A Practical Approach to Successfully Navigate the Safety and Regulatory Continuum for Mature Products

- David Balderson
Global Vice President - Safety Operations
Sciformix Corporation

While development of promising new products is an obvious area of focus for biopharmaceutical companies, maintenance of already established marketed products is a critical activity that cannot be ignored. Ensuring regulatory compliance and reducing product risk whilst still working within the cost constraints presents unique challenges to companies in managing established products and requires innovative and cost-effective approaches that can help ensure patient safety and compliance while continuing to meet ever -increasing and complex regulatory demands. Rather than handling all products in the same way, marketing authorization holders (MAHs) have an opportunity to look at managing the more stable mature products differently and more efficiently, allowing them to consider the benefits of an integrated safety, regulatory and benefit-risk model.

The Importance of Mature Products

Mature products, those that are still sold substantially but are long past their marketing exclusivity, have a significant role in the healthcare industry in both the developed and developing world. Mature products make up a large portion of many pharmaceutical organizations portfolios these are likely to be sold well into the future despite being in the final stages of their lifecycle.

Established products have proven effectiveness and safety profiles making them even more important in emerging markets compared to newer products. However, since the cost of maintaining mature products is usually significantly lower than launching newer ones, pharma companies can focus on tailoring them for individual market needs, innovating the formula, dosage forms or packaging for optimal results, or expanding geographically.

Yet, due to increasingly stringent drug regulations in emerging markets, the documentation needed to remain compliant for mature product maintenance has risen dramatically in the last decade. Pharmacovigilance (PV) activities must be continued, while maintaining regulatory dossiers and managing labels is all required to uphold licenses. Non-compliance can result in critical regulatory penalties, with significant financial implications. The most significant financial impact for any manufacturer is when blockbuster drugs pass their patent exclusivity, requiring most companies to look carefully at minimizing costs to sustain their profitability.

A Pragmatic Approach to Managing Mature Products

Organizations have the opportunity to manage their mature products differently from others in their portfolio by focusing on efficiency to free up resources. Mature products, by nature, are typically more stable with a predictable revenue stream, thus, the reduced amount spent on managing the product can increase profitability. A more pragmatic approach can be taken to streamline processes making it less resource intensive. In some aspects, such as the frequency of Periodic Safety Update Reports (PSUR) production, the regulations also support a more streamlined approach and although aspects such as signal detection activities need to be maintained, there are opportunities to take a more pragmatic approach by reducing the frequency of many routine activities.

Figure 1. The Safety Continuum

There are three main areas to traverse when managing mature products, namely , safety and risk management, labeling and regulatory. Taking an integrated approach for these three areas is vital to efficient management. Yet, often these functions can act independently within organizations which can result in overlapping and duplicative work or in worse case scenarios some elements being missed completely, due to fragmented processes and oversight. Furthermore, with the evolution of Good Pharmacovigilance Practices (GVP) in Europe and many other regions following suit, more rigorous standards need to be upheld. This requires a substantially skilled manpower pool who are knowledgeable of each region's regulations, which often means stretching the same resources between mature product portfolios and new products.

The Safety Continuum

Whilst mature products are often much more stable and well defined than new ones, safety activities are still required, although usually under less scrutiny. These are done to ensure the product remains safe and effective for patients.

PV is a central function to supporting the safety of a product and ensuring the benefits out-weigh the risks of using the drug. It is acknowledged that some products, across multiple classes that have been on the market for a long time, still require extensive support from a PV perspective. These include clozapine, thalidomide, isotretinoin, and leaner approaches to managing these products are not applicable. However, even the majority of the stable mature products can still go through many changes due to increasing exposure, differences in physician practices, new or untested drug interactions and pharmacogenetic variations as they are introduced to new patient populations. A variety of activities are therefore still required, along with risk management plans that may go beyond routine PV. These activities from single adverse event processing to signal identification and risk management are part of the safety continuum, which is illustrated in the figure below.

Signal Management

Signal management can be defined as the activities performed to identify new risks or changes in character or severity of a known risk. It remains an essential component in assuring the safe use of a drug throughout its lifecycle. Avoiding and minimizing risks can be done through alerting patients and

Figure 2. The integrated safety, regulatory and labeling contin uum.

healthcare providers to the identification of a new risk or change in a known risk. This requires discussion with regulators, changes to labels and occasionally direct communications. This can often include a spectrum of teams in an organization from PV, to clinical development, to regulatory affairs and medical information, especially if the communications become urgent. Even for mature products, signal management remains an essential part of the safety continuum and product lifecycle.

