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Call for Proposals CEPI (CEPI-CfP-003)Project description template

Cover page: This is the “Project description” for the Call for Proposals (CfP3) Human vaccine development against Rift Valley fever (RVF) and Chikungunya (CHIK). Instructions on how to complete the project description form are presented in italics. It is mandatory to submit complete information and to comply with the given format and maximum page/word-restrictions as indicated. Before submission, please delete this disclaimer text, as well as all guideline text that is in italics in sections throughout this document, and replace with your own text. Please keep the headings in bold under each section and indicate if not applicable.

The text format requirements for the Project description are: - Calibri light theme, font size 11- Single spacing- Maximum page length (excluding appendices): 40 pages in total.

In addition to this project description, applicants must also upload the following documents using the templates provided:- Overall Budget (Excel file) and Overall Budget narrative (PDF file)- Individual Sub-awardee Budget (Excel file) and Sub-awardee Budget narrative (PDF file)- A maximum of 10 CVs or bio sketches (max. 2 pages per CV/bio sketch for Applicants, Partners and Key Experts) (PDF

file)- Signed letters of support for all partners confirming their agreement to participate in the proposed projects and

agreeing with the content of the proposals (PDF file)

Deadline for proposal submission is the 5th of March 2019 15.00 CET. If you are planning on submitting, please let us know by 1st February 2019 to best plan for the subsequent review process. Please contact CfP team before 26 of February for uploading instructions. We encourage you to submit your proposal well in advance of the deadline.Contact detail: [email protected]

1. Project summary1.1. Project Title Give the title of the project.

1.2. Project summary (500 words)Give a summary of the proposed project, including rationale, technology, targeted pathogen, R&D objectives, expected outcomes and timelines (preferably within a timeframe of 12-15 months). Please outline the composition of the consortium with names of institutions/partners, project duration and total project costs.

Identify the development status of the candidate vaccine:- Current phase of vaccine development.

o Choose one of the following categories: Preclinical (candidate constructed, AND/OR immunogenicity data, AND/OR challenge data, AND/OR ready for

Phase I clinical trial) In Phase I clinical trials Ready for Phase IIb / III clinical trials In Phase IIb / III clinical trials

- Safety and immunogenicity data in target population.- Licensing strategy (e.g. FDA animal rule, WHO EAUL or other)

Version 1.0, date: 04 Jan 2019

2. About the applicant organization / consortium2.1. About the applicant organization and cooperating partner(s) / consortium

Provide a brief description (2-3 pages) of the organization and cooperating partners. Describe size - number and experience of leadership and senior employees, key project staff R&D achievements, number of years in operation, research environment, any affiliations to national and international R&D networks, etc.

2.2. The experience and track record of applicant organization, principal investigator and cooperating partner(s)Describe competence and experience in relation to the project, including one or more of the following:

Preclinical studiesDescribe the experience and capacities for preclinical studies and investigations, including availability of animal facilities and testing experience in the project consortium for performing the project.

Phase I / II clinical vaccine trials Describe the experience of applicant organization or consortium in clinical trials (notably FIH), including:- Previous clinical testing of vaccines in high-income countries - Previous clinical testing of vaccines in low- and middle-income country settings (LMICs)- Previous clinical testing of vaccines based on the proposed technology platform- Establishing and running clinical trial sites- Systems to ensure and track-record of GCP audits/inspections

Bringing vaccine to IND and Phase II enabling studies Describe the experience in bringing vaccine candidates to IND/IMP and Phase II enabling activities.

Phase III clinical efficacy vaccine trials Describe the experience of applicant organization or consortium in clinical trials, including:- Previous experience with bringing vaccine projects through clinical development to licensure- Previous clinical testing of vaccines in high-income countries - Previous clinical testing of vaccines in low- and middle-income country settings (LMICs)- Previous clinical testing of vaccines based on the proposed technology platform- Establishing and managing clinical trial sites

Bringing vaccines through a regulatory pathway over the past 10 years Describe the experience in bringing vaccine candidates through standard regulatory pathways for market authorization, your track-record of licensing vaccines through alternative regulatory pathways for product registration and / or delivery for emergency use to national (e.g. US FDA’s “Animal Rule”) or supranational organizations (e.g. WHO EUAL). Include experience with WHO prequalification.

