Regulatory lifecycle management includes ongoing submissions to address labeling changes, chemistry, manufacturing and control (CMC) updates, Periodic Safety Update Reports/Periodic Benefit-Risk Evaluation Reports (PSUR/PBRER) and other safety variations, administrative changes and renewals to ensure regulatory compliance in every country where a product is registered, as well as new registrations in emerging markets for established products. For one major biopharma company, the maintenance of roughly 5,000 product licenses in 150 markets has generated more than 25,000 submissions over the last four years. The top 30 pharma companies are making thousands of regulatory submissions globally on an annual basis; more than 80 percent of these are related to post-approval activities.
Escalation of time-consuming regulatory workload puts greater pressure on biopharma staffing resources, which are already strained by ever-tighter development timelines. For example:
- In the pre-approval arena, resources are stretched by rising development costs and the imperative to reduce time to market. Greater support is needed to manage the complexity of global development pathways, changing licensing procedures and the engagement of multiple regulatory agencies.
- In the post-approval arena, the volume of lifecycle regulatory work is increased by line extensions, new clinical indications, registration of existing products in emerging markets and patent-life management strategies. Greater focus on post-approval drug safety and quality is driving a worldwide escalation in compliance demands and growing regulatory requirements. To cite one example, the U.S. Food and Drug Administration (FDA) expects to start collecting quality metrics data from biopharmaceutical manufacturers in January 2018 to help assess how well a sponsor can measure key elements of a quality drug production operation.
The outsourcing strategy described here, called the “One-team Model,” is a closely integrated and managed partnership co-developed by a biopharma company and its provider—in this case PPD, a global CRO—to manage all post-approval regulatory activities across a large global product portfolio. The One-team Model expands the functional service partnership (FSP) model to increase efficiencies with constant operational re-engineering throughout the lifetime of the partnership. It standardizes high-quality lifecycle strategies and associated submission packages by fully aligning goals and processes between the respective regulatory teams.
Innovating the FSP model
Traditional FSP models implement broad, portfolio-based functions, such as data management or medical writing, in structures aimed at streamlining operations. An FSP bundles and conducts repetitive, high-volume tasks across multiple projects.
The classic FSP “hub-and-spoke” model—which centralizes core operations (the hub) and distributes outputs to multiple, geographically dispersed users (the spokes)—has succeeded in increasing efficiencies in other areas of product development, including biometrics and medical writing. What biopharma companies need to make this approach deliver the same benefits for regulatory lifecycle management is an outsourcing model that combines operational efficiencies with high levels of local regulatory expertise.
This partnership has created a solution by adopting certain features of this strategy and advancing it further by embedding strategic regulatory and product knowledge expertise within its delivery. In the One-team Model, PPD leverages its global regulatory knowledge and expertise through the provision of core regulatory submission leads (RSL) and specialists who partner at a strategic level internally with the sponsor and who direct the highly efficient centralized core regulatory operations team.
The regulatory centers provide core functions—such as planning, document authoring, data compilation, publishing and direct submission (where applicable)—in locations that offer lower cost together with high-quality, experienced regulatory staff. These centers are located in Latin America (Mexico), Asia (India and the Philippines), and Eastern Europe (Bulgaria).
The specialized centers generate submission packages to support product licenses worldwide. They provide the resources and dedicated technologies needed to manage large-volume document preparation workloads and deliver ready-to-submit documents to the sponsor’s country-based regulatory experts. Planning and preparation of submissions are conducted under the guidance of regulatory experts experienced in post-approval submission requirements for global jurisdictions.
To provide the country-specific requirements and maintain the all-important relationships with local health authorities, the partnership combines the sponsor’s local, in-country regulatory managers, and the provider’s local offices and regulatory intelligence database.
Road map to the one-team model
The One-team Model was designed to manage an outsourcing project of unprecedented size and scope. Teams comprised of regulatory experts from both companies and change management experts from the provider crafted a tightly integrated partnership that defined strategy, planning and operational roles and responsibilities, set standards for quality submissions, and improved processes and procedures for maximum time and cost efficiencies.
