Pull Incentives for Vx Development RFI 7.6.pdf

Project NextGen: Potential Market Shaping Strategies for Vaccine Development

Request for Information

1 BACKGROUND

The Biomedical Advanced Research and Development Authority (BARDA), part of the Administration for Strategic Preparedness and Response (ASPR) in the U.S. Department of Health and Human Services (HHS), provides an integrated, systematic approach to the development of the necessary vaccines, drugs, therapies, and diagnostic tools for public health medical emergencies. BARDA supported end-to-end product development of multiple first-generation COVID-19 vaccines, leading to U.S. Food and Drug Administration (FDA) licensure or authorization of four vaccines.

While existing vaccines against COVID-19 are still very effective at preventing serious illness and death, their efficacy against disease has diminished over time due to the emergence and circulation of new variants and to waning immunity. On June 15, 2023, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) recommended a change in strain to combat these issues for the currently licensed and authorized vaccines.

However, even with proposed updates, the ability of the current generation of vaccine technologies to reduce infection and transmission among individuals is not optimal, nor is their ability to provide the broad protection needed to protect against a broader set of beta coronaviruses. BARDA, in collaboration with the National Institutes of Allergy and Infectious Disease, is supporting advanced development of next generation COVID-19 vaccine candidates through Project NextGen that could elicit broader and more durable protection against variants of concern, into clinical trials to evaluate their immunogenicity, safety, and efficacy against SARS-CoV-2 infection. BARDA is interested in leveraging public-private partnerships, flexible authorities, and cutting-edge expertise to drive innovation off the bench to the patient to save lives.

2 OBJECTIVE OF REQUEST FOR INFORMATION

The primary intent of this Request for Information (RFI) is to explore additional ways in which Project NextGen could better ensure that next generation COVID-19 vaccine technologies ultimately benefit people and bolster preparedness against future variants, by reducing technological, regulatory, and market risk.

https://medicalcountermeasures.gov/nextgen

“Pull” incentives have the potential to accelerate the development and commercialization of both near term and technologically distant next generation COVID-19 vaccines, to complement more typical “push” funding, e.g., grants or contracts. BARDA has an area of interest (AOI) in a broad agency announcement (BAA) that is seeking proposals for phase 2b clinical trials for vaccine development that may show improved efficacy signals compared to licensed or authorized products. However, there are other key aspects of vaccine performance that could impact uptake (e.g. safety, route of administration, etc.) and a broader draft Target Product Profile is included below for any comments in terms of potential targets for a pull incentive: https://sam.gov/opp/0b30fe1ef71046d090e0beef36b5234c/view.

However, there are some commercial barriers to the development of next-generation COVID-19 vaccines, which is why public investment is so critical and underpins the need for Project NextGen.

However, BARDA recognizes that a push funding approach alone may not lead to the commercialization of next-generation vaccines, either because some companies may not opt to pursue a partnership due to commercialization barriers of a new vaccine beyond even positive phase 2b clinical trial results.

In this case, pull incentives could include milestone-based payments, either with respect to a specific research & development (R&D) entity or competitively open to registered entities, advanced market commitments, and/or prize competitions. There are many potential advantages of pull incentives. They reward only upon achievement of objectives thereby lowering the risk to government, they create an opportunity for a wider field of participants, in this case vaccine developers, to participate and advance product development, and they create greater certainty that financial rewards will be available upon achievement of objectives, even if years into the future, creating a more even playing field between developers at early and later stages of development. Most importantly, pull incentives can significantly reduce the risk that a vaccine, once developed, is available and accessible to those who will benefit from it and help meet public health and health security needs.

We are seeking informed and constructive input on the sets of questions below from a diverse set of stakeholders including product developers, economists, patients, clinicians, and others. BARDA recognizes that specific communities may have input on all the questions or only a few and encourages respondents to focus on questions they feel best positioned to address.