Manufacturing Describe the manufacturing experience at various scales, including an overview of the manufacturing process steps and timing, and any form / fill / finish experience and timing for pandemic response (as needed). Mention GXP level and bodies involved in inspections (if any).

Infrastructures and facilities in-house Describe any infrastructure and facilities available to support the project.

Vaccine trials and associated results published by the applicant’s PI in the last 5 yearsPlease list clinical trials, with trial ID hyperlink and associated results published by PI in the last 5 years.


3. Project status3.1. The proposed vaccine candidateDescribe the immunological principle, construct, formulation and proposed route of administration of the vaccine candidate, and the potential progress in establishing a correlate of protection or a sufficiently plausible surrogate marker.

3.2. Scientific rationaleDescribe the scientific rationale for/if:- The proposed vaccine candidate technology, rationale for antigen choice, antigen presentation and platform selected- The immune response induced and likely mechanism for providing protection against the target pathogen - The mode and route of vaccine administration- If an adjuvant is used, justify the choice of adjuvant and explain the expected benefits of its use- The use of a specific formulation (e.g. nanoparticles)3.3. Preclinical evidence to dateDescribe the current state of preclinical development for the proposed vaccine candidate, including (if available): - Data on immunogenicity for the targeted or relevant pathogens including functional antibody responses and protective immunity

(both in humans and animals, as available)- Data on protection in relevant animal challenge models - Data on passive protection (transfer of antibodies or lymphocytes)- Data from toxicology studies relevant for the planned trial3.4. Clinical evidence to dateDescribe any safety and immunogenicity data from Phase I / First in human (FIH) trials if available. Include safety, local and systemic reactogenicity and immunogenicity data, study population, assays validates, and any concerns/useful observations. 3.5. Assays, animal models and supporting relevant data developedProvide a brief description of research achievements produced by your consortium that will directly support the development of the candidate in this proposed project, such as: - Assays validated and/or suitable for assessment of immunological responses to vaccine for targeted or relevant pathogen- Animal models developed for eliciting an immune response and clinical protection- Antigen characterization- Protective mechanism studies relevant for the target pathogens3.6. Evidence from other pathogens Give a description of any data available on the same vaccine platform for pathogens other than CHIKV & RVFV, including preclinical, toxicology, safety and reactogenicity profiles, especially data from candidates in a more advanced stage of development or already licensed. Also include if there are any particular points of attention based on the experience to date with the candidate vaccine or the platform, such as points raised by ethical committees / DSMBs / regulatory agencies.3.7. Evidence on Chemistry, Manufacturing & Control (CMC) Describe the status of Good Manufacturing Practice (GMP) activities (as needed), including information (if possible) on any of the following areas (the areas to include depend on the phase of development):- Drug substance & drug product / vaccine CMC activities (e.g. Analytical methods; Purity & impurity characterization; Quality

assurance / control)- Manufacturing capacity (in quantities and related timing)- Costs Of Goods Sold (COGS) and/or estimates including rationale for these


4. Project plan4.1. ObjectivesThe Project Plan section should be designed to ensure that adequate control can be maintained during each Work Package, as well as ensuring that any delays/failures do not jeopardise the entire project.The Work Packages to be used for the project plan are set out below. You can include one or more work packages (for same pathogen in your project plan). Work packages are expected to run concurrently.

CHIKV RVFVWP1 - Clinical trial activities WP1 - Clinical trial activitiesWP2 - CMC activities WP2 - CMC activitiesWP3 - WHO PQ activities WP3 - WHO PQ activitiesWP4 - Correlate of protection studies WP4 - Animal immunogenicity studiesWP5 - Enabling science WP5 - Animal protective efficacy studiesWP6 - Reproductive toxicology studies WP6 - Transition to human product

WP7 - Reproductive toxicology studiesWP8 - Correlate of protection studiesWP9 - Enabling science

Points to note:- Objectives for the relevant phase(s) of development to your project should be clearly defined.- Milestones and Deliverables should be clearly delineated. These are particularly important when moving between activities (e.g.

completion of toxicology batch manufacture and moving into preclinical testing).- Development phase endpoints should be defined that ought to be considered when conducting an end-of-phase evaluation of

your project.