The goal was to design a customized partnership to support all post-approval regulatory work and implement a culture of continuous improvement based on documented “road maps” to define and direct the working partnership in five areas:
- Performance oversight
- Processes, tasks, planning, roles and responsibilities
- QA, QC, business continuity
- Contract and budget, scope, resourcing
- IT systems, reports, queries
In addition to freeing the sponsor’s regulatory staff to focus on pre-approval work, the integrated partnership would create a platform to:
- Generate consistent, high-quality submissions across global markets
- Track, report and deploy new regulation and evolving regulation in emerging markets
- Implement key performance indicators (KPI) and metrics to monitor partnership performance, while using metrics to inform continuous improvement activities
- Act as a catalyst for change based on reviewing current practices, and recommending and implementing new processes, procedures and behaviors
The framework: Five steps in the one-team model
The first challenge was to decide which regulatory competencies would remain in-house with the sponsor and which would be outsourced. The partners began by establishing a framework that delineated the major regulatory submissions and post-approval activities, together with the groups that would be responsible for conducting them and the sequence in which they occurred. The framework designated five major fields of activity and assigned responsibilities within each, as well as the core strategic competencies for the partnership manager (PM).
Handover Trigger. The sponsor’s marketed product lead (MPL) informs PPD that a regulatory lifecycle action is required. The sponsor’s MPL executes the handover, officially assigning the work to the PPD RSL and provides the key corporate target milestones. Planning for pre-defined activities like license renewals can be triggered directly by the RSL, who has access to the data that drives the efforts.
Strategy, Resourcing and Overarching Planning. The RSL defines the submission strategy and the detailed tasks, milestones and timelines to achieve on-time submissions. The plan for submission includes input from the specialists who help ensure that the plan is built upon the latest regulatory requirements for relevant countries. In the One-team Model, the RSLs are responsible for product expertise, retention of product knowledge and owning the strategy for the product’s entire life cycle.
Supporting Documents. The sponsor’s relevant functional teams provide the supporting documents and data for the submissions.
Submission Planning, Compilation, Publishing and Dispatch. Once the overarching submission plan is confirmed by the MPL and RSL, this is executed by the specialists in the regulatory centers. Working together with the sponsor’s functional teams—for example, the medical or CMC specialists—they execute the plan to deliver the submission package according to the agreed timelines.
The specialists prepare submission packages using their knowledge of local requirements and that of the sponsor’s functional teams. When new local requirements are identified, they are added to PPD’s regulatory knowledge database, which maintains and reports on global regulatory intelligence, including clinical trial requirements and marketing authorizations.
The PPD RSL oversees the timely execution of the submission plan by its specialists. Before dispatching the package to the sponsor’s in-country managers, the RSL also conducts quality control prior to final publication of the submission documents/dossier.
Local Country Submission Interface. The sponsor’s local country affiliate serves as the interface between the package preparation and its submission to the local regulatory agency. The sponsor’s country affiliates finalize the global package in line with local requirements—such as providing translations—and then submit it to the local health authority according to the agreed strategy and timelines. For some countries/regions that utilize electronic submissions (e.g., those using the EU eSubmission Gateway and the FDA’s Electronic Submissions Gateway), PPD specialists submit the package directly to the authorities.
Initial and ongoing risk assessment is considered essential to the successful functioning of the partnership.
Initial Risk Assessment. Five general categories of potential risk were identified at the start of the partnership: technology; cultural differences; governance; ownership of roles and responsibilities; and processes. Specific work streams were established to examine the frequency, probability and impact of the major risks in each category, and to agree on mitigation approaches. These work streams proved highly effective in reducing the impact of major risks and ensuring that mitigations were conducted in a timely manner, without impacting the delivery of milestones.
Ongoing Risk Assessment. It was agreed that ongoing risk assessment would be conducted at both the product and process levels. Designated staff assess and prioritize risks twice a year for regulatory lifecycle management processes. If critical risks are identified, mitigation actions are determined, agreed upon and implemented.
At the product level—that is, for each regulatory submission—risk assessment and mitigation is conducted by the RSLs to manage risks related to the specific submissions and deliverables, such as those associated with regulatory timelines and commitments.
To date, ongoing risk assessment has proved highly effective in ensuring that processes are fit for purpose and aligned with the needs of the partnership and the ever-changing regulatory environment.
Measuring performance: Key metrics
Successful management of the integrated steps across the partnership demands close monitoring of overall performance at the partnership level, as well as performance of the two organizations.
Overall Partnership KPIs/KQIs. Objectives are reflected in the KPIs and key quality indicators (KQI). KPIs and KQIs were established to ensure, for example, that dossiers are submitted according to mandatory regulatory agency deadlines for all types of regulatory deliverables, and that there are no critical findings in any audit carried out via the partnership.
PPD team KPIs/KQIs: These metrics reflect the work of the PPD team members, for example, those pertaining to timely planning in the partnership’s regulatory information management system (RIMS). KPIs and KQIs ensure that all RIMS sequences associated with a submission are created within the established timeline and that all regulatory packages provided to country regulatory agencies contain the required (published) submission documents.