3 TOPICS FOR INPUT

3.1 ESTABLISHING THE OBJECTIVE

For pull incentives to be effective, BARDA would need to clearly articulate and widely publish a detailed yet concise set of technical, clinical, and user-derived specifications to potential participants. These target product profiles (TPPs) would additionally serve as a condition of award, whether as a cash prize for achieving a specific milestone or incentivization of commercialization (if applicable) once approved by appropriate regulatory bodies. BARDA may choose to reward the achievement of specific vaccine performance characteristics that go above and beyond what a regulatory body may currently consider for licensure due to their high public health value, e.g., broad protection against future variants or the ability to limit infection and/or transmission among individuals.

BARDA recognizes that vaccine candidates, platforms, and technologies are in various stages of development, and are being developed by a constellation of large and small companies, non-profit https://sam.gov/opp/0b30fe1ef71046d090e0beef36b5234c/view https://sam.gov/opp/0b30fe1ef71046d090e0beef36b5234c/view organizations, and academic labs. Some of the higher value candidates, such as those that might offer pan-coronavirus protection, prevention of infection, or more effectively block transmission between individuals, may be in earlier stages of development. As a result, they may not be ready for clinical efficacy studies for two or more years. To provide sufficient incentives and clear pathways for advanced development and commercialization of those candidates, BARDA is considering a two-track approach that seeks to both develop near-term COVID-19 vaccine candidate(s) that improves on the duration and breadth of protection, as well as other goals such as transmission blocking that may have higher public health value in the US and globally. The use of pull incentives to accelerate development and stimulate private investment would require the clear articulation of the target product profiles (TPP) that maximizes the benefit to health security preparedness, as well as consumer interest and uptake for new COVID-19 vaccines. While the focus of this RFI is to obtain information, BARDA does not want to restrict the range of responses.

Further, for pull incentives to work effectively, product developers would have to demonstrate with sufficient evidence that their vaccine meets or exceeds the TPPs, and any other conditions set by BARDA as a condition of prize award. BARDA would likely provide specific information up front on how these could be adequately satisfied to reduce uncertainty among participants.

Below are the draft next generation COVID-19 vaccine TPPs on which BARDA proposes to base any potential incentives. The TPPs are focused on both more near-term profile (“threshold”) and on more technologically distant and optimal (“optimal”). The benchmarks for these TPPs have been established based on BARDA’s deep expertise, research, and evidence, and are proposed to be used as a basis for any pull incentive as discussed in later sections. Many of the specific product attributes are designed to advance public health priorities, including availability and benefit to diverse populations.

Table 1. Draft Target Product Profile (TPP) highlighting threshold and optimal attributes.

Vaccine Characteristic Threshold Optimal Indication for use • Immunization to prevent severe disease and death caused by COVID-19 against circulating and/or future COVID-19 variant

• Immunization protecting against circulating and/or future COVID-19 variant related symptomatic disease, serious illness, hospitalization, and death.

• Protects against viral transmission/spread

• Pan-Sarbecovirus protection

Target population • Healthy adults ≥ 18 years and older including elderly who received any full primary course COVID-19 vaccine at least 2-3 months prior

• Individuals at risk of severe disease.

• All age groups, including healthy adults, children above 6 months of age, and elderly at risk of severe disease.

• Data should support administration to pregnant or lactating women, and individuals who have comorbidities and immunocompromised

Safety/Reactogenicity Demonstrate at least similar risk/benefit profile through clinical and Tox studies compared to currently FDA licensed or authorized COVID vaccines (standard of care (SoC))

Demonstrate improved risk/benefit profile through clinical and Tox studies compared to currently FDA licensed or authorized COVID vaccines (SoC)

1 Vaccines immunogenicity data should be collected at different timepoints in a year (3, 6, 9, 12 months) following booster vaccination to evaluate persistence/durability of immunity 2 Measurement of cell-mediated immunity (the quantity and quality of T-cell responses) is encouraged to better characterize antibody responses and clinical protection 3 For non-spike/non-RBD Ags - induction of statistically valid immunogenicity endpoints, protective binding Ab levels, functional Fc-mediated antibody protection and virus neutralization/inhibition activity using validated assays is desired (discuss with FDA)

4 Data on antigen specific T-cell responses including CD4+ T-cells and CD8+ cytotoxic T-lymphocytes (CTLs) and relevant cytokines would be desirable.