Having read the above instructions, please outline the objectives for your project here. 4.2. Expected outcomesIn this section, outline the expected outcomes and the criteria which will need to be met for the successful completion of the relevant phase of development of your proposed project. 4.3. Preclinical and non-clinical strategyPresent the preclinical strategy and brief synopsis of studies proposed. Animal models (at least 1 and preferably 2 or more) should be relevant both to the proposed disease target and the vaccine-construct, and you should be able to demonstrate that the proposed number of animals in the study design(s) have gone through a power analysis to reduce the number of animals, but also to ensure the validity of the study design(s).

Please note that should your application proceed to latter stage evaluation you will be asked to complete an NC3R questionnaire outlining your animal studies. CEPI is bound by these principles and will not fund unethical studies.

In presenting the preclinical and non-clinical strategy, include clarifications and rationale for: - How you plan to establish key immunogenicity/efficacy data in relevant animal models- Dose-ranging/rationale for doses for clinical testing

4.4. Clinical strategy Present the clinical development plan for vaccine pre-qualification studies and a brief synopsis of the proposed trials (as needed). Where applicable, include clarifications on:- Clinical objectives and anticipated endpoints including strategy to validate a potential surrogate of protection- Clinical trial plans, locations and numbers of study subjects for safety, immunogenicity and efficacy studies- Target study populations

4.5. Regulatory strategyOutline your proposed regulatory strategy for overall development through to a future licensed product. Pay particular attention to any non-standard elements of your platform (novel, without any regulatory guidance…) which are likely to result in the need for detailed scientific advice. In presenting the regulatory strategy, include:- a description of actions you would undertake to be under review within WHO emergency use assessment and listing procedure

(EUAL), when applicable[1][1]. - clarifications also on how you plan to obtain regulatory advice with respect to preclinical and clinical development, regulatory

approval to conduct clinical trials including in low- and middle-income countries (LMICs), and regulatory approval for licensure.

4.6. Process development and manufacturing strategy

[1][1] http://www.who.int/medicines/news/public_consult_med_prods/en/Version 1.0, date: 04 Jan 2019

Describe process development, manufacturing and validation strategy and product form that will be used to prepare material for each development phase. Include clarifications on:- Production processes from preclinical through Phase I (“First-in-Man”) to end of Phase III studies and beyond (if relevant)- Analytical and Process qualification and validation with regards to purity, safety, potency, stability and BSE risk- Other Quality assurance/ control processes (as relevant)- Technology Transfers to final scale of manufacturing- Studies on formulation which may aid vaccine pre-qualification

Please refer to Section 5.3 and should your project focus on CMC development then please fill out the template found in Appendix I.

4.7. Quality management strategy Explain how quality will be maintained throughout the project in all critical elements (clinical, preclinical, manufacturing). Detail your strategy and any mechanisms you may have already implemented.

4.8. Project governance and partners Describe anticipated collaborations with key partners/vendors and the approach to manage all partners and deliverables, including a specification of the activities to be performed by the collaborators & vendors. Describe plans for building capacity and a hiring plan which documents the ability of the consortium to staff the project appropriately.

4.9. Access policy Equitable access is a key requirement that applies to the outputs and outcomes of projects funded by CEPI. Equitable access to epidemic vaccines in the context of an outbreak means that appropriate vaccines are first available to populations when and where they are needed to end an outbreak or curtail an epidemic, regardless of ability to pay. We are also mindful of the importance that biological materials and data arising from CEPI funding may be useful in other projects funded by CEPI and beyond.

- Please explain how such equitable access requirements will be met during performance under the project and with respect to the outputs or outcomes of the project.

- Further, explain how you will obtain access to and rights of use of data and biological materials (including pathogen samples) that may be essential or useful to work under this project.

- Please explain how you would get any necessary governmental permissions to ensure such access is legally and ethically secured.

4.10. Pre-Award Project ImplementationCEPI may provide funding for pre-award costs that are incurred in the period from proposal submission to signature of a partnering agreement to advance the implementation of the project which is the subject of the proposal. Any such pre-award costs are, however, undertaken at the risk of the applicant. Funding by CEPI of pre-award costs would only be provided to applicants that: (i) are ultimately successful in their CfP3i application to CEPI, (ii) provide documentation to demonstrate to CEPI’s satisfaction that such costs did relate to advancing the activities proposed in the CfP3i application, and (iii) comply with CEPI budgetary rules and procedures. For the purpose of clarity, the pre-award costs eligible for CEPI funding do not include costs related to the preparation of the application itself (such as costs of technical, legal and financial consultants to develop or revise the CfP3i application and product development plan).

