Master Alliance Provisions Guide (MAPGuide)

How Can Product-Specific Factors Affect the
Terms of an Agreement?

The particular context of some product development funding agreements means that they need to include provisions designed to address issues that are specific to the product. This commentary examines two examples of such provisions:

1. Stewardship obligations for antibacterial products; and

2. Preparedness and response provisions for products intended for use during a disease outbreak.

1. Stewardship obligations

The commercialization of antibacterial products needs to be accompanied by specific safeguards to mitigate the risk of antimicrobial resistance (AMR), which would make products ineffective and result in an inefficient use of funding. Funding agreements can address the need for such safeguards through the use of stewardship obligations that require product developers to take steps to prevent inappropriate use of a product, including acting in compliance with recognized industry guidelines for combating AMR. Stewardship requirements can also be included as a component of the access plan for the product.

Examples from the MAPGuide

The purpose of [Funder] is to protect humanity from the most serious threats from drug-resistant bacterial infections by accelerating antibacterial product development. Over the long term, the new products invented or developed with [Funder] funding (the “Products”) must be sustainably managed and used to promote “Access, Not Excess,” including:

(i) Thoughtful and effective stewardship of new Products whose utility is diminished by resistance, to prevent inappropriate use and therefore premature resistance, in line with the Global Action Plan on Antimicrobial Resistance developed by the World Health Organization;

(ii) Through planning for and ensuring appropriate access to new Products, especially in low and middle-income countries; and

(iii) Avoidance of misaligned commercial incentives, which go against the above-stated goals.

Therefore, the [Developer] agrees that Products will be manufactured, marketed, and sold under practices consistent with the applicable principles of the Davos Declaration on Antimicrobial Resistance – January 2016 or the Industry Roadmap for Progress on Combatting Antimicrobial Resistance – September 2016.

The Stewardship and Access Plan. When its Product enters Phase III trials (or Phase IIb trials, if they are intended as the pivotal trials to support registration, or otherwise, when the [Developer] is preparing a Product that is not a therapeutic or preventative for First Approval as defined in Section [x] below), the [Developer] shall create and provide to the [Funder] within ninety (90) days, a plan reasonably describing how it intends to meet the above stewardship and access obligations for the Product, (the “Stewardship and Access Plan”). 

Source: taken from the template CARB-X (Funder) cost-reimbursement agreement with subrecipients (Developer) for the early stage development of antibiotics, vaccines, and rapid diagnostics against bacterial threats. Read in context.

To delink sales representative remuneration from the quantity of antimicrobial supplied in England and not to otherwise promote or encourage inappropriate use;

To act and behave in a manner consistent with the principles of good antimicrobial stewardship and to comply with any antimicrobial stewardship recommendations resulting from the [Health Technology Assessment] and / or [Public Health England] and/or published by [the National Institute for Health and Care Excellence];

To support education of healthcare professionals regarding appropriate use of the antimicrobial consistent with good antimicrobial stewardship;

Source: taken from a supply agreement used by NHS England with both Pfizer and Shionogi for the supply of antibiotics. The agreements use a new subscription model approach intended to prevent the over-prescription of antibiotics while still creating a viable and sustainable market to encourage continued innovation and supply by product developers. If this model proves successful, it has potential for use in LMIC markets. Read in context.

2. Outbreak Preparedness and Response

Some funding agreements are entered into to develop diagnostics, therapeutics, or vaccines in anticipation of health emergencies in the form of disease outbreaks, epidemics, or pandemics. Some key considerations for these agreements include:

    • How the developer and funder can be best prepared to act if an outbreak occurs before the completion of the product development and approval process;
    • How a finished product should be stored before the occurrence of an outbreak (e.g., a stockpile), and who should have control over access, so that it can rapidly be made available when and where it is needed; and
    • The actions that the developer and funder should take to respond when an outbreak occurs.

Some approaches that can be used to address these considerations include:

    • Ensuring alignment between the agreement parties as to when emergency response activities are triggered by defining when a disease outbreak is deemed to have occurred, and providing for elevated preparedness when an outbreak appears highly likely;
    • Mitigating against the risk of potential supply shortages in the event of an outbreak through a requirement to identify Trusted Manufacturers who could provide additional manufacturing capacity if needed for emergency response (also discussed in more detail here);
    • An agreed approach to conducting clinical trials in the event of an outbreak, particularly if there is a limited pool of potential participants.
    • An obligation for the developer to manufacture a stockpile of a final product that the funder may utilize if needed for emergency response; and
    • An agreement between the parties that there may need to be extensions or reductions to project scope as a disease outbreak and related response mechanisms evolve.