5 Parameters to consider - challenge virus strain, dose, route, and volume in the animal test species and appropriate clinical end point for that species. It is highly desired that protection/challenge studies provide evidence of protective efficacy for the same or a similar virus strain as the candidate vaccine intended for clinical use.

6 Per FDA, use of species other than NHPs, if possible and “when scientifically justified”, in general toxicity and reproduction toxicity testing for small molecule and biological product drug development programs is highly encouraged.

Clinical Efficacy, immune response 1,2,3

• Vaccine efficacy (VE) and protection against severe infection equivalent or superior to FDA approved vaccines

• Non-inferior to licensed vaccine (SoC) as measured by immune-bridging studies

• Vaccine efficacy (VE) and protection against severe infection or superior to FDA approved vaccines

• Demonstrated ability to reduce viral transmission (by at least ~70%) from vaccine recipients infected with SARS- CoV-2

Nonclinical safety, efficacy 4,5,6

• Indication of immunogenicity, efficacy/neutralizing activity, and protection (humoral, cellular) in appropriate preclinical models that have been used in licensed vaccines (SoC)

• Strain-specific and cross-reactive Abs

• No risk of vaccine-associated enhanced respiratory disease (VAERD) and on CNS

• Lack of toxicity and reproductive Toxicity in an FDA acceptable animal models for SARS-CoV-2

• Indication of immunogenicity, efficacy/neutralizing activity, and protection (humoral, cellular, mucosal)

• Strain-specific and cross-reactive Abs in preclinical models

• No risk of vaccine-associated enhanced respiratory disease (VAERD) and on CNS

• Lack of toxicity and reproductive Toxicity in an FDA acceptable animal models for SARS-CoV-2

• Reduce and neutralize virus transmission and viral infectivity (≥90% and/or ≥4 log10 reduction), replication/shedding and demonstrate protection in challenge studies against circulating and other variants

Potency • Demonstrated product-specific potency, measured by validated in vitro and/or in vivo methods, that is indicative of lot release & stability of potency over time upon storage.

• Clinical and preclinical IND enabling animal studies should demonstrate Ag-specific immunogenicity and/or clinical effect (humoral, cellular, mucosal) at the target dose; is non-inferior to the currently available COVID-19 vaccine

• Demonstration of consistent potency across manufacturing lots

Durability and breadth of protection

• Confers protection against symptomatic severe disease (hospitalization) or death from SARS-CoV-2 of at least 70% for at least 6 months after booster dose against circulating SARS-CoV-2 variants, across all populations

• Confers protection against symptomatic, severe disease (hospitalization) or death from SARS-CoV-2 of at least 80% for at least 1 year after booster dose against circulating and prior/ancestral SARS-CoV- 2 variants, across all populations

7 Manufacturing platform ability to pivot and scale rapidly to replacement of the strain in the authorized vaccine with a different/shifting strain is highly desired.

Dosing regimen

• Single-dose booster

• Used as a heterologous booster to primary vaccination or prior infected subjects

• Vaccinate against FDA recommended variant or VOC

• Single-dose booster

• Vaccinate against FDA recommended variant or VOC

• Used as a heterologous booster to primary vaccination or prior infected subjects

• Allows for dose-sparing for pediatric populations and high dose for immunocompromised patients

Route of administration • Similar to current FDA approved COVID- 19 vaccines i.e., IM route of administration

• Parenteral routes of administration (IM, ID) are acceptable.

