PVA Process Map

Product development and marketing can be executed in diverse collaborations or support structures. While the types of business relationships can vary significantly, the overall responsibility for the pharmacovigilance system always remains with the Marketing Authorization Holder (MAH) / sponsor. Business relationships that affect the PV system are documented in PV contractual arrangements, often referred to as pharmacovigilance agreements (PVAs) or safety data exchange agreements (SDEAs), as required by regulations. Such agreements become an essential component of the PV system and allow MAH/ sponsor to fulfill obligations towards Health Authorities and PV partners.

PVAs follow a lifecycle that begins with establishing a new partner collaboration and ends with termination of the PVA. Management of PVAs requires time, resources and expertise. Failure to have a PVA in place in a timely manner may result in delays to clinical trial start, launch, and/or asset transfer, and may result in inspection/audit findings.

*A THICK LINE AROUND EACH BOX INDICATES THAT THERE ARE TOOLS ASSOCIATED WITH THIS STEP OF THE PROCESS. ADDITIONAL TOOLS FOR OTHER STEPS ARE UNDER DEVELOPMENT.

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    Phase 1

    Pre-PVA actions can drive success for the overall PVA lifecycle and oversight of PVA activities. Having well-established procedures in the Pre-PVA Phase can help companies to build a foundation for the PVA process and mitigate challenges, e.g., delays or inefficiencies in PVA creation in later phases.

    Key steps in Phase 1 that may help build this foundation can include:

    • Know and engage your internal stakeholders
    • Assess the contractual situation (”Is a PVA needed?”)
    • Provide input to main agreement
    • Evaluate partner PV system / due diligence
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    Know and engage your stakeholders

    Optimal and timely involvement of PV in new business collaborations is key to successful PVA development.

    The process of how the information about new PV-relevant business collaborations is transferred internally can be structured via procedures, trainings, tools or communication channels. Well-established cross-functional interfaces can support the information flow.

    The function responsible for PVAs can engage and foster internal collaborations with the relevant stakeholders, e.g., with business development/licensing function, in four simple steps:

    • Baseline existing procedures and activities related to managing new collaborations and interactions with affected stakeholders – are there any gaps?
    • Identify relevant internal stakeholders responsible for setting-up and managing collaborations and main contracts.
    • Touch base with internal stakeholders to convey value of timely and optimal PV involvement and educate what information is needed for PVA creation.
    • Establish regular interactions with selected internal stakeholders.

    HELPFUL TIP: Interfaces with internal stakeholders at this stage and early planning can support optimal assignment of resources for creation of the PVA and associated collaboration.

    Shape Tools and Resources

    Click here to learn how to socialize the value of including PV in early discussions and get a slide deck to tailor your outreach.

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    Assess the contractual situation

    The existence of clear internal business rules / guidance that are based on the applicable regulations can help support consistency and quality of PV-relevant agreements.

    Consider having a process in place to assess the PV relevance of Main Agreements, which can include following elements:

    • Define the types of PV-relevant partnerships, including criteria to assess PV relevance, i.e.:
      • Partnerships that potentially generate safety data/information throughout the clinical development and the post-approval phases or
      • Include delegation of PV activities to the partner
    • Introduce a tool (e.g., decision tree) to assess PV relevance of contracts: Is a PVA needed?
    • Define the responsibility for PV relevance assessment of contracts e.g., Main Agreement owner or PV function.
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    Provide input to main agreement

    Review of the Main Agreement and the intended set-up by a PV-knowledgeable person could prevent inefficiencies later in the process. Consider having clearly defined responsibility for reviewing the Main Agreements by the appropriate function.

    If the contract was assessed as PV-relevant, the appropriate PV clause is typically included in the Main Agreement. Consider having standard PV clauses or PV text modules in place that can address common scenarios:

    1. PV clause defining safety information exchange when no separate PVA is required​
    2. PV clause defining safety information exchange with cross-reference to the separate PV agreement​

    HELPFUL TIP: Efficiency could be gained by keeping certain PV clauses or PV text modules easily accessible to the function responsible for Main Agreement.