Sponsor KPIs/KQIs. These metrics apply to the work of the sponsor’s team, such as metrics pertaining to the handoff trigger, which aim at ensuring entry into RIMS within the agreed timetable.
The partnership recognized that a smooth transition to this new operating model would depend on effective change management. The sponsor’s regulatory staff would be learning and implementing new approaches to conduct post-approval work, which would require that they trust PPD’s processes and staff as the outsourcing partner took on its designated responsibilities.
The change management transition team was comprised of key stakeholders from the two entities. With both partners designing the model, the decision-making process and benefits were clear to both organizations. Key stakeholders then became advocates for the partnership within their own organizations. Regular communication updates were shared with all stakeholders; timelines and milestone metrics were communicated to all.
Co-development of responsibilities, timelines and quality standards became an effective catalyst for change with the partner organizations. For example, the sponsor adopted the KPIs for internal use and created a recognition and reward incentive program to enhance employee acceptance of the new model.
The one-team model in action
Earlier in the article, we spoke of the need to develop trust within the partnership. It has taken time to build mutual respect and confidence across the co-designed model. Both companies would agree that the creation of a harmonious partnership culture, now capable of working closely and effectively, has been as important to achieving the partnership’s benefits as the new model’s structuring of activities.
The partnership has accomplished its primary goal of managing post-approval licenses for the sponsor’s global product portfolio in full compliance with good regulatory practices. This highly efficient performance serves to increase the return on investment of existing mature licenses by new submissions and approvals in emerging markets. Reduction of the sponsor’s post-approval regulatory workload has enabled in-house staff to focus on pre-approval work. In addition to the efficiencies provided by the centralized management of this huge regulatory workload, the model offers the flexibility to respond quickly to changing regulatory requirements and the sponsor’s corporate policies.
An example of this responsive flexibility—an attribute highly sought after by global companies—is demonstrated by the response required by the team following the implementation in 2016 of the sponsor’s new standard operating procedure (SOP) aimed at the creation and updating of referenced product information and its global implementation. The new SOP requires that each safety variation be dispatched globally within 180 days of signal validation.
PPD managed a multiplicity of updates in the company’s core data sheets (CCDS) for five products, all having the same active pharmaceutical ingredient. Within the reduced SOP-mandated timeline, the company created and dispatched more than 700 submissions generated by the CCDS update by quickly re-engineering resources and concomitant deliverables.
The benefits achieved by the One-team Model point to the value of integrated sponsor-provider partnerships. The model offers both efficiency and flexibility to better manage regulatory workflows, and expand capacity for post-approval license maintenance for new products in new markets and emerging countries, while releasing valuable in-house resources to focus on accelerating new products to market. In addition, the model provides drivers for an organization’s own change by leveraging ongoing experience from the provider and expanding the platform to conduct new tasks and services.
In this joint effort, for example, the partnership was redesigned after the first year of operation to optimize processes, tools and structure. This redesign established a pathway for more upstream strategic input and allowed for future geographical expansion. Changes in roles and responsibilities had important impacts on operational efficiencies. Before the partnership, the sponsor operated through marketed product leads and emerging marketed product leads (EMPL). These roles have since been combined into one MPL to partner more efficiently with PPD’s RSL. The role of the PPD PM has now been expanded to manage across the partnership rather than just the company’s elements. This change eliminated duplication and empowered the PM to liaise with a broader group of the sponsor’s stakeholders.
Integrated partnerships will continue to drive alignments of sponsors and outsource providers in more flexible, efficient configurations. The future of the One-team Model is now taking shape in a number of new PPD-sponsor partnerships marked by greater provider-sponsor integration and more cross-functional services. PPD also has expanded the One-team Model to incorporate pharmacovigilance, medical writing and preclinical/CMC regulatory work. In addition, the one-team platform facilitates the evolution to outsource local in-country regulatory activities—traditionally conducted in-house, which further enables the most effective and efficient delivery for full lifecycle activities.
The success of the One-team Model is a compelling argument for the wider application of this outsourcing approach as advancing technologies and increasing cost drivers heighten demand for outsourcing partnership solutions.
- Figure based on PPD lifecycle regulatory services provided to a top-10 biopharma company
- FDA; CDER SBIL Chronicles, Nov 30, 2016. FDA’s Quality Metrics Reporting Program: Submission to Quality Metrics Data. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/UCM531066.pdf