• IN and/or Oral mucosal administrations and/or other non-parenteral needle-free approaches are preferred

• ROAs that allow for rapid deployment, administration and public vaccine uptake preferred

Presentation • Single dose and/or multi-dose product presentation for IM administration

• Single dose storage format regardless of delivery mechanism Single dose -use mucosal administration (intranasal or oral) and/or needle-free ID patches

• Lack of need for reconstitution

• Product format allows for dose-sparing

(pediatric population) and/or high dose for immunocompromised patients, if needed

Contraindication No contraindications preferred and/or reduced hypersensitivity or cross-reactivity to any of the vaccine components (e.g., allergic reactions and/or thrombocytopenia etc.) compared to current FDA licensed/authorized vaccine(s)

Shelf life stability & Storage

• Finished Drug product stable for at least ≥1 year at 2-8° C and/or –20° C

• Finished Drug product stable for at least ≥2 year at 2-8° C

Refrigeration/Freeze-thaw stability

• No freeze sensitivity/potential damage

• Stable over ≥5 or more out-of-refrigeration (refrigerated products preferred over frozen)

Manufacturability, availability7

• Scalable to produce and release 100M doses in 100 days from the date the circulating variant sequence is available

• Validated and reproducible process; acceptable Drug substance and Drug product yield and stability

• Phase-appropriate qualified/validated processes and assays amenable to tech transfer and scale up.

• Production platform suitable to pivot to newer variants annually

• Submission of relevant Drug Master files to expedite manufacturing is desirable

• Manufacturing capacity that is responsive to national preparedness efforts with minimal lead time

Price/dose • < $10/dose

• Inexpensive and simple manufacturing process with US manufacturing capacity preferred

Registration • Meets criteria for US FDA BLA approval and licensure

• Meets criteria for US FDA BLA approval and licensure

• WHO Prequalification

1. Are there additional vaccine characteristics missing, or are there any currently on the list you would remove and why?

2. Are there any target performance levels that should be modified and why?

3. Which criteria may be feasible in the near-term (next 2-3 years) and which may be longer-term goals (5+ years)?

4. Which of these product attributes are most important to our health security preparedness and why?

5. Which of these product attributes would most incentivize end users (patients, caregivers, clinicians) to choose to get vaccinated?

6. Are there specific populations, for which an optimal vaccine design is likely to benefit? Are there features of a possible vaccine that are currently missing that might provide additional benefit to specific populations?

7. Are there any other features of the TPP that may improve availability in low-middle income country settings, expanding the global reach of vaccines that may be eligible for prizes?

3.2 MEASURING A PRODUCT’S ABILITY TO MEET THE OBJECTIVE

The ability to objectively measure and evaluate a vaccine based on a given attribute will be critical to administering any type of pull incentive. BARDA recognizes that many of the most desirable features of a vaccine as described in the above TPP are often difficult to measure and therefore difficult to evaluate reliably, and with sufficiently low cost and ease. Additionally, in many cases some attributes, such as transmission blocking, while valuable from a public health perspective, might go beyond the regulatory evaluation framework of safety and efficacy. However, to avoid discouraging continued innovation and investment in these more desirable features for products in development, BARDA is seeking input on opportunities for incorporating and/or developing new testing and evaluation methodologies or products.

1. Given the objectives suggested above, how should product developers prove (including to BARDA) that their vaccine meets or exceeds either of the TPP attributes?

2. What trials, assays, tests, processes, etc. already exist and are validated by the scientific community that can prove a product is able to meet or exceed optimal product attributes?

Please provide specific feedback for each attribute.

3. What trials, assays, tests, processes, etc. will need to be developed to be able to prove a product can meet or exceed optimal product attributes? This can include approaches to lower cost, improve reliability, and expand accessibility of existing assay tools such that their use in large scale clinical trials may be more feasible or to establish entirely new types of assays/tools.

