChallenge@mail.nih.gov by 5:00 pm Eastern Time on February 28, 2021.

The Reduction-to-Practice stages will occur from November 2020 to July 2022

Stage 2: Prototype Development and Milestones Delivery

First milestone delivery and site visits: June-August 2021

Second milestone delivery and site visits: January-April 2022

Third milestone delivery: July 2022

Stage 3: Prototype Delivery, Independent Testing and Validation

Delivery of prototypes for validation and testing by one or more NCATS-designated laboratories: July – September 2022

Winner and runner-up announced: September 2022

FOR FURTHER INFORMATION CONTACT Dobrila D. Rudnicki, Ph.D., NIH, 301-594-2080. dobrila.rudnicki@nih.gov or send an email to NCATSASPIREChallenge@mail.nih.gov

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THE IC'S STATUTORY AUTHORITY TO CONDUCT THE CHALLENGE

The main mission of NCATS is to coordinate and develop resources that leverage basic research in support of translational science and to develop partnerships and work cooperatively to foster synergy in ways that do not create duplication, redundancy, and competition with industry activities (42 USC 287(a)). In order to fulfill its mission, the NCATS supports projects that will transform the translational process so that new treatments and cures for diseases can be delivered to patients faster by understanding the translational process in order to create a basis for more science-driven, predictive and effective intervention development for the prevention and treatment of all diseases. The NCATS is also conducting this Challenge under the America Creating Opportunities to Meaningfully Promote Excellence in Technology, Education, and Science (COMPETES) Reauthorization Act of 2010, 15 U.S.C. 3719 (LINK). In line with these authorities, this Challenge will lead to innovative prototypes for developing technology to revolutionize discovery, development and preclinical testing of new and safer treatments of pain, OUD, and overdose; the result will be generalizable tools that will be widely available to fill longstanding gaps that have impeded the marriage of basic and translational sciences, especially in the field of automated and synthetic chemistry.

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RULES FOR PARTICIPATING IN THE CHALLENGE

NCATS refers to participants in the NCATS ASPIRE Challenges as “innovators” because all solutions will require highly innovative approaches to achieve success. Innovators may be individuals, 18 years of age or older, participating singly or as part of one or more teams. Teams are not limited in the number of members. Each team must designate a lead who must be a U.S. citizen or permanent resident who is responsible for all correspondence regarding this Challenge. Teams may also merge, collaborate, subdivide, or otherwise organize themselves and their members as needed to prepare a solution to submit to this Challenge. Innovators may also be entities, provided they are incorporated in and maintain a primary place of business in the United States. For purposes of this announcement, “innovator” refers to a participating single individual, a participating team, or a participating entity.

