Basket Clinical Trials of Drugs Targeting Shared Molecular Etiologies in Multiple Rare Diseases

Basket Clinical Trials of Drugs Targeting Shared Molecular Etiologies in Multiple Rare Diseases is sponsored by National Center for Advancing Translational Sciences (NCATS) / National Institutes of Health (NIH). These grants fund research teams to adapt the shared molecular etiology approach from oncology to rare diseases, which could include amyloidosis if shared molecular etiologies are identified.

Expired RFA-TR-21-010: Basket Clinical Trials of Drugs Targeting Shared Molecular Etiologies in Multiple Rare Diseases (U44 Clinical Trial Required) This notice has expired. Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Center for Advancing Translational Sciences ( NCATS ) Funding Opportunity Title Basket Clinical Trials of Drugs Targeting Shared Molecular Etiologies in Multiple Rare Diseases (U44 Clinical Trial Required) U44 Small Business Innovation Research (SBIR) Cooperative Agreements - Phase II July 13, 2022 - This RFA has been reissued as RFA-TR-22-029 October 28, 2021 - Reminder: FORMS-G Grant Application Forms & Instructions Must be Used for Due Dates On or After January 25, 2022 - New Grant Application Instructions Now Available.

See Notice NOT-OD-22-018 . September 13, 2021 - Updates to the Non-Discrimination Legal Requirements for NIH Recipients. See Notice August 5, 2021 - New NIH "FORMS-G" Grant Application Forms and Instructions Coming for Due Dates on or after January 25, 2022.

August 5, 2021 - Update: Notification of Upcoming Change in Federal-wide Unique Entity Identifier Requirements. See Notice NOT-OD-21-170 April 20, 2021 - Expanding Requirement for eRA Commons IDs to All Senior/Key Personnel. See Notice NOT-OD-21-109 March 8, 2021 - Notice of Correction to Application Types Allowed for RFA-TR-21-010.

See Notice NOT-TR-21-023 . Funding Opportunity Announcement (FOA) Number Companion Funding Opportunity See Section III. 3.

Additional Information on Eligibility . Assistance Listing Number Funding Opportunity Purpose The purpose of this Funding Opportunity Announcement (FOA) is to support basket clinical trials of drugs targeting shared molecular etiologies in more than one rare disease.

To facilitate clinical trial start up, and leverage existing datasets, preference will be given to applications focusing on diseases that are under study by the Rare Disease Clinical Research Network (RDCRN), and that involve collaborations with RDCRN clinical investigators.

Open Date (Earliest Submission Date) Letter of Intent Due Date(s) April 13, 2021, September 13, 2021, January 12, 2022 All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s) 2021, October 2021, February 2022 August 2021, January 2022, May 2022 Required Application Instructions It is critical that applicants follow the SBIR/STTR (B) Instructions in the SF424 (R&R) SBIR/STTR Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts ).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV . When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review. Part 1. Overview Information Part 2.

Full Text of Announcement Section I. Funding Opportunity Description Section II. Award Information Section III.

Eligibility Information Section IV. Application and Submission Information Section V. Application Review Information Section VI.

Award Administration Information Section VII. Agency Contacts Section VIII. Other Information Part 2.

Full Text of Announcement Section I. Funding Opportunity Description While there are thousands of rare diseases, the number of underlying etiologies is much smaller. Moreover, many disease etiologies underly multiple traditional diseases.

This is most readily seen for rare monogenic diseases, where the most common etiologies include premature termination codons, protein misfolding, and abnormal RNA splicing. Other examples of rare disease shared molecular etiologies include, but are not limited to, triplet repeat expansions, epigenetic dysregulation, and signallopathies (e.g., mTOR-opathy, RAS-opathy, etc.).

Small businesses are developing drugs targeting shared molecular etiologies. However, the standard approach in clinical trials is to focus on one disease at a time, with the choice of diseases often based on prevalence.

This approach inevitably results in clinical trials in only the most common rare diseases, with the exclusion of patients with the least common diseases, even though the scientific rationale for the use of the drug may be as strong, if not stronger, in the lower prevalence rare diseases.

One potential solution to this problem is to adapt the basket trial approach that has been developed for tissue agnostic oncology drugs, i.e. for clinical trials of drugs that target molecular defects common to anatomically different cancers. Notably, this approach has already resulted in regulatory approvals from the US FDA ( https://www. fda.

gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions ). One potentially important difference between oncology and rare diseases, however, is the relative diversity of clinical outcome measures in rare diseases compared to cancer.