    During the Main Agreement review, consider key aspects that impact the PV processes and PVA creation and content:

    ✓ Product
    ✓ Type of partnership and relationship between parties
    ✓ Decision making, governance model & safety strategy
    ✓ Product owner, Sponsor/Marketing Authorization Holder status & responsibilities
    ✓ Territorial scope, including local/regional specificities and requirements
    ✓ Reference Safety Information management / update
    ✓ Clinical trial strategy
    ✓ Safety database
    ✓ Delegation of PV activities
    ✓ Recalls
    ✓ Ancillary agreements (e.g. Quality Agreements, Service Level Agreements, Regulatory Service Agreements, Supply Agreements, other agreements that pertain to related services such as divestments & acquisitions)

    HELPFUL TIP:  Consider necessity of duplication of information across documents. Eliminating overlap may reduce discrepancies / potential confusion and the need for future updates to multiple documents. Where overlaps exist, provide clarity as to whether the PVA or Main Agreement terms prevail.

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    Evaluate partner PV system / due diligence

    Evaluation of potential partner / business and/or due diligence can be performed prior to signature of the main agreement and PVA. This assessment/ qualification could be a cross-functional process and the outcome may:

    • contribute significantly to decision making by the company/organization and
    • help mitigate potential risks and impact on the PV system.

    This assessment / qualification aims to enhance the amount and quality of information on the potential partner/ business to the decision makers and could include, for example: evaluation of partner PV system, processes, capabilities, or data assessment.

    Evaluation methodologies can be adapted depending on each business case: e.g. questionnaire, PV system assessment, qualification audit.

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    Phase 2

    Efficiency, accuracy and quality in Phase 2 is greatly influenced by the activities that occur in Phase 1, as clarity on key internal and partner stakeholders, contractual strategy and set-up is ascertained in that phase.

    Development and negotiation of the PVA is key for both parties in the contract to ensure their PV system requirements and regulatory compliance obligations can be met.  The PVA includes core topics to be covered, bridges the understanding of key terms and definitions, and establishes agreed timelines for safety data exchange.

    Each agreement must be negotiated by both parties and often within a certain timeframe, as the PVA may be directly linked to clinical trial start, launch or asset transfer activities. This important phase can be summarized in the following key steps:

    • Engage with internal functions as needed
    • Select PVA template and draft PVA
    • Negotiate and review PVA
    • Finalize and sign PVA

    Note: Some PVAs may involve more than two parties.

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    Select PVA template & draft PVA

    Having appropriate PVA templates or PV text modules in place based on applicable PV regulations can facilitate drafting of new PVAs. Drafting appropriate PVA structure and content that covers all applicable aspects and relevant topics for business partners forms the basis for the following negotiation phase.

    Key steps for the function responsible for PVA creation are:

    • Select appropriate PVA template
      PVA templates should reflect different scenarios depending on business relationships or collaboration types and provide a broad range of flexibility for PVA topics.
    • Draft PVA
      Business partners should decide what template to use as a starting point to draft a new PVA; often, the parties will select the template of the licensor or product originator.

    HELPFUL TIP:  Considerations on PVA templates creation and maintenance:

    1. Template content often focuses on data to be exchanged and demarcation of PV responsibilities of the parties. One challenge is utilizing the right level of details in the template to avoid the need for frequent PVA template updates. Therefore, consider in the template:
      • citing or referring to applicable laws/ SOPs rather than repeating internal SOPs and copying PV regulations
      • limiting detailed information (e.g., internal naming conventions or product dosage, forms)
      • avoiding too detailed requirements, (e.g., local HA reporting rules)
    2. Regular templates review can ensure the content is up-to-date:
      • changes in the applicable regulation (or specific inspection findings) may trigger a PVA template update. Consider including PV Intelligence in the PVA template maintenance process.
      • also consider adequately reflecting changes in the relevant internal process in the PVA templates update

    Shape Tools and Resources

    Click here to download the Glossary.