1. To be eligible to win a prize under this challenge, an innovator (whether an individual, team of individuals, or entity)—
   • Shall have complied with all the requirements set forth in this announcement;
   • Shall be 18 years of age or older at the time of this announcement;
   • In the case of a private entity, shall be incorporated in and maintain a primary place of business in the United States, and in the case of an individual, whether participating singly or in a group, shall be a citizen or permanent resident of the United States. However, non-U.S. citizens and non-permanent residents can participate as a member of a team that otherwise satisfies the eligibility criteria. Non-U.S. citizens and non-permanent residents are not eligible to win a monetary prize (in whole or in part). Their participation as part of a winning team, if applicable, may be recognized when the results are announced.
   • May not be a Federal entity or federal employee acting within the scope of their employment;
   • May not be an employee of the Department of Health and Human Services (HHS, or any component of HHS) acting in their personal capacity;
   • Who is employed by a federal agency or entity other than HHS (or any component of HHS), should consult with an agency Ethics Official to determine whether the federal ethics rules will limit or prohibit the acceptance of a prize under this challenge;
   • May not be a judge of the challenge, or any other party involved with the design, production, execution, or distribution of the Challenge or the immediate family of such a party (i.e., spouse, parent, stepparent, child, or stepchild). 
2. Federal grantees may not use Federal funds from a grant award to develop their Challenge submissions or to fund efforts in support of their Challenge submissions.
3. Federal contractors may not use Federal funds from a contract to develop their submissions or to fund efforts in support of their submission.
4. Submissions must not infringe upon any copyright or any other rights of any third party.
5. By participating in this Challenge, each innovator agrees to assume any and all risks and waive claims against the Federal government and its related entities (as defined in the COMPETES Act), except in the case of willful misconduct, for any injury, death, damage, or loss of property, revenue, or profits, whether direct, indirect, or consequential, arising from participation in this Challenge, whether the injury, death, damage, or loss arises through negligence or otherwise.
6. Based on the subject matter of the Challenge, the type of work that it will possibly require, as well as an analysis of the likelihood of any claims for death, bodily injury, property damage, or loss potentially resulting from Challenge participation, no innovator participating in the Challenge is required to obtain liability insurance or demonstrate financial responsibility in order to participate in this Challenge.
7. By participating in this Challenge, each innovator agrees to indemnify the Federal government against third party claims for damages arising from or related to Challenge activities.
8. An innovator shall not be deemed ineligible because the individual or entity used Federal facilities or consulted with Federal employees during the Challenge if the facilities and employees are made available to all individuals and entities participating in the Challenge on an equitable basis.
9. By participating in this Challenge, each innovator grants to the NIH an irrevocable, paid-up, royalty-free nonexclusive worldwide license to reproduce, publish, post, link to, share, and display publicly the submission on the web or elsewhere. Each innovator will retain all other intellectual property rights in their submissions, as applicable.
10. NIH reserves the right, in its sole discretion, to (a) cancel, suspend, or modify the Challenge, and/or (b) not award any prizes if no entries are deemed worthy.
11. Each innovator agrees to follow all applicable federal, state, and local laws, regulations, and policies.
12. By participating in this Challenge, each innovator warrants that he or she is the sole author or owner of, or has the right to use, any copyrightable works that the submission comprises, that the works are wholly original with the innovator (or is an improved version of an existing work that the innovator has sufficient rights to use and improve), and that the submission does not infringe any copyright or any other rights of any third party of which the innovator is aware. To receive an award, innovators will not be required to transfer their intellectual property rights to NIH, but innovators must grant to the federal government a nonexclusive license to practice their solutions and use the materials that describe them. This license must grant to the United States government a nonexclusive, nontransferable, irrevocable, paid-up, royalty-free license to practice or have practiced for or on behalf of the United States throughout the world any invention made by the innovators that covers the submission. In addition, the license must grant to the federal government and others acting on its behalf, a fully paid, nonexclusive, irrevocable, worldwide license in any copyrightable works that the submission comprises, including the right to reproduce, prepare derivative works, distribute copies to the public, and perform publicly and display publicly said copyrightable works. To participate in the Challenge, each innovator must warrant that there are no legal obstacles to providing the above-referenced nonexclusive licenses of innovator’s rights to the federal government.
13. Each innovator must comply with all terms and conditions of these rules, and participation in this Challenge constitutes each such innovator’s full and unconditional agreement to abide by these rules. Winning is contingent upon fulfilling all requirements herein.
14. By participating in this Challenge, each innovator agrees to allow NCATS to publicly display (e.g., on web sites) solution abstracts, as submitted by innovators in the submission package.
15. By participating in this Challenge, each innovator assures NCATS that any data used for the purpose of submitting an entry for this Challenge, were obtained legally through authorized access to such data.

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SUBMISSION REQUIREMENTS AND TEMPLATE

Details on submission requirements for Stage 1 are provided below. Details on submission requirements for Stage 2 of this Challenge will be available to Stage 1 winners no later than 30 days after the Stage 1 winners are announced. Details on submission requirements for Stage 3 of this Challenge will be available to Stage 2 winners no later than 30 days after Stage 2 winners are announced.