Signal Detection to Implementation of the Label

A label change is an example of a truly collaborative and cross-functional process which has a high degree of operational complexity and is often an outcome from signal management, subsequent to the validation of a safety signal. The label change communicates formally important and, at times, essential information to regulators, patients and HCPs, regarding the safe use of a product. Label changes are also a complex procedure involving cross -functional processes, requiring written safety practices and high level expertise. For mature products there is normally a large amount of safety data that needs to be managed efficiently. In order to complete a safety driven label change, an organization must have written practices in place to organize the different functional groups with the required expertise.

The Regulatory Continuum

Regulatory submissions are often time intensive and require multiple teams and stakeholders to fulfil, but for mature products the strategy for filing is often managed regionally or locally, requiring an understanding of the local environment. However, in order to manage the regulatory activities, the local regulatory resources still require documentation and support from central regulatory experts who are often unable to dedicate time to supporting mature products as the focus is on the new product portfolio. With this and the increasing pressure to be cost and time efficient, new operating models and adapted standard operating practices(SOPs) need to be considered. Typically these allow local or regional regulatory professionals to manage activities themselves by re-purposing documents that have been created centrally.

Dossier Repurposing

When maintaining mature products, some key strategies allow for expedited safety labeling and regulatory procedures. The first of these is dossier repurposing, which consists of reusing and reformatting the existing dossier submitted in highly-regulated countries to then meet regionspecific requirements. Obtaining regulatory approval of new uses for existing drugs is an important part of innovating mature products. Sections of existing dossiers can be repurposed, along with the creation of any additional content needed to meet the specific requirements in order to file applications for mature products with wellestablished safety and efficacy profiles. This includes changes from prescription to over the counter drugs .

License Maintenance and Renewals

MAHs of pharmaceutical products are responsible for validating the effects of any manufacturing or product quality (generally CMC) related changes to the identity, strength, quality, purity, and potency of the drug as these factors can affect the safety or efficacy of the drug. CMC changes are a significant source of license maintenance activity and are inevitable due to many reasons including continuous process improvement in manufacturing and quality of the product, changing business needs, or implementation of regulatory authority stipulations. Deviations or violations from filing such documentation can result in regulatory actions such as warning letters and import alerts. License renewals are also required periodically to continue marketing a drug. In order to keep a continuous supply of product these activities must be managed ahead of drug license expiration dates and site registrations.

An Integrated Safety, Regulatory and Labeling Continuum for Mature Product Maintenance

Organizations should consider the merits of an integrated safety, regulatory and labeling service model for mature product maintenance with a flexible structure that promotes continuous improvement, whilst lowering the costs and maximizing product value. The figure below illustrates an example matrix of the different activities that need to be managed within an integrated framework.

Mature Product Lifecycle Management

A meaningful way to address the challenges in today's complex regulatory environment is to focus on an integrated team approach to product lifecycle management. Most pharmaceutical companies suffer from building virtual walls between functional silos, along with data and processes being separated, thus, making it difficult for cross-functional information to flow quickly and securely.

Outsourcing regulatory and safety activities for mature products is a viable option and can streamline the process while minimizing costs. A partner can employ a centralized approach and is able to communicate with multiple teams globally and efficiently manage data to fully coordinate operations. Ideally a partner should manage the end-to-end safety and regulatory deliverables to support mature products, however, a flexible model can be employed if required. A dedicated and integrated team is able to proactively manage risks, including generating risk management plans and risk mitigation strategies. They are also able to track regulatory commitments, such as US FDA annual reports and PSURs, and ensure all deliverables are submitted on time .

Furthermore, for generic products the regulatory intelligence capabilities of an outsourced vendor can be leveraged to track and implement updates to the reference label.

As with any outsourced model, internal resources would still be required to manage relationships with the vendor and provide access to necessary data, over time this will diminish and the provider will be able to manage the safety and regulatory activities to support the entire mature product portfolio in a much more independent manner.

An integrated regulatory, safety, risk management, and product labeling model was implemented at a large generics company to manage their product portfolio. With the client's products being manufactured at various locations worldwide, and teams located in different geographies, the main challenge was to manage the data generated across the different locations and coordinate regulatory submissions. A dedicated crossfunctional team with in-depth knowledge of the product portfolio, various regulatory information management systems, and publishing tools was assigned to the project. Data was collated into a single repository that allowed for early identification of potential risks, the ability to quickly address emerging problems, improved efficiency, and reduced the need for regulatory oversight from the client. The reliance on input from the client has reduced over time and they are being successfully supported through this integrated model.


Whether product lifecycle activities are managed internally or by a service provider, creating a structure in which all elements (people, process and technology) are integrated is critical to being able to successfully manage mature products efficiently. This allows all stakeholders to be aligned and companies can streamline tasks and free up resources to focus on other activities.