Mature Products

Mature products are often still sold in substantial numbers with a widespread global footprint, despite being long past their marketing exclusivity. They are critical to an organisation’s growth and revenue, alongside the development of new ones. Since they have been on the market for a while, they open up the possibility for marketing authorisation holders (MAHs) to manage processes in a more efficient and cost-effective manner – allowing them to consider an integrated safety, regulatory and benefit-risk model.

Their Importance

While at the end of their lifecycle, mature products are still likely to be sold well into the future and have a crucial role in the healthcare industry across different markets. Their proven effectiveness and safety profiles make them particularly significant in emerging markets where they can be introduced, manufactured and distributed more quickly. Since the cost of maintenance is substantially lower than that of a new product, pharmaceutical companies can focus on tailoring them to individual market needs, which is usually done through formula innovation, changing the dosage form or altering the packaging.

A blockbuster drug passing its patent exclusivity has a significant financial impact for the manufacturer. As generics enter the market, most firms have to re-evaluate the cost spent on product maintenance and minimise expenditure in order to sustain their profitability. As the industry has matured, the requirement for adequate documentation to maintain compliance with local regulations across many of the emerging markets has grown. Maintaining regulatory dossiers and managing labels is necessary to uphold licenses, along with pharmacovigilance (PV) activities. Noncompliance with any stipulations can result in serious penalties, often with significant financial implications.

Streamlining Management

When overseeing the management of mature products, three critical areas must be considered: risk management, labelling and regulatory. When looking at how these functions operate, a more pragmatic approach can be taken to streamline

Organisation OptimisationWhile 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

David Balderson at Sciformix Corporation

operations. While the frequency of some regulatory submissions is set, the supervision of others, including periodic safety update reports (PSURs), supports the consolidation of practices, meaning that the frequency of some routine activities can be reduced while remaining compliant. This allows organisations to concentrate on efficiency and frees up resources. Furthermore, taking an integrated approach across these three areas within an organisation can prevent any activity being duplicated or even neglected as resources focus on the new product pipeline.

However, with the evolution of good PV practices in Europe, strict standards need to be kept. This requires a substantially skilled manpower pool, knowledgeable of each region’s regulations, often stretching the same resources between mature product portfolios and new goods.

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Figure 1: The safety continuum

Lifecycle management and monitoring of a product’s benefit risk profile is a complex process, yet firms can optimise their oversight of these activities and implement processes that mitigate risk as well as facilitate effective collaboration

• Individual case safety report review (designated medical event, targeted medical events, important

medical event, sentinel/index cases, unlabelled cases)

• Aggregate review (listings, frequency analysis, case series, aggregate reports)

• Active surveillance (studies, registries, sentinel sites)

• Periodic and ad-hoc signal detection

Signal detection

and validation

Signal

assessment

BRE

Riskmanagement

Recommendations for

risk management

BRE reportPeriodic BRE

report

• New safety and efficacy data analysis

• Signal review

• Benefit risk evaluation (BRE)

• Safety specifications

• PV plan implementation

• Evaluation

Risk managementplan

Safety Continuum

Even with mature products, lifecycle management must be performed to ensure that they remain safe and effective for patients and healthcare practitioners (HCPs). PV departments are responsible for continually monitoring the safety profile of a drug, and a central element of lifecycle management is to guarantee that the benefits outweigh any risks associated with use.

Products often go through many changes due to increasing exposure, differences in doctors’ practices, new or untested drug interactions and pharmacogenetic variations as they are introduced to new patient populations. As a result, continuous monitoring is still required, including collection and assessment of reports of adverse drug reactions from all sources, ad hoc and periodic reviews of aggregate safety data and identification of

signals, as illustrated in Figure 1. It is also acknowledged that some mature products with considerable risk management interventions like clozapine, thalidomide and isotretinoin demand extensive support and leaner approaches to managing them are not generally applicable.

Signal Management

To identify any new or further understand known risks, activities from signal detection, validation and assessment through to benefit-risk evaluation must be carried out, and this remains an essential component in assuring the safe use of a drug throughout its lifecycle. Ongoing signal management provides a continual risk assessment of the product through many coordinated activities completed both within and external to the PV team. Any change in risk must be discussed with regulators requiring activities such as

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Figure 2: The complex process from confirmed safety signal to implementation

Confirmedsafety signal

Core data sheet (CDS) development

update and approval

Local packaging insert development update, submission and health

authority (HA) approval

Packaging and web updates

Decision on

safety signal

Impact assessment

CDS update

Licensing partner (LPT) update

HA submission LPT negotiation HA approval

Mockup creation Artwork planning Artwork creation

Artwork approval

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education, changes to labels and, at times, alterations to the manufacturing process.

In addtion to regulatory communication, in urgent cases, rapid widespread communication may be initiated through means such as press releases, ‘Dear Healthcare Professional’ letters, website postings and emails. These activities often include coordination between multiple departments in an organisation. Signal management remains an indispensable part of lifecycle management, even for stable mature products, and often encompasses multifunctional expertise and activities within a company (see Figure 2).