Instructions for submission for Stage 1: Please format the submission using the Submission Template and submit it to NCATSASPIREChallenge@mail.nih.gov as a PDF. Brief instructions on the submission process can be found below. Detailed instructions are provided in the submission template.

Each submission for Stage 1 requires a complete “Submission Package.” The Submission Package includes a Cover Page (up to 1 page), a written proposal (up to 12 pages) that describes the prototype, qualifications statements (up to 5 pages each), and references (up to 1 page). Detailed instructions on the content of the Submission Package can be found in the submission template.

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THE PRIZE

Amount of the Prize; Award Approving Official. 

The total prize purse is $2,875,000. Prize amounts at each stage for each winning innovator are below. As stated in the Rules for Participating in the Challenge, “innovator” refers to a participating single individual, a participating team, or a participating entity.

Stage 1: Planning: Up to $120,000 per innovator (maximum of 5 innovators). Only the winners of Stage 1 will be invited to participate in Stage 2 of the Challenge.

Stage 2: Prototype Development and Milestones Delivery: Up to four (4) innovators will receive $150,000 upon completion of Milestone 1. Up to three (3) innovators will receive $200,000 for achievement of Milestone 2 and will advance to Stage 3 after completion of Milestone 3. Only the winners of Stage 2 will be invited to participate in Stage 3 of the Challenge.

Stage 3: Prototype Delivery, Independent Validation and Testing: Innovators must successfully complete Milestone 3 before a prototype will be accepted at one or more NCATS-designated laboratories for Stage 3. One (1) grand prize winner will be awarded $750,000, and one (1) runner-up winner will be awarded $325,000.

The NIH reserves the right to cancel, suspend, and/or modify this Challenge at any time through amendment to this notice. In addition, the NIH reserves the right to not award any prizes if no solutions are deemed worthy. The Award Approving Official will be Lawrence A. Tabak, D.D.S., Ph.D., Principal Deputy Director of the National Institutes of Health (NIH).

Payment of the Prize. Prizes awarded under this competition will be paid by electronic funds transfer and may be subject to Federal income taxes. HHS/NIH will comply with the Internal Revenue Service withholding and reporting requirements, where applicable.

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BASIS UPON WHICH SUBMISSIONS WILL BE EVALUATED AND WINNERS WILL BE SELECTED

Stage 1 (Planning):

The goal of this stage of the Challenge is to design a solution that integrates the four component areas (Integrated Database, Electronic Synthetic Chemistry Portal, Predictive Algorithms and Biological Assays) that can be elaborated into a working prototype in the second stage of the Challenge. This integrated solution is expected to incorporate each of the requirements and desired features as detailed in the individual component areas. It is anticipated that this challenge will require a large, multi-expert team that is likely to be in multiple locations. Only complete submissions will be reviewed.

A panel of technical experts with subject matter expertise directly relevant to each of the four component areas will evaluate the Stage 1 designs based on ability to fulfill the criteria listed below. The Stage 1 winners will be selected by a panel of federal judges, which may include program staff, subject to the final decision by the Award Approving Official. The NCATS will provide feedback from the technical experts and judges to the winners and non-winners on their respective submissions.

Evaluation Criterion 1: Overall Impact and Innovation (30 points)

• How comprehensive and innovative is the combined solution overall?
• What is the potential impact of the solution on the development of novel treatments for pain, OUD, and/or overdose?
• What are major strengths and weaknesses of the designed platform?
• Are the solutions to the component areas well integrated and form a logical workflow?
• How likely is it that the integrated solutions can be successfully deployed in the ensuing reduction-to-practice stage?
• Does the team represent an outstanding group of innovators with a wide spectrum of expertise that can tackle multiple problems simultaneously?
• Did the team identify potential roadblocks and suggest additional expertise they would utilize to facilitate resolutions?
• To what degree is the plan for a working prototype adaptable to future translational problems, beyond those focusing on treatments of pain, OUD, and overdose?
• To what degree are the basic principles generalizable to additional and/or new translational questions?