The purpose of this FOA is to provide support for basket clinical trials of drugs targeting shared molecular etiologies in more than one rare disease, and in the process to identify and overcome challenges in adapting the oncology basket trial model to rare diseases. Projects proposed for this FOA will require individuals with expertise in carrying out clinical trials in rare diseases.

Applicants are strongly encouraged to collaborate with investigators at academic institutions and negotiate an agreement for carrying out the proposed clinical trials. NCATS will give priority to projects involving clinical investigators who are part of the Rare Disease Clinical Research Network (RDCRN) and which focus on diseases under study in the RDCRN. See https://www.

rarediseasesnetwork. org/ for additional information. The funding opportunity will utilize a Small Business Innovation Research (SBIR) U44 cooperative agreement to support Investigational New Drug (IND) enabling studies, including translational bench/ in vitro , and animal studies as necessary, to support the preparation and submission of the IND.

This cooperative agreement will also support the subsequent small clinical trial, involving at least two different rare diseases.

It is expected the immediate next steps following completion of the small clinical trial supported under this cooperative agreement will be: future clinical trial design decisions made based on the information and data collected; a larger clinical trial that will lead to a marketing application; or a marketing application if only a small clinical trial is needed. Applicants should have strong supporting data.

Innovation and impact will in part be judged on presenting a credible path towards U.S. regulatory submission/Institutional Review Board (IRB) approval at the end of the SBIR. All projects (other than Direct to Phase II applications) will be Fast-Track applications which include both SBIR Phase I and Phase II components.

Phase I of the Fast-Track will support translational activities leading to submission of an IND to the FDA, as well as an IRB application. Phase II of the project period will support the clinical trial in rare disease patients. The duration of Phase I of the Fast-Track will depend on the maturity of the project at entry.

Only those Phase I projects that have met specific criteria (see below) will be eligible for transition to Phase II of the Fast-Track after NIH administrative review. Phase II of the Fast-Track will support a small clinical trial, as described above.

The SBIR U44 cooperative agreement mechanism is milestone-driven and involves significant input from NIH program staff regarding project and milestone planning, monitoring of research progress, and go/no-go decision-making.

NIH staff may also provide assistance to investigators in familiarizing them with the regulatory development process and the criteria needed to advance drugs targeting shared molecular etiologies in rare disease patients into clinical trials. Applicants are strongly advised to contact the Scientific/Research contact listed below prior to submission.

Projects must focus on a clinical trial of a single drug targeting a shared molecular etiology that underlies at least two different rare diseases. Examples of such shared molecular etiologies are given above. Including at least two different diseases in the clinical trial is requirement for support under this FOA.

For entry to the program, projects should have: Comprehensive supporting data based on bench, in vitro , and/or in vivo models supporting efficacy in the intended rare disease patient population and indication. Identified at least two different diseases for inclusion in the clinical trial.

For both diseases, one or more clinically meaningful outcome measures, based on input from both clinicians and patients, and / or supporting literature, should be specified. A compelling case for a successful IND submission of the clinical trial at the end of SBIR Phase I. Applicants are encouraged, but not required, to consult with FDA via a Pre-Submission meeting prior to applying for funding through this grant mechanism.

Fast-Track Phase I scope: Examples of studies that may be proposed during SBIR Phase I include, but are not limited to: Bench-top and animal testing to demonstrate proof of concept and safety. Activities to become current Good Manufacturing Practice (GMP) compliant. Regulatory activities, including pre-submission meetings with FDA.

Limited clinical data, e.g. safety studies in human volunteers, is also allowable during SBIR Phase I if it is necessary to support the IND submission for the small clinical trial conducted in SBIR Phase II. Fast-Track Phase II scope: Phase II will support the clinical trial of a single drug targeting a shared molecular etiology, including patients from at least two different diseases.

Examples of activities non-responsive to this FOA include: Basic research and studies of disease mechanisms. Animal model development: all necessary in vivo models must be well established and characterized, and available to the applicant. Development of outcome measures or natural history studies.

A clinical trial of the drug in a single disease. Clinical trials in cancer. However, rare diseases which have an increased risk of cancer are allowed, as long as the primary clinical outcome measure is not carcinogenesis or tumor progression.