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    Negotiate & Review PVA

    Negotiation and review of draft PVAs by the parties often requires flexibility and potential adaptation of processes on both sides.

    During this phase, the party who drafted the PVA shares it with the partner for review and comments. Internal review of the PVA draft by internal stakeholders from both parties may be necessary in order to find an appropriate compromise or solutions for respective topics under discussion. The parties aim to come to an agreement in all topics defined in the PVA, which are acceptable by both parties and are fitting to the parties’ systems and processes. A final internal approval by stakeholders or legal function is often required in companies before the PVA can move to the signature step.

    HELPFUL TIP: PVA are often required to be agreed between the parties within a certain timeframe to ensure compliance with regulations and meet business expectations. Efficiencies in PVA negotiations may be generated through project management techniques!

    Shape Tools and Resources

    Click the links below to access the Systematic Approach to PVA Negotiation Tools:

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    Finalize and sign PVA

    Once the parties have agreed on the PVA contents and the final review has been completed (e.g., legal / leadership endorsement or other as per  internal processes) , the PVA can be signed.  This process may involve, for example, wet-ink, digital, or electronic signature, as agreed between the parties in accordance with the parties’ policies and processes. The signed PVA is the legally binding document for all parties.

    Following signature, the PVA is implemented without delay, per internal  procedures, to ensure compliance with regulatory and partner expectations.

    HELPFUL TIP: PVA e-signature using a validated GxP compliant tool has become an increasingly utilized signature option, though acceptance of e-signatures varies.

    Shape Tools and Resources

    Click this link to access the Digital Signatures for PV Agreements Tool.

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    Engage with Internal functions as needed

    Throughout the drafting, reviewing, negotiating, and signing processes, engagement with internal functions is essential for successful implementation of PVA provisions.

    Internal functions may be consulted by the PVA author to provide their input and review of respective PVA sections where the function is responsible or involved in the process.  Furthermore, different levels of review and/or endorsements (e.g., from legal, QPPV, leadership) may be required based on the type of PVA, and/or internal  procedures.

    HELPFUL TIP:  Internal functions may be partially or wholly responsible for taking action based on PVA clauses. Therefore, some companies may proactively involve these internal stakeholders during development/update and approvals of PVA templates.  This proactive PVA template alignment may mitigate the need for review steps of each PVA by the respective stakeholders during negotiations, provided the PVA does not deviate from the template.

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    Phase 3

    Successful PVA implementation can be defined as:

    1. stakeholders can comply with the terms of the agreement and
    2. the PVA is acted upon. Effective implementation will invoke maintenance activities for PVAs, i.e., periodic review or compliance monitoring. Failure to have a PVA correctly implemented may result in compliance issues.

    Having a plan or procedure in place supports broader PVA responsible functions understanding of how and what to communicate to internal operational teams. At the same time, the receiving internal operational teams will benefit from understanding the PVA terms to support effective actions are implemented for the PVA.

    This phase is comprised of two general steps:

    • Register PVA in contract oversight system
    • Activate PVA
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    Register PVA in contract oversight system

    Systematic filing of PVAs facilitates tracking and management of PVAs (executed PVAs, amendments etc.).

    Use of a centralized system as a PVA repository may allow oversight for PVAs and can support:

    • ability to generate reports and PSMF Annex B,
    • audit & inspection readiness,
    • management of the contract lifecycle such as tracking periodic review or termination

    Information in a centralized system may also include key data such as a list of products, territories, and details of provisions outlined in the PVA. PVAs should ideally be accessible to relevant stakeholders, may allow easy review requirements, retrieve PVA obligations, and eventually facilitate monitoring of PVA obligations.