Evaluation Criterion 2: Design of Individual Components (40 points)

Reviewers will evaluate how well individual components integrate into the comprehensive platform design as a whole while considering the essential design features of the individual components.

Design Features

Component 1: Integrated Chemistry Database for Translational Innovation in Pain, Opioid Use Disorder and Overdose

• The solution provides the required information necessary for development of novel treatments and therapies for pain, drug/addiction and/or overdose
• The database includes bioactivity results (Component 4) and experimental results (Component 2), that are incorporated
• The data contained within the database can be mined by the machine learning algorithms developed in Component 3
• The web portal front-end or complete API enables clear and easy management and retrieval of data and tools. This dashboard/portal integrates with Component Areas 2 (eSCP) and 3 (algorithms/machine learning
• The solution is based on well-designed strategies for data curation and updates, e.g. indicating how will new data be incorporated
• The structural and functional variability/complexity of currently available pain drugs, opioids and treatments for addiction and overdose is well represented in the database
• The collected data meet the FAIR* requirements (findable, accessible, inter-operable, and reusable: https://www.nature.com/articles/sdata201618)

Component 2: Electronic Synthetic Chemistry Portal for Translational Innovation in Pain, Opioid Use Disorder and Overdose

• The molecular design capabilities of the portal are optimized to advance the highest quality hypothetical attributes of target molecules and their utilized synthetic execution plan
• The data collected will enable further mechanistic understanding that is essential to control and optimize chemical reactions so that by-products are reduced, yields are increased, and reaction specificities are improved
• The eSCP is designed to utilize high quality data from both positive and negative experiments for future discovery and development of novel structures and chemistries of relevance to the treatment of pain and opioid use disorder
• All deposited data, including chemical structures, are in a format that can be easily accessible to advanced machine learning algorithms and/or applications, such as Component 3
• The deposited data integrate with the chemistry database (Component 1)
• The solution provides a dashboard that is integrated with the portals/dashboards associated with the database (Component 1) and machine learning algorithms (Component 3). The eSCP parses reaction information to include precise, unambiguous ontological annotation and reaction role descriptors (e.g. solvent, catalyst, other specific additive roles etc.)
• This information is well organized, e.g. information is  organized in a manner to provide comprehensive reaction analytics (similar, but not limited to: breakdown of reaction types represented; most commonly used reagents and catalysts; time related patterns associated with reaction development, including reaction networks that summarize typical reaction steps and reaction pathway associations with common intermediates or final targets)
• The eSCP can integrate chemical data with those from biological screening assays (Component 4)
• It is easy to extract the data from the eSCP document and record in database tables with appropriate metadata suitable for mining and analysis with advanced machine learning applications (Component 3)
• The eSCP integrates retrosynthetic tools, machine learning, and computational chemistry tools in a manner that facilitates future upgrades and additional links to bioassay data (Component 4) and related chemical structure and synthesis information. User interfaces are appealing and designed for intuitive use
• The eSCP includes documentation and management of laboratory chemical/sample inventory, equipment management, usage and label printing and barcodes

Component 3: Predictive Algorithms for Translational Innovation in Pain, Opioid Use Disorder and Overdose

• The solution uses its own, initial, structurally diverse training datasets that can be used to demonstrate the algorithms’ functionality on the set
• The demonstration of why/how this solution can outperform existing algorithms
• The demonstrated ability to provide critical information necessary for the development of novel treatments and therapies for pain, drug/addiction and/or overdose
  • The algorithms make use of the database (Component 1) and bioassay data (Component 4). In other words, it is easy to adjust the model or training set as additional data becomes available
  • The algorithms are documented for completing a task on a training set and making predictions on a new set of compounds, and the steps are precisely stated
  • The algorithms are implemented with open source codes/packages or commercial software packages
  • The web portal or tool/platform used by the algorithms interfaces/integrates well with that for Component 1
  • The innovators have explained how their algorithms meet the criteria of precision, uniqueness, finiteness, definiteness, input, output, and effectiveness
  • The algorithms can identify or prioritize molecules for synthesis or suggest reaction conditions (Component 2), and can identify structural and/or functional similarities in a diverse set of molecules
  • The algorithms can compare the mechanism of action between multiple drugs and identify structural/functional similarities between them
  • The algorithms are successful in identifying structurally diverse drugs with similar pharmacological effect
  • The algorithms can provide additional context for drug activity that can be used to identify or anticipate off-target effects