Please indicate if you will undertake project implementation activities at your own risk before finalisation and signature of the CEPI Partnering Agreement?:

Yes ☐

No ☐

If yes, please list the activities which you will undertake at your own risk:

5. Project plan supporting documents 5.1. Project scheduleProvide a detailed Gantt chart presented by Work Package, including milestones for the advancement of your project through the proposed phase of development, including from submission to signature and within 12-15 months after signature.

5.2. Risk assessmentIdentify at least four of the highest risks to the project in terms of probability of occurrence. Minimal impact is defined as: > 3 months


completion delay or 10% over budget. Mitigation strategies should also be considered. A CEPI risk register template will be provided if your application proceeds to due diligence.

5.3. CMC templatePlease fill out the Chemistry Manufacturing and Control template found in Appendix I5.4. Plan for further development after CfP3iInclude here information to illustrate your product development plan for your project after CfP3i funding is exhausted. We are interested in your overall plan for advancing your project through later phases of development (where relevant) and licensure / WHO PQ, in order to see further funding needs beyond CfP3i and potential additional funding in CfP3ii


6. Target Product ProfilePlease describe your Target Product Profile (TPP) for the vaccine candidate in the table below and how this could affect the use of the vaccine or response to emergency situations.

Vaccine characteristics Expected Rationale / Justification

Indication for use Include contra-indicationsTarget population including age, gender and other potential restrictions such as immune status

Safety/Reactogenicity

Measures of efficacy Include response time for protective immunity

Dose regimen

Duration of protection

Route of administration

Coverage

Product stability and storage

Presentation

Registration and prequalification


7. Anticipated use potential 7.1. Suitability of the vaccine candidate for use in disease outbreak settings Describe how the vaccine candidate would be used in an outbreak situation, highlighting aspects of the expected target product profile especially suitable for an outbreak response. Include aspects related to the expected product profile.

7.2. Suitability of the vaccine candidate for routine use Describe whether and how the vaccine candidate could and would be used routinely (e.g. expanded programmes on immunization).

7.3. Application to other pathogensDescribe if the platform has been or could be suitable for other pathogens, including those of the WHO priority list of emerging infectious diseases.


8. Budget and sources of funding8.1. Sources of fundingPlease complete an Excel budget file and accompanying Budget Narrative document for the project overall and for each sub-awardee (e.g., consortium partners). The Excel budget file and Budget Narrative templated, along with instructions for completing the budget file, can be downloaded on the same webpage together with this document.


9. Other information (optional)9.1. Status of vaccine pipeline in other pathogens of epidemic importancePlease indicate any other vaccine that you are currently actively developing or that is on hold due to financing constraints, and which is targeting one of the WHO priority pathogens, or any other infectious pathogen of epidemic preparedness importance. Please clarify:- Name of vaccine candidate- Type of platform technology- Current phase of development (discovery; preclinical; Phase I; Phase II; Phase III)- Current status of development (active; on hold)- Funding need (in US$) to advance the vaccine candidate through preclinical, Phase I, Phase II, stockpiles for Phase IIb / III,

Phase III, and stockpiles for emergency use (up to 1m doses) – as relevant


Appendix 1. CMC templateInstructions for applicants:

To support your application for CEPI’s CfP-3, this template requests the current and predicted CMC process scale and yields. We recognize that your programs may be only in pre-clinical development at this time, however, projecting the process for later development stages, based on experience with other programs, helps to understand the strategic approach and projected outcomes, should clinical stages be successful. We realize that your specific process may have gaps in some items in the following tables and that some aspects may be considered as work in progress, or not applicable to your particular technology, in such case, please input N/A. However, we ask you to complete the table to the best of your ability and leverage existing experience where it is available.

NOTE: Where applicable, please state any assumptions or other reference processes used to populate this template. For non-traditional production processes, please specify units of measure in the comments column.

Process specifications:

ParameterDevelopment stage

Comments (specify if yields are achieved or projected)Pre-clinical Clinical P1/P2 P3/Stockpile/

CommercialAnticipated clinical dose (units/dose: mcg, PFU, etc.) and Anticipated dose volume

e.g., 15 mcg/0.5 mL dose or 2x10^7 PFU/05 mL

Cell lineScale and format of USP

e.g., 10L CSTR, Single use/ stainless steel, Wave bioreactors, 40T multitrays, etc.