Examples from the MAPGuide

Increased Outbreak Preparation Need” means when, having considered all reasonably accessible and relevant information including epidemiological data, travel and migration patterns and the likely availability of other products or product candidates, [Funder] determines, in its sole discretion in consultation with experts (for example a sub-group or subcommittee of [Funder]’s Scientific Advisory Committee that [Funder] determines has appropriate expertise), that there is a heightened need for the Product to address potential Outbreaks.

“Outbreak” means a Public Health Emergency of International Concern declared by WHO, or a public health emergency on a national or regional scale declared by one or more public health agencies, in each case as a result of a material increase in the number of cases of people infected with [Disease] including any regional out-break, an epidemic or a pandemic.

Source: taken from a development funding agreement between CEPI (Funder) and Valneva (Developer) for manufacturing and late-stage clinical development of a Chikungunya vaccine. Read in context.

[Developer] acknowledges that the pool of subjects available in areas of Outbreak to participate in a clinical study to test products such as the Product may be limited. Accordingly, if [Funder] reasonably determines in consultation with experts (for example a sub-group or subcommittee of [Funder]’s Scientific Advisory Committee that [Funder] determines has appropriate expertise) that a product other than the [Developer]’s Product has substantially greater potential, as determined in accordance with WHO guidance or relevant local regulatory guidance and should be used for a particular clinical study of subjects in areas of Outbreak, the [Developer] agrees that it shall abide by such decision and will not proceed with any clinical study of the Product with subjects from areas of Outbreak unless agreed with [Funder]. In the event that [Developer] must discontinue a clinical study of the Product in areas of Outbreak according to [Funder]´s determination pursuant to this Clause [x], then [Funder] shall (i) cooperate with [Developer] in an appropriate wind down of the study and (ii) to the extent not funded in advance by [Funder], reimburse [Developer] for [Developer]’s reasonably incurred non-cancellable expenses relating to such discontinued clinical study. For clarity, [Developer] shall not pay back any sums already received from [Funder] that have been actually spent by [Developer] in connection with such discontinued clinical study. For the purposes of this Clause, [Funder] agrees that nothing in this Clause [x] will prevent (i) [Developer] from undertaking a Pivotal Study in any country; or (ii) [Developer] fulfilling its obligations under its risk management plan prepared by [Developer] in connection with its biologics license application in any country, including but not limited to post registration efficacy trials or any other commitment with any relevant regulatory authority to conduct a clinical study that would support the development of the Product . For the purposes of this Agreement, “Pivotal Study” shall mean a clinical study designed to fulfil the requirement for the filing of an application for a marketing authorization for a Product and that is acceptable to the relevant regulatory authority as a basis for the grant of a marketing authorization.

Source: taken from a development funding agreement between CEPI (Funder) and Valneva (Developer) for manufacturing and late-stage clinical development of a Chikungunya vaccine. Read in context.

Subject to the undertakings to be defined in the Additional Work Packages and – upon [Developer]’s request, subject to a separate confidentiality agreement to be concluded between the [Developer] and the Trusted Manufacturer – the [Developer] will support [Funder] in appointing one or more Trusted Manufacturers that are technically and operationally capable of and willing to rapidly Manufacture Product for use in the Field in the Affected Territory on an ongoing basis both during and after completion of the Project, in accordance with [Funder]’s requirements, as set forth herein.

Subject to the undertakings in the Additional Work Packages the [Developer] shall:

(i) grant appointed Trusted Manufacturers all necessary rights to use (on a non-exclusive, royalty-free and license-fee free basis) the Background Technology and Project Technology to further Develop the Platform, and to Manufacture Products for use in the Field in the Affected Territory in accordance with the [Funder] Production Timescale and in the quantities reasonably likely to be necessary in the event of an Outbreak or risk of Outbreak in the Field and at a cost of goods in line with the methodology to determine pricing obligations set out in the [Funder] Equitable Access Policy;

[…]

(iii) at the request of [Funder], enable Trusted Manufacturers to establish a warm base for the further Development of the Platform, and Manufacturing of Products for use in the Field in the Affected Territory. […]

[Developer] nominees for Trusted Manufacturers. Upon [Funder]’s request, [Developer] will use Reasonable Efforts to notify [Funder] of suitable Trusted Manufacturers for appointment by [Funder].