Stand-alone SBIR Phase I or Phase II applications. Delayed onset studies that do not have a clinical trial described in the submission. Applications must propose one or more milestones associated with each objective in each year of the project.

Milestones are goals that measure success and efficacy that can be used for go/no-go decision-making for the project and should have quantitative criteria associated with them (see Section IV. 2 for details). Applications should include quantitative milestones and go/no-go decision points.

Projects must include milestones to be used for measuring success in achieving each of the research plan’s objectives. NIH program staff will contact the applicant to discuss and negotiate the proposed milestones and any changes suggested prior to funding the application. The final agreed upon and approved milestones will be specified in the Notice of Award (NoA).

Progress towards achievement of the final set of milestones will be evaluated by NIH program staff. If justified, future milestones may be revised based on data and information obtained during the previous project period. If, based on the progress report, a funded project does not meet the milestones, funding for the project will be discontinued.

In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, portfolio balance and program priorities, competitive landscape, and availability of funds.

NIH encourages increasing the rigor and reproducibility of observed results. In some cases, conducting additional critical experiments will be important for NIH to have confidence in making a funding decision. Therefore, NIH Program Staff may recommend additional experiments that should be conducted prior to or during the award.

Any additional experiments would be negotiated with the PI as a new or revised milestone of award. In some cases, these studies could be supported with additional funds.

Fast-Track Phase I to Phase II transition: An administrative review will be conducted by program staff to decide whether a SBIR Phase I project will be transitioned into SBIR Phase II based on the following: Successful achievement of the defined milestones for SBIR Phase I of the project Obtaining an IND for the clinical trial from FDA Likelihood of success in carrying out the clinical trial Submission of the final clinical protocol and supporting documents to NIH for administrative review, and notification of approval by NIH Agreement on updated timeline, milestones and budget for the clinical trial.

D. Pre-application Consultation As a U44 cooperative agreement, NIH program staff will be involved in the planning and execution of the projects. Applicants are strongly encouraged to consult with NIH Scientific/Research staff when planning an application.

Early contact provides an opportunity for Scientific/Research staff to provide further guidance on program scope, goals, and developing appropriate milestones, and also to determine whether the proposed project meets the goals of the FOA. Applicants should contact NCATS Scientific/Research staff at least 10 weeks before a receipt date. See Section VIII.

Other Information for award authorities and regulations. Section II. Award Information Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement.

Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI. 2 for additional information about the substantial involvement for this FOA.

Application Types Allowed New (Phase I, Fast-Track) New (SBIR Direct Phase II) The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for the FOA. Required: Only accepting applications that propose clinical trial(s) Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Total funding support (direct costs, indirect costs, fee) normally may not exceed $ 256,580 for Phase I awards and $ 1,710,531 for Phase II awards.

NIH has received a waiver from SBA, as authorized by statute, to exceed these total award amount hard caps for specific topics. The current list of approved topics can be found at https://sbir. nih.

gov/funding#omni-sbir . Navigate to the Program Descriptions and Research Topics document, Appendix A or the current "SBA approved topics list for budget waivers". Applicants are strongly encouraged to contact program officials prior to submitting any application in excess of the hard caps listed above and early in the application planning process.

In all cases, applicants should propose a budget that is reasonable and appropriate for completion of the research project. According to statutory guidelines, award periods normally may not exceed 1 year for Phase I and 2 years for Phase II. Applicants are encouraged to propose a project duration period that is reasonable and appropriate for completion of the research project.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA. Section III. Eligibility Information Only United States small business concerns (SBCs) are eligible to submit applications for this opportunity.

A small business concern is one that, at the time of award of Phase I and Phase II, meets all of the following criteria: Is organized for profit, with a place of business located in the United States, which operates primarily within the United States or which makes a significant contribution to the United States economy through payment of taxes or use of American products, materials or labor; Is in the legal form of an individual proprietorship, partnership, limited liability company, corporation, joint venture, association, trust or cooperative, except that where the form is a joint venture, there must be less than 50 percent participation by foreign business entities in the joint venture; SBIR and STTR.

Be a concern which is more than 50% directly owned and controlled by one or more individuals (who are citizens or permanent resident aliens of the United States), other business concerns (each of which is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States), an Indian tribe, ANC or NHO (or a wholly owned business entity of such tribe, ANC or NHO), or any combination of these; OR SBIR-only.