Component 4: Biological Assays for Translational Innovation in Pain, Opioid Use Disorder and Overdose

• The utilized assay is creative, original and biologically and physiologically relevant
• The utilized assay will accelerate discovery, development and preclinical testing of new and safer treatments of pain and/or OUD, and overdose
  • The assay is designed to be amenable for validation taking into consideration the target being studied using appropriate drugs/compounds and controls
• The data collection and analysis is automated. For example, assay results are stored in the database (Component 1)
  • The length of time it takes to perform the assay in full is appropriate. The timing of the assay is appropriate. (An assay’s development cycle time is reasonable)
  • Secondary/specificity/selectivity assays are used to confirm the initial data
  • Instrumental, computational and data storage requirements are specified 
• The protocols are well described, sufficiently clear and detailed to facilitate inter- and intra-laboratory utility and reproducibility
• Appropriate experiments that will address the stability of the assay components and reagents have been developed

Evaluation Criterion 3: Integration, Adaptability, User-friendliness and Accessibility (30 points)

• How well is each of the single components (Integrated Database, Electronic Synthetic Chemistry Portal, Predictive Algorithms and/or Biological Assays) integrated in the overall solution?
• How feasible and straightforward is the proposed workflow?
• Does the workflow proposed capture all four components, for example: does the predictive algorithm generate a hypothesis based on data from the integrated chemistry database, which then puts the resulting reactions in the eSCP? Are biological assay results stored in the chemistry database?
• What are major strengths and weaknesses of the overall solution presented?
• Which component(s) are the most and least developed?
• How likely is it that any weaknesses in the approach/design can be successfully addressed?
• How user-friendly are the individual components and the integrated platform as a whole?
• Are there possibilities to further simplify the approaches/processes used in the prototype?
• To what extent are there features incorporated or planned to be incorporated that would allow remote access to the platform?
• To what is extent is the team strongly focused on user-friendliness and dedicated to simplifying the solution for eventual use by non-expert scientists?

Stage 2 (Prototype Development and Milestones Delivery):

A team of program staff and subject matter experts will conduct site visits to evaluate the Stage 2 prototypes based on progress towards achievement of the milestones described below. Site visits will occur three times during Stage 2. While a general timeframe for the site visits is indicated above, the exact dates will be based on availability of program staff and subject matter experts. The comprehensive platform must be presented at a single, central location during the site visits.

A team of non-federal technical reviewers and program staff with expertise directly relevant to the Challenge will conduct site visits. The summaries prepared by the site visit team will then be reviewed by federal employees serving as judges, who will select the Challenge winners, subject to the final decision by the Award Approving Official.

A general description of milestones follows; however, additional details on milestones for Stage 2 will be available to Stage 1 winners no later than 30 days after the Stage 1 winners are announced:

Milestone 1

• Deliverable 1: Successful implementation and scaling of the biological assay to high-throughput format.
• Deliverable 2: Quantifiable progress towards the development of the database that will be used to manage and retrieve data from the chemical syntheses and biological assays.

Milestone 2

• Deliverable 1: Quantifiable progress towards the identification of a new molecular entity with activity against a biological target relevant to pain, opioid-use disorder or overdose.
• Deliverable 2: Documented use of the eSCP during the execution of a chemical synthesis.  
• Deliverable 3: Documented use of the machine learning algorithms to provide critical information for the design or synthesis of novel treatments and therapies for pain, drug addiction, and/or overdose.