[Funder] nominees for Trusted Manufacturers. [Funder] may nominate by notice in writing to [Developer] Third Parties as suggested Trusted Manufacturers. The [Developer] shall consider any Third Parties nominated by [Funder] as potential Trusted Manufacturers in good faith. Where a Third Party nominated by [Funder] is not acceptable to the [Developer] on reasonable grounds (including commercial grounds), the [Developer] shall notify [Funder] promptly of its decision and the reasonable grounds and [Funder] shall not appoint such Third Party as a Trusted Manufacturer.

Source: taken from a development funding agreement between CEPI (Funder) and CureVac (Developer) for the development of CureVac’s mRNA platform for the rapid manufacturing of vaccines against infectious diseases. Read in context.

 Within [***] of receipt of marketing approval for the Product from the FDA, [Developer] will produce, at [Developer]’s own cost, a [***] safety stock comprised of not less than two hundred thousand (200,000) doses of final Drug Product. For clarity, [Developer] will use commercially reasonable best efforts to keep such deadline of [***], however, it will be subject to the lead times of [Developer]’s contract manufacturers and the time required for the release testing of the Product. [Developer] may use such safety stock to supply the [Developer]’s Traveler’s Market and will replenish such stock on a rolling basis at [Developer]’s cost. The stock in paragraph [x] and this paragraph [x] is referred to as (“Safety Stock”). 

In case of an Outbreak or Increased Outbreak Preparation Need, [Funder] may utilize such Safety Stock in the Affected Territory by giving notice in writing to [Developer] and [Developer] will dispatch all or some only of the Safety Stock, as instructed by [Funder] and [Funder] shall pay any reasonable costs incurred in connection with the utilization of the Safety Stock, including but not limited to transportation, distribution and storage in the Affected Territory. For clarity, [Developer] shall make no charge for the supply of the Safety Stock allocated to and used by [Funder] in accordance with this paragraph 15.2 (iii) and the storage costs of such Safety Stock, incurred prior to dispatch to the Affected Territory, shall be borne by [Developer].

If the Safety Stock is used by [Funder] in the case of an Outbreak or Increased Outbreak Preparation Need, [Funder] or such third parties as [Funder] may nominate shall be responsible for the costs of transportation of such Safety Stock from [Developer]’s facility. If, following the use of the Safety Stock as directed by [Funder], [Funder] wishes to replenish the Safety Stock, [Developer] shall produce such quantities of Product as are required to replenish the Safety Stock and [Funder] shall pay [Developer] for the costs of the production of such Product.

[Funder] will notify [Developer] in writing in the event of an Outbreak or if there is an Increased Outbreak Preparation Need, in each case identifying the Affected Territory (“Outbreak Notice”). Once an Outbreak Notice has been provided by [Funder], [Funder] shall have the right to direct how the Safety Stock referred to in Clause [x] or any Product manufactured pursuant to Clause [x – preparation for outbreaks] may be used and to whom it may be provided in the Affected Territory. […]

In addition to the Safety Stock referred to in Clause [x], [Funder] may request that [Developer] undertake, at [Funder]’s expense, the manufacturing and maintenance of an additional stockpile of Investigational Product or Product for use in or for the Affected Territory. Such Product may be used for further clinical trials in Outbreak conditions to advance vaccine development, or pursuant to an emergency use authorization, in each case in emergency situations based on national or international guidance (such as WHO), or in such other manner within an Affected Territory as [Funder] may reasonably determine. An additional Work Package covering this activity will be negotiated expeditiously and in good faith by the Parties.

Source: taken from a development funding agreement between CEPI (Funder) and Valneva (Developer) for manufacturing and late-stage clinical development of a Chikungunya vaccine. Read in context.