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    Activate PVA obligations

    This step enables the timely and adequate activation of PV obligations in scope of the PVA by the appropriate stakeholders (i.e.those that are designated to take action on PVA activities/oversight). For example, actions may include exchange of ICSRs, RMP, PBRERs, signal information, safety labelling, etc. with the business partner.

    This process:

    • Supports to identify and share any safety document requiring distribution to the business partner at the time of a PVA activation within the agreed timelines
    • Helps to establish mechanisms to facilitate the ongoing performance of activities (e.g., set up of ICSR distribution rules).
    • Is relevant for both new and updated PVAs in case of any changes
    • Includes sending the PVA (e.g., via email or a centralized system) to the applicable internal stakeholders with any additional information or clarification that may be required for its implementation and followed by confirmation of PVA activation for each stakeholder as described in each company or organization’s respective procedures.

    HELPFUL TIP:  Consider distributing the PVA prior to its effective date to allow for set up of the activities to take place in a timely manner (e.g., activation of submission rules).

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    Phase 4

    A signed and implemented PVA goes into the maintenance phase, enabling the PVA to be kept up to date and activities are continuously acted upon.  Proactive monitoring of PVA provisions may help both parties adhere to the requirements. Finally, consider a regular review of the PVA to help determine if/when the PVA needs to be re-negotiated / updated or terminated. Overall, this phase supports more effective PVA oversight, which can help minimize compliance risks.

    These activities can be described in three steps:

    • Review and update PVA
    • Monitor PVA compliance
    • Terminate PVA (if required)
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    Review & Update PVA

    Changes to processes/procedures, legislation or collaboration changes, and audit-inspection findings, among other topics, may impact the contents of the PVA and may prompt an ad hoc PVA update.

    Moreover, companies may consider having a process in place for periodic review of active PVAs. This helps support:

    • Awareness of changes to the main contract (e.g., contract status or scope of the collaboration, products, territories, MAH status, etc.)
    • Assessment of any other changes impacting the activities covered by the PVA (See “Periodic PVA Review: Checklist & Documentation”

    Key steps for the function responsible for PVA review are:

    • Review the PVA and assess the potential need for PVA update
    • Initiate PVA re-negotiation or amendment, if applicable (→ cycle to Phase 2)
    • Document PVA review (Especially when upon a periodic review PVA update was NOT required)

    HELPFUL TIP:  Consider revising  internal and partner contact details within each periodic review. Update of contact information in the appendix may not warrant a full signatory process.

    Shape Tools and Resources

    Click here to download the Periodic PVA Review: Checklist & Documentation.

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    Monitor PVA compliance

    Monitoring compliance to the PVA may allow early identification of issues as they arise. Consider risk-proportionate monitoring, allowing the company/organization to demonstrate clear oversight of PVA performance. A strong monitoring program can inform the risk-based audit strategy and the frequency of partner audits.

    1. Identify the obligations in the PVA to monitor. Consider routine monitoring  such as ICSR reconciliation and compliance to ICSR submission timeframes. Identify topics for enhanced monitoring e.g. critical activities such as exchange of product label updates or Emerging Safety Issues. Consider enhanced monitoring for significant alliance partnerships or those with highest business impact.
    2. Determine monitoring methods, frequency and thresholds for action. Metrics can be a useful tool to measure PVA compliance. Other solutions could also include periodic review. Consider determining the frequency and thresholds for monitoring based upon the nature of the arrangement, relative volume of exchange and impact on pharmacovigilance obligations.
    3. Define the mechanisms for partner and internal stakeholder feedback. Consider real-time feedback for frequent activities. Document periodic review at defined timepoints (e.g., bi-annually or annually) as an opportunity to improve compliance. Assess and consider impact to improve internal processes and/or the PVA. Use assessment outcomes as an input to the pharmacovigilance risk-based audit program.
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    Terminate PVA

    The PVA remains in force as long as the Main Agreement is in force or as long as PV responsibilities between the Parties exist regarding the Product. Having effective and appropriate processes for PVA termination in place supports keeping oversight of PVAs & the PSMF up-to-date.