Milestone 3

• Deliverable 1: Detailed description and requisite documentation for the successful transfer of the comprehensive platform to one or more NCATS-designated laboratories for independent validation and testing. This document should include detailed shipping/transfer plans and set-up procedures for the platform.
• Deliverable 2: Detailed description of how the prototype performs in one or more workflows specified by the innovator. This document should include thorough operating instructions for executing the workflow using the platform.  

Stage 3 (Prototype Delivery, Independent Validation, and Testing):

Prototypes will be transferred to one or more NCATS-designated laboratories for independent testing and evaluation of the extent to which the criteria below have been met. At the conclusion of this validation and testing stage, representatives from one or more of the NCATS-designated laboratories will create a report evaluating the prototype based on the criteria described below. These reports will be evaluated by a panel of federal judges who will select the grand prize winner and runner-up, subject to the final decision by the Award Approving Official.  

Evaluation Criterion 1: Overall Impact and Innovation (40 points)

• What is the potential impact of the solution on the development of novel treatments for pain, OUD, and/or overdose?
• To what extent does this platform outperform existing solutions or workflows for drug discovery?
• What are major strengths and weaknesses of the prototype?
• How well does the working prototype reflect an improvement over the initial design? Does the final prototype incorporate new developments or insights from the field?
• Given that innovation is considered using a groundbreaking or paradigm-shifting approach or using existing approaches in an innovative way, to what degree is the platform innovative, creative, and original?

Evaluation Criterion 2: Performance (60 points)

• Is each of the four components (Integrated Database, Electronic Synthetic Chemical Portal, Predictive Algorithms, and Biological Assays) operational and show seamless integration?
• Are the operating instructions developed in Milestone 3 clear, accurate and easy to follow?
• Does the platform’s workflow capture and integrate all four components, for example: does the predictive algorithm generate a hypothesis based on data from the integrated chemistry database, which then puts the resulting reactions in the eSCP? Are biological assay results stored in the chemistry database?
• Does the platform support a diverse set of use cases or is it a specialized solution?
• Has the platform identified 5-10 structurally diverse molecules or molecular series with biological activity against a target relevant to pain, OUD, or overdose? Are these molecules suitable for future pharmaceutical development or is additional optimization needed?

Evaluation Criterion 3: Integration, Adaptability, User-friendliness and Accessibility (50 points)

• How well is each of the single components (Integrated Database, Electronic Synthetic Chemistry Portal, Predictive Algorithms and Biological Assays) integrated in the overall solution? Are the solutions to the component areas synergistic?
• What are major strengths and weaknesses of the overall solution presented?
• Which component(s) are the most and least developed?
• To what degree is the working prototype adaptable to future translational problems, beyond those focusing on treatments of pain, OUD, and overdose?
• To what degree are the basic principles amendable to additional and/or new translational questions?
• How user-friendly are the individual components and the integrated platform as a whole?
• Are there possibilities to further simplify the approaches/processes used in the prototype?
• To what extent are there features incorporated or planned to be incorporated that would allow remote access to the platform?
• To what is extent is the team strongly focused on user-friendliness and dedicated to simplifying the solution for eventual use by non-expert scientists?
• What is the anticipated overall cost of use, for example: are there consumable, storage or web-hosting costs associated with this platform?
• Did the team consider how the platform might be improved or built onto in the future? For example, could the platform be integrated with an automated synthetic chemistry module in the future?

Evaluation Criterion 4: Portability, Robustness and Reproducibility (50 points)

• Is the use case as presented the most optimal way to demonstrate the functional utility of the comprehensive platform?
• Are the documentations provided sufficient to transfer and replicate the system to an independent facility?
• How accessible are team members to assist the one or more NCATS-designated laboratories in setting up and operating the prototype?
• What is the footprint of the system? How specialized or available are the components and equipment?
• Have the investigators presented strategies to troubleshoot potential problems?
• How reproducible are the bioassay results?
• How robust is the platform? How well does it stand up to frequent or continuous use?
• What is the throughput of the system? Have the innovators considered ways to increase the throughput?

For more information about the ASPIRE Challenges, view the Frequently Asked Questions.

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