[…] In consultation with relevant public health authorities in the Affected Territory, [Funder] may request that [Developer] discuss in good faith whether and how the Project Results could be utilized in response to the Outbreak Notice. [Developer] is committed to use commercially reasonable best efforts to address Outbreaks and Increased Outbreak Preparation Need wherever they occur in the world. Following receipt of an Outbreak Notice, [Developer] will use its commercially reasonable best efforts to increase the supply of Product available for use by [Funder] or its nominees to an amount which equals at least [***] of the production forecast for the Products prepared by [Developer] immediately prior to service of the Outbreak Notice and [Developer] will use its commercially reasonable best efforts to ensure that such increased capacity is available for delivery to [Funder] within [***] of the date of service of the Outbreak Notice. For clarity, [Developer] will use commercially reasonable best efforts to keep such deadline of [***] (including discussing with [Developer]’s contract manufacturers how they can meet the proposed deadlines), however, [Developer]’s ability to meet deadlines will be subject to the lead times of [Developer]’s contract manufacturers and the time required for the release testing of the Product. In the event that [Funder]’s request for Product to meet the increased demand during an Outbreak or Increased Outbreak Preparation Need is in excess of the quantities that [Developer] is able to supply to [Funder] based on [Developer]’s commercially reasonable best efforts, [Developer] shall not be obliged to supply Product to [Funder] under this Clause [x] to the extent that the supply of such quantities of Product to [Funder] would result in [Developer] being in breach of any binding contracts in existence on the date of service of the Outbreak Notice (which for the avoidance of doubt may include the supply of Products to customers for [Developer]’s Traveler’s Market or in connection with any clinical trials). […]

Additional Product Development. Pursuant to an Outbreak Notice, [Funder] may request that [Developer] undertake additional Product development at [Funder]’s expense or undertake other activities, including the pursuit of regulatory approvals and licensure to the extent not already obtained, with the aim of addressing the needs of the Affected Territory. An additional Work Package covering these activities will be negotiated expeditiously and in good faith by the Parties.

Trusted Collaborator: Promptly after receipt of a written request from [Funder] (or at any earlier time), [Developer] will propose a third party, for example, a Sub-Awardee, as a preferred alternative to itself (“Trusted Collaborator”), that is capable of performing the work and would be prepared to undertake activities pursuant to Clause [x – preparation for outbreaks] in the event that [Developer] declines [Funder]’s request to do so, or if [Developer] and [Funder] do not reach agreement on a new Work Package. [Funder] may also propose a Trusted Collaborator to [Developer]. Neither Party may unreasonably decline to accept the designation of a proposed Trusted Collaborator.

Source: taken from a development funding agreement between CEPI (Funder) and Valneva (developer) for manufacturing and late-stage clinical development of a Chikungunya vaccine. Read in context.

Outbreak response activities include:

i. the collection and sharing of trial subject information in accordance with Funder Policies, including information about pathogens such as sequence data;

ii. engagement with affected communities to establish mutual trust;

iii. integration of [Developer] research efforts into Public Sector Agencies’ epidemic response;

manufacture of additional investigational doses of Product (if necessary) or manufacture to replenish Investigational Stockpile;

iv. negotiation of clinical trial contracts;

v. performance of independent ethics reviews; and

vii. implementation of prepared clinical trial designs.

Source: taken from an anonymised product development funding agreement. Read in context.

The Parties acknowledge the possibility that, as the Outbreak develops in ways not foreseen in the initial Work Package(s), a Project Expansion may become essential. For example, the extent or severity of the Outbreak may increase, the Project Vaccine may be prioritized by public health authorities for clinical studies and/or manufacture or advances in vaccine technology may permit acceleration of the Project. Alternatively, it may become necessary for [Funder] to limit Project scope or defer certain activities. For example, the WHO may determine that the Outbreak is no longer a Public Health Emergency of International Concern (“PHEIC”), third party products may be prioritized for development or deployment by an international decision-making process, [Funder] may need to focus its resources on other product in its portfolio, or the Project Vaccine may not appear to meet Outbreak response needs.

Implementing Changes in Project Scope or Timing. At the request of either Party, and as a matter of urgency, the Parties shall discuss in good faith: (i) whether a Project Expansion may be undertaken at [Funder]’s cost through modification of an existing Work Package, approval of an additional Work Package or utilization of the Project Continuity Plan in Clause [x – continuity]; or (ii) how best to limit Project scope or defer certain activities in a Work Package. For clarity, during the Outbreak, [Funder] reserves the right to terminate a Work Package if this is necessary in its sole discretion, provided [Funder] pays [Developer] all costs incurred or obligated to date and including any non-cancellable costs under such Work Package, and also provided that, if requested by [Funder], [Developer] shall reasonably demonstrate the incurred, obligated or non-cancellable nature of such costs.

Source: taken from a development funding agreement between CEPI (Funder) and Novavax (Developer) for a COVID-19 vaccine. Read in context.

Related Commentaries

Product-specific provisions need to be supported by reporting requirements that enable a funder to monitor a developer’s compliance with the obligations.

Authors: Bridie Telford

First publication date: November 21, 2022