Be a concern which is more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these.

No single venture capital operating company, hedge fund, or private equity firm may own more than 50% of the concern, unless that single venture capital operating company, hedge fund , or private equity firm qualifies as a small business concern that is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States; OR SBIR and STTR.

Be a joint venture in which each entity to the joint venture must meet the requirements set forth in paragraph 3 (i) or 3 (ii) of this section. A joint venture that includes one or more concerns that meet the requirements of paragraph (ii) of this section must comply with 121. 705(b) concerning registration and proposal requirements.

Has, including its affiliates, not more than 500 employees. If the concern is more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these falls under 3 (ii) or 3 (iii) above, see Section IV. Application and Submission Information for additional instructions regarding required application certification.

If an Employee Stock Ownership Plan owns all or part of the concern, each stock trustee and plan member is considered an owner. If a trust owns all or part of the concern, each trustee and trust beneficiary is considered an owner. Hedge fund has the meaning given that term in section 13(h)(2) of the Bank Holding Company Act of 1956 (12 U.S.C.

1851(h)(2)). The hedge fund must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State. Portfolio company means any company that is owned in whole or part by a venture capital operating company, hedge fund, or private equity firm.

Private equity firm has the meaning given the term private equity fund in section 13(h)(2) of the Bank Holding Company Act of 1956 (12 U.S.C. 1851(h)(2)). The private equity firm must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.

Venture capital operating company means an entity described in 121. 103(b)(5)(i), (v), or (vi). The venture capital operating company must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.

ANC means Alaska Native Corporation. NHO means Native Hawaiian Organization. SBCs must also meet the other regulatory requirements found in 13 C.

F. R. Part 121.

Business concerns, other than investment companies licensed, or state development companies qualifying under the Small Business Investment Act of 1958, 15 U.S.C. 661, et seq. , are affiliates of one another when either directly or indirectly, (a) one concern controls or has the power to control the other; or (b) a third-party/parties controls or has the power to control both.

Business concerns include, but are not limited to, any individual (sole proprietorship) partnership, corporation, joint venture, association, or cooperative. The SF424 (R&R) SBIR/STTR Application Guide should be referenced for detailed eligibility information.

Small business concerns that are more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these are NOT eligible to apply to the NIH STTR program.

Phase I to Phase II Transition Rate Benchmark In accordance with guidance from the SBA, the HHS SBIR/STTR Program is implementing the Phase I to Phase II Transition Rate benchmark required by the SBIR/STTR Reauthorization Act of 2011. This Transition Rate requirement applies to SBIR and STTR Phase I applicants that have received more than 20 Phase I awards over the past 5 fiscal years, excluding the most recently-completed fiscal year.

For these companies, the benchmark establishes a minimum number of Phase II awards the company must have received for a given number of Phase I awards received during the 5-year time period in order to be eligible to apply for a new Phase I award Fast-Track, or Direct Phase II (if available) . This requirement does not apply to companies that have received 20 or fewer Phase I awards over the 5 year period.

Companies that do not meet or exceed the benchmark rate will not be eligible to apply for a Phase I Fast-Track, or Direct Phase II (if available) award for a period of one year from the date of the application submission.

The Transition Rate is calculated as the total number of SBIR and STTR Phase II awards a company received during the past 5 fiscal years divided by the total number of SBIR and STTR Phase I awards it received during the past 5 fiscal years excluding the most recently-completed year. The benchmark minimum Transition Rate is 0. 25.

SBA calculates individual company Phase I to Phase II Transition Rates daily using SBIR and STTR award information across all federal agencies. For those companies that have received more than 20 Phase I awards over the past 5 years, SBA posts the company transition rates on the Company Registry at SBIR. gov. Information on the Phase I to Phase II Transition Rate requirement is available at SBIR.

gov. Applicants to this FOA that may have received more than 20 Phase I awards across all federal SBIR/STTR agencies over the past five (5) years should, prior to application preparation, verify that their company’s Transition Rate on the Company Registry at SBIR. gov meets or exceeds the minimum benchmark rate of 0. 25.

Phase II to Commercialization Benchmark In accordance with guidance from the SBA, HHS, including NIH, SBIR/STTR Programs are implementing the Phase II to Commercialization Rate benchmark for Phase I applicants, as required by the SBIR/STTR Reauthorization Act of 2011. The Commercialization Rate Benchmark was published in a Federal Register notice on August 8, 2013 ( 78 FR 48537 ).