Please provide specific feedback for each attribute.

4. Which of these optimal TPP attributes should be tested and validated by an independent third party to ensure a consistent and fair evaluation is applied across all candidate products and why?

• Conduct post-marketing efficacy commitments as per FDA requirements

3.3 PRIZE AWARD AMOUNTS AND STRUCTURE

BARDA recognizes that both the size and the shape of the incentives matter. Overall, Project NextGen is a $5B initiative, focused on the development of therapeutic antibodies, vaccines, and enablers such as advanced manufacturing and flexible therapeutic platforms. Based on input from this RFI, BARDA will consider whether and how to deploy pull incentives with current funding, to increase the chances of successful next generation vaccines, whether candidate products are currently in later stages or earlier stages of development and whether they align to threshold or optimal TPP. BARDA has not yet determined what size and shape of incentives are needed for successful deployment of any pull incentives, in addition to the existing phase 2b efficacy studies sought in the previously referenced BAA.

Therefore, BARDA is seeking community input on what those incentives should be. Specifically, BARDA is seeking input on:

I. The size of the overall prize pool necessary to effectively and competitively incentivize private industry, for both new and emerging companies as well as more experienced companies, to develop next generation COVID-19 vaccines for each respective track and;

II. The distribution of that pool along various stages of development and commercialization including numbers of winners.

III. Any potential interest among other funders to work with BARDA to enhance any effort that BARDA initiates, either in direct collaboration or in coordination.

We envision two types of pull incentives8 and that incentives can be offered at one or more milestones9.

For either scenario, BARDA would likely use a pre-registration process to identify viable participants at the outset. This would have two advantages. First, that BARDA would have a chance to confirm eligibility and alignment of the vaccine with the TPP, and to ensure that the endpoints align with BARDA’s expectations of awards. Second, private investors and the boards of directors of companies participating will have greater confidence of eligibility towards investing in the product development.

8 (1) Single payment for successful completion of milestone, pre-negotiated with specific organizations, or (2) single payment for successful completion of milestone, competitive to a wide field of participants.

9 (1) The completion of a phase II study, (2) an award of a BLA, and (3) successful market entry through reimbursement or another pathway for at least one year.

Figure 1. Two Tracked Award Structure Approach

Please answer the questions in this section based on the assumption that prize funds are awarded without any special rights provided to the US Government on intellectual property or purchase commitments of products.

3.3.1 Questions Regarding Pull Incentive Structures

Table 2. Scenarios and Accompanying Questions

SCENARIOS DESCRIPTION QUESTIONS

SCENARIO #1 BLA OR

COMMERCIALIZATION

PRIZE ONLY -

THRESHOLD

One grand prize upon successful commercialization of a product, either at a BLA award stage, meeting minimum requirements, or after 1 year of commercialization.

1. Should BARDA make awards based on award of a BLA or after 1 year of commercialization?

2. Should BARDA consider awarding to multiple winners, first to finish, or some other criteria?

3. Is a grand prize likely to stimulate private investment in R&D? Why or why not?

4. What would be an appropriate measure of successful commercialization?

SCENARIOS DESCRIPTION QUESTIONS

SCENARIO #2 BLA OR

COMMERCIALIZATION

PRIZE ONLY -

OPTIMAL

One grand prize upon successful commercialization of a product, either at a BLA award stage, meeting optimal requirements, or after 1 year of commercialization.

SCENARIO #2:

ADDITION OF

INTERIM PRIZES FOR

COMPLETION OF

PHASE 2

Interim prizes for demonstrated progress toward the optimal TPP after completion of a phase 2 clinical efficacy trial, and one grand prize upon successful commercialization of a product that sufficiently meets the optimal TPP.