    Termination of main agreement typically triggers PVA termination. There may be circumstances where the Main Agreement terminates but survival clauses remain active for the PVA, or where the PVA terminates, and the Main Agreement remains in effect.  It is helpful to understand the appropriate timing for PVA termination through good communication with affected stakeholders, e.g., internal business function.

    There are a few key actions that can help better navigate PVA termination:

    • Consider defining standards on PVA termination process and documentation e.g. via updating a centralized system
    • Communication of PVA termination to relevant stakeholders to ensure discontinuation of PVA terms (this can follow the “Implement PVA” standards)

    HELPFUL TIP:  If the PVA is terminated with subsequent obligations, understand what surviving clauses are kept in effect after termination, e.g. safety data exchange, data privacy, records retention and if the conditions of the contract termination require agreement in writing e.g. via “termination letter”

TOOLBOX: Pre-PVA Involvement of Pharmacovigilance (PV) Function

PROBLEM STATEMENT:

  • Functions managing business collaborations are the key internal stakeholders to involve PV in a timely manner when it comes to a new business relationship or main agreement amendment.
  • Although companies often have processes that address these cross-functional responsibilities, the lack of awareness or understanding about when to involve the PV function is likely attributed to inefficient or ineffective communication.

SOLUTION:

  • This slide deck offers points to consider through tangible elements of communication and stakeholder management that can help improve the timely involvement of PV.
  • Optional example text for effectively communicating with stakeholders about timely involvement of the PV function is provided in a slide deck and can be customized based on the individual needs and processes in any organization.

TOOLBOX: Systematic Approach to PVA Negotiations
A customizable agenda and slide deck for PVA negotiation kick-off meetings

PROBLEM STATEMENT

  • PVA negotiations can have long durations, often resulting from repeated steps due to the lack of structure and common understanding.  This may include, but is not limited to, the following:
    • Lack of relevant stakeholder involvement
    • Lack of understanding for partner requirements and practices
    • Different understanding of business set-up between the partners

SOLUTION

  • This solution offers ideas for improved PVA negotiation efficiency through applying elements of project management.
  • Systematic approach to PVA negotiations is based on a simple structure, proactive communication, and common understanding between partners, including:
    • Clear kick-off agenda and timeline agreement
    • Stakeholder role/responsibility identification
    • Common understanding of PVA scope and business set-up

TOOLBOX: Systematic Approach to PVA Negotiations Excel Gantt Tool

PROBLEM STATEMENT

  • Negotiations can have long durations, often resulting from repeated steps due to the lack of structure and common understanding. This may also include a lack of planning and commitment to the PVA finalization timelines.

SOLUTION

  • This solution is an Excel-based Gantt tool that can improve PVA negotiation efficiency through applying elements of project management by:
  • Agreeing on the PVA finalization timelines
  • Reaching common understanding between partners on the deliverables

TOOLBOX: Digital Signatures for PV Agreements Tool

PROBLEM STATEMENT

  • Some companies continue to decline to accept digital signatures even if allowed by local legislation
  • Overcoming barrier for not accepting digital signatures may allow for greater efficiency in the PVA process

SOLUTION

  • This slide deck offers:
    • A summary of the potential advantages of using digital signatures
    • A summary of the potential challenges companies might encounter with digital signatures and how to potentially overcome them
    • Slides could be used to support partner discussions on adoption of digital signatures in territories where it is allowed by local legislation

TOOLBOX: Periodic PVA Review: Checklist & Documentation

PROBLEM STATEMENT:

  • PVAs require periodic review as part of maintenance.
  • Documentation of PVA periodic review may be requested during audits and/or inspections.

SOLUTION:

  • This checklist is designed to provide suggestions for consideration for conducting periodic PVA reviews.
  • This checklist may be modified to align with your company process.
  • This document may also be used to document that the review was completed.