This requirement applies to companies that have received more than 15 Phase II awards from all agencies over the past 10 years, excluding the two most recently-completed Fiscal Years. Companies that meet this criterion must show an average of at least $100,000 in revenues and/or investments per Phase II award or at least 0. 15 (15%) patents per Phase II award resulting from these awards.

This requirement does not apply to companies that have received 15 or fewer Phase II awards over the 10 year period, excluding the two most recently-completed Fiscal Years. Information on the Phase II to Commercialization Benchmark is available at SBIR.

gov. Applicants to this FOA that may have received more than 15 Phase II awards across all federal SBIR/STTR agencies over the past ten (10) years should, prior to application preparation, verify that their company’s Commercialization Benchmark on the Company Registry at SBIR. gov meets or exceeds the benchmark rate listed above.

Applicants that fail this benchmark will be notified by SBA annually and will not be eligible to apply for New Phase I, Fast-track or Direct Phase II (if applicable) awards for a period of one year. Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply. Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement , may be allowed. Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted.

Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission. Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number.

After obtaining a DUNS number, applicants can begin both SAM, SBA Company registry, and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application. System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually .

The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code. SBA Company Registry See Section IV.

Application and Submission Information , SF424(R&R) Other Project Information Component for instructions on how to register and how to attach proof of registration to your application package. Applicants must have a DUNS number to complete this registration. SBA Company registration is NOT required before SAM, Grants.

gov or eRA Commons registration. eRA Commons - Applicants must have an active DUNS number number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.

gov registration, but all registrations must be in place by time of submission . eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants.

gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants. gov registration. Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account.

PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support.

Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support. Under the SBIR program, for both Phase I and Phase II, the primary employment of the PD/PI must be with the small business concern at the time of award and during the conduct of the proposed project.

For projects with multiple PDs/PIs, at least one must meet the primary employment requirement. Occasionally, deviations from this requirement may occur.

For the STTR program, the PD(s)/PI(s) may be employed with the SBC or the single, partnering non-profit research institution as long as s/he has a formal appointment with or commitment to the applicant SBC, which is characterized by an official relationship between the SBC and that individual.

Such a relationship does not necessarily involve a salary or other form of remuneration The primary employment of the PD/PI must be with the SBC or the Research Institution (where they are PD/PI at) at the time of award and during the conduct of the proposed project. Each PD/PI must commit a minimum of 10% effort to the project.

The SF424 (R&R) SBIR/STTR Application Guide should be referenced for specific details on eligibility requirements. For institutions/organizations proposing multiple PDs/PIs, see Multiple Principal Investigators section of the SF424 (R&R) SBIR/STTR Application Guide. Projects proposed for this FOA will require multidisciplinary efforts to succeed.

Applicants are encouraged to collaborate with clinical investigators who are experienced in carrying out clinical trials in rare diseases, such as those involved with the Rare Disease Clinical Research Network (RDCRN). This FOA does not require cost sharing as defined in the NIH Grants Policy Statement. 3.

Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct. NIH will not accept similar grant applications with essentially the same research focus from the same applicant organization.

This includes derivative or multiple applications that propose to develop a single product, process, or service that, with non-substantive modifications, can be applied to a variety of purposes. Applicants may not simultaneously submit identical/essentially identical applications under both this funding opportunity and any other HHS funding opportunity, including the SBIR and STTR Parent announcements.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept: A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.

A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application. An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101 ).

A Phase I awardee may submit a Phase II application either before or after expiration of the Phase I budget period, unless the awardee elects to submit a Phase I and Phase II application concurrently under the Fast-Track procedure.

To maintain eligibility to seek Phase II or IIB support, a Phase I awardee should submit a Phase II application, and a Phase II awardee should submit a Phase IIB application, within the first six due dates following the expiration of the Phase I or II budget period, respectively. Contractual/Consortium Arrangements In Phase I, normally, two-thirds or 67% of the research or analytical effort is carried out by the small business concern.

The total amount of all consultant and contractual arrangements to third parties for portions of the scientific and technical effort is generally not more than 33% of the total amount requested (direct, F&A/indirect, and fee). In Phase II, normally, one-half or 50% of the research or analytical effort is carried out by the small business concern.

The total amount of consultant and contractual arrangements to third parties for portions of the scientific and technical effort