Yield of USP (dose/L)Harvest processDSP step 1 (% recov.)DSP step 2 (% recov.)DSP step 3 (% recov.)DSP step 4 (% recov.)DSP step 5 (% recov.)DSP step 6 (% recov.)DSP step 7 (% recov.)DSP step 8 (% recov.)DSP step 9 (% recov.)DSP step 10 (% recovery) and estimated overall yield (doses/L of USP)DS storage temp ( ̊C)DP storage temp( ̊C)Existing data on storage stability of in- process materials?

e.g., 6 mo @ -80 ̊C for DS and DP

DSP recovery (%)DS productivity (dose/L)Formulation/fill/finish (stabilizers, adjuvants, final container, delivery device, lyophilized, etc.)Proposed presentation and volumes.

e.g., single dose vial, multi dose vial, Prefilled syringe, etc.

Estimated Cost of Goods (USD or €/dose)


Please state CMOs, (if any), and stage of contract negotiations (Existing Contract, MOU, Preferred supplier status, etc.)

Key source materialsAnimal derived raw materials used in manufacturingSingle use components used in DS manufacturingGMP-certified ingredients confirmed (Y/N)Are there components that could result in difficulties of acceptance among communities following certain religious norms (e.g. material from pork or canine origin)?

Additional Information Please indicate sources of key specialty raw material/device to be used in the process. Do you have FTO? Please indicate any existing CMC-related IP and its potential impact on freedom to operate. Please indicate your knowledge of other products on the market or in clinical testing using the same or similar

technology. Have you had any formal or preliminary discussions with any competent regulatory authority regarding any aspect of

the process? If so, please provide the outcome as an appendix to this form. If using an adjuvant other than Aluminium salt, describe previous clinical or commercial experience.


i. Confirm status of the following for each target in the application and other targets if applicable:

Item Y(date)/N/NA Quantity prepared

Mfg. by: Comment

MCB prepared If not complete, estimate timing of completion

MCB releasedWCB preparedWCB releasedMVS preparedMVS releasedWVS preparedWVS releasedPre-clinical batches preparedClinical batches prepared

Additional Information For nucleic acid platforms consider MCB/MVS equivalent to library or template generation, USP equivalent to any

amplification step and DSP equivalent to the removal of in-process impurities.

Formulation Stability Data:

Please confirm the following for each target:

Stage: (state stability where available)

Time at 5oC

(mo.)

Time at 25 oC (mo.)

Time at elev. temp (mo.)

Time at frozen

temp (T, mo.)

Prescribed Storage

(Temp/time)

Comments / Rationale for

specifications

MCB stability studiesMVS stability studiesDS stability studiesDP stability studiesStability risks of any specialty process ingredients

List Specific Release Assays (current and projected, “in-sourced and outsourced”):

Stage MCB MVS DS DP


Purity (residuals for DS and DP)

Potency

Sterility

Safety

Stability

Key Characterization Assays

Identity

Additional Information For potency assay and key characterization assays, please provide information of the status of the assay development –

performed under non-GMP, assay qualified, assay validated, performed under complete GLP, etc. For nucleic acid (NA) platforms –Please elaborate your strategy to test integrity of NA sequence, and how RNAse/DNAse

activity is managed.

Summary of Technology Experience to date:

Please list all experience, including experiences of others using the same technology /process:

Parameter Disease Target Disease Target Disease Target Disease Target

Target Molecule

Pre-clinical Scale (USP, L)

Process yield at DP (dose/L)P1/2 Clin. Scale (USP, L)

Process Yield at DP (dose/L)

P3 Clin. Scale (USP, L)


Proposed Commercial Scale (USP, L)


Anticipated use of delivery device (if applicable)

Delivery Device/System information Describe the delivery device supply chain have you established Is the same delivery device intended for use, both in clinical trials and in the developing world setting? If not, what are the required steps to finalize a suitable delivery system? Would there be a need for bridging studies?

What are the risks related to the device development and manufacturing? What is the regulatory pathway for such a combination product (drug device combination)?

What is your status when it comes to implementation of the new MDR and ISO13485-2016?


Do you have a system to prevent re-use of disposables (if applicable)? What is the key evidence supporting the selected delivery method (e.g. dose (volume), electroporation parameters and

human tolerability data) you intend to use in the current project Provide a project plan for the deployment of the device to support the proposed Clinical Study timelines in this

document and achieve all necessary regulatory approvals and certifications (including WHO PQ)


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