Implementation

A label change is often required as a result of signal management activities – a collaborative process with a high degree of operational complexity. Timely updating of labels is a key step in conveying essential information to regulators, patients and HCPs relating to the safe use of a product and, as a result, is under a significant amount of regulatory scrutiny. Businesses must have written practices in place to complete a safety-driven label change to organise the various functional groups with the necessary expertise. The precursor to the label

is typically the company core data sheet (CCDS) that comprises minimum safety data that needs to be present on product labels, including local labelling information for specific regions. Any updates to the CCDS need to reflect accurately in the product’s label within defined timeframes to meet compliance obligations. This increases in complexity for local labelling documents in different languages.

Lifecycle management and monitoring of a product’s benefit-risk profile is a complex process, yet firms can optimise their oversight of these activities and implement processes that mitigate risk as well as facilitate effective collaboration. For mature products with an established safety profile, most of the label changes are not driven through alterations to the core safety profile, rather meeting the differences in local requirements as it is introduced to new markets. Therefore, companies have an opportunity to apply a different focus compared to those with a more dynamic safety profile, with more emphasis on providing flexibility.

Regulatory Continuum

Meeting regulatory obligations across multiple markets, while ensuring the accuracy of all information and that all deadlines

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are met, is a challenge for many organisations. Difficulties arise due to resource constraints and competing prioritisation of those resources as well as the coordination across a variety of domains of expertise. For mature products, the decision-making authority on regulatory activities between the central and local or regional staff is often a challenge as it necessitates a balance between consistency and alignment with global strategy while requiring understanding of the local environment and needs.

With the increased pressures to be both time- and cost-efficient, various organisations are opting to alter their standard operating procedures and developing new models to remain competitive. These typically allow local or regional regulatory

professionals to manage activities themselves by re-purposing documents that have been created centrally. Dossier Repurposing

As many companies expand into larger geographies, aligning the regulatory strategies saves time and cost, resulting in quicker access to patients. A logical strategy is to repurpose core dossiers, usually those submitted in highly regulated, developed markets to meet region or country-specific requirements. Development of, and regulatory approval for, ‘new uses’ of already approved drugs is an important component for mature products – for example, changing them from prescription to over the counter drugs. This is done through reusing sections or data from already submitted documentation to support the new application. Agencies across the globe have well-defined guidelines and procedures to change the status of a product by submitting an application with proper justification.

License Maintenance and Renewals

MAHs of pharma products are responsible for validating the effects of any manufacturing or product quality (generally chemistry, manufacturing and controls [CMC]) related changes to the identity, strength, quality, purity and potency of the drug as these factors can affect both safety and efficacy. CMC changes are a significant source of license maintenance activity and are inevitable due to many reasons, including continuous process improvement in manufacturing and enhancing the quality or stability of a product. 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. To keep a continuous supply of product, these activities must be managed ahead of license expiration dates.

Lifecycle Management

By integrating the multiple functions needed throughout a product’s lifecycle, the complex regulatory environment challenges can be addressed. However, many companies still keep these functions separate, which can exacerbate the issues with resource prioritisation across the different functions needed.

This process can be streamlined by employing a service provider to conduct the regulatory and safety activities. Ideally, a partner organisation should be able to manage end-to-end safety and regulatory processes to avoid creating inefficiencies through separating out the management of the lifecycle. By creating a centralised approach, communication with global teams and data management can be done efficiently, ensuring that all deliverables for mature products are submitted on time. As with any outsourced model, some internal resources would still be needed to convey requirements to the vendor and provide necessary access to data. However, this will lessen

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David Balderson is Global Vice President Safety Operations at Sciformix Coporation and has over 18 years of experience in safety and regulatory operations. Throughout his career, he has been a key driver of process improvement initiatives, from the development

of processes to support the EU Clinical Trial Directive through to the development of an electronic interface between the study and safety databases. David holds a BSc in physiology and pharmacology as well as a PhD in neuroscience, both from the University of Manchester, UK. Email: ask@sciformix.com

About the author

over time and the provider will be able to manage the safety and regulatory activities to support the entire mature product portfolio in an independent manner. Using a dedicated team for risk management means they will have the time to proactively address any emerging problems. They will also be aware of regulatory commitments and stay on top of deadlines, such as meeting regulatory commitments and submitting PSURs.

A key problem often encountered by large pharma and generic organisations is that, as their products are manufactured and marketed at various locations globally, managing all data across regions and coordinate regulatory submissions can be challenging. By implementing an integrated regulatory, safety, risk management and product labelling model through a vendor, this would be managed by a dedicated cross-functional team. Therefore, data could be collated into one central repository to allow for early identification of risks, resulting in the ability to quickly address emerging problems and improve efficiency.

In Summary

An integrated regulatory, safety and labelling team approach is critical to efficiently manage mature product portfolios and optimise the use of valuable resources.

This can be done internally by refocusing resources or developing distinct, streamlined processes specific to mature products. However, outsourcing the activities to a service provider allows internal resources to focus on the new product pipeline and support products through the critical peri-approval period, while providing assurance that all key deliverables are being met across the company’s mature product lifecycle.

ask@sciformix.com

+ 1 (877) 576-5005