1. What should BARDA set as the interim and grand prize pay outs and why?

2. Should BARDA base interim pay outs on positive clinical trial data or simply on their completion?

3. How many interim prizes should BARDA consider?

4. Would an interim pay out spur continued investment by private investors or company internal resources to continue with development

5. What are the main points of consideration for a company to continue with development of a vaccine beyond phase 2? How does potential prize money affect that decision?

1. What should BARDA set as the grand prize payout and why? *Please provide number and the economic reasoning behind the selected amount, considering costs of development and potential ROI from product once marketed

2. If early-stage direct funding support (i.e., grants or contracts) was available, how would that affect the size of the prize payouts in scenarios 1, 2 and 3 above necessary to incentivize private industry participation?

3. Would the change in prize pool be proportional to the amount of direct funding support? Please provide an explanation for your answer.

4. Which of the scenarios would encourage the most participation by private industry and maximize chances for at least one product to be commercialized that meets optimal TPP?

5. Which scenario, if any or both, would fail to properly incentivize private industry to commercialize a vaccine that meets optimal TPP?

6. Should BARDA consider having partial awards for meeting some but not all TPP attributes?

7. Are there other pull incentive structures beyond prize awards that would be better at incentivizing private industry to develop next generation COVID-19 vaccines than those mentioned in Scenarios 1, 2, or 3?

8. How should BARDA factor in risk of technological failure into the incentives?

9. How should BARDA define and determine successful commercialization and why? One example could be successful achievement of BLA. Another could be whether major insurers reimburse for vaccination or whether it’s available at major healthcare systems and/or pharmacies.

3.4 FEATURES OF THE AWARD STRUCTURE

BARDA is requesting your feedback on collaboration opportunities with procurement organizations and your thoughts on additional considerations.

3.4.1 Collaboration Opportunities

1. Should BARDA consider collaborations with organizations that might include offering Advance

Market Commitments10 (AMCs) or complementary prizes? In this case, for international procurement, a procuring organization provides an advanced market commitment to purchase specific volume of bulk or fill finish vaccine, over several years.

1. What volume of an AMC is likely to increase private participation or stimulate private investment? How does payment value of the vaccine influence this answer?

2. Are there specific conditions of an AMC that might be attractive or unattractive for participation among vaccine developers (e.g., price cap, guaranteed AMC vs payment once doses delivered, top-up payments etc.)?

3. If you are a funding organization interested in partnering with BARDA on this effort, what specifically would you be willing to offer and under what terms and conditions?

4. If you are not interested in a direct collaboration, are there other modes of sponsorship you would consider, e.g., offering prizes or AMCs separate from BARDA? Would you be willing to agree to coordinate with BARDA as part of that?

3.4.2 Additional Considerations

1. Should BARDA consider requiring any participant to allow their products to be used as comparators for future vaccine development as a condition of receiving a prize or AMC? Why or why not?

2. Should BARDA consider any pricing benchmarks, e.g., compared with pricing in other countries considered by World Bank as high income?

3. What other considerations on the terms of awards should BARDA consider not described above?

10 An advance market commitment (AMC) is a binding contract, typically offered by a government or other financial entity, used to guarantee a viable market for a product once it is successfully developed.

4 INSTRUCTIONS FOR SUBMITTING A RESPONSE

Respondents do not have to respond to any specific question. Commenters responding to this RFI may provide comments in a format that is convenient to them.

All responses should be submitted in .pdf form via email to Caleb Owen, Contracting Officer, at caleb.owen@hhs.gov by NLT 5:00 PM EST on August 10, 2023.

5 ADDITIONAL INFO

Disclaimer:

This RFI is issued for information and planning purposes only and does not constitute a solicitation. All information received in response to the RFI that is marked as proprietary will be handled accordingly by the Government. In accordance with FAR 15.201, responses to this notice are not offers and cannot be accepted by the Government to form a binding contract. Responders are solely responsible for all expenses associated with responding to this RFI. All information submitted in response to this RFI shall remain with the Government and will not be returned.

mailto:caleb.owen@hhs.gov