Penetration of Established Products
Increase in patent expiries and competition in market expansion opportunities has led to substantial penetration of generic medicinal products in both developed as well as emerging markets. It is estimated that generic competition eroded $67 billion from top drug companies’ annual sales in the United States between 2007 and 2012, with more than three dozen drugs losing patent protection during this period [1]. There was an annual decline of 3.5% in 2012 in total U.S. drug spending as patients accessed lower-cost generic versions [2], and this trend is set to continue over the next five years, with the patents set to expire on a large number of top-selling pharmaceutical products. Indeed, EvaluatePharma’s analysis [3] shows that more than $290 billion of prescription drug sales are at risk from patent expirations between 2011 and 2018. Emerging markets are offering many new opportunities with their spending power and potential for high volumes. These markets are very price-sensitive and the generics manufacturers are typically ahead of the innovator pharmaceutical companies in the price game.
Why Is Safety Monitoring Now of Critical Importance for Established Products?
With growing consumption of generically manufactured established products, it is absolutely crucial for organizations to understand the impact on safety monitoring requirements and on the required infrastructure, processes, and resources to ensure patient safety, product success, and brand equity. At the beginning of this century, there was a general belief that monitoring product safety was important for new pharmaceutical products during development and for a few years after their launch. Hence, manufacturers of established pharmaceutical products did not focus as much on pharmacovigilance (PV). Large generics manufacturers established drug safety units, but their volume and scope was limited. It has become clear over the past few years that safety monitoring is perhaps just as important for established products as it is for new products, for various reasons.
- Realization of the importance of post-approval safety monitoring and the need to create large and complete databases of adverse event experiences; a large part of the data on post-approval experience comes from generic products given the growth in the generics market.
- Longer development timelines have meant shorter periods of exclusivity for the innovators. Thus, the generic versions start selling before substantial post-approval data on the innovator molecule is collected. Moreover, generic products become available much quicker in many more countries than the innovator product. Thus, new populations are exposed to the medicines shortly after regulatory approval of the innovator product and a large portion of the post-approval safety experience is on generic products.
- Formulation changes and other manufacturing process changes between the innovator product and its generic versions may lead to variation in the safety profi les. Hence, it is crucial to monitor safety of the generic products.
- Regulators expect written procedures for safety data exchange between partners. Although PV may not be the driver of such an agreement, the Marketing Authorization Holder (MAH)/Application Holder is ultimately responsible for maintaining compliance with the application itself, and applicable laws regarding good manufacturing practices, quality standards, and adverse event reporting.
Evolution of Safety Monitoring Needs of the Manufacturers
Safety regulations have evolved for manufacturers of new medicines as well as established products. Evolution of the generics industry and a rapidly increasing generics portfolio of the innovator companies have shaped the industry-wide pharmacovigilance requirements.
The generics industry has quickly become very fragmented with a lot of players in the market simultaneously selling their individual versions of the same molecule. Therefore it is essential to clearly make the distinction in safety reports of diff erent generic brands, and at the same time it is also important for the regulators to be able to pool safety data from all products with the same active moiety. Adding to this complexity, formulations may diff er across manufacturers with respect to the excipients used and the manufacturing process. The percentage of excipients may also diff er for diff erent formulations produced by the same manufacturer, depending, for example, on the relative tablet/capsule sizes of diff erent dosage formulations. The excipients are supposed to be “inactive” ingredients, but some have been known to cause Adverse Events (AEs), e.g., diarrhea caused by use of lactose which was used as a fi ller.
Many manufacturers sell internationally, either by setting up subsidiaries in other countries on their own or through partnerships with large companies. To keep up with these global changes, safety reporting regulations have evolved in all countries around the world, with some regulators also requiring “foreign reports” to be submitted. Hence, it has become imperative for manufacturers to have a harmonized, advanced, and robust pharmacovigilance system in place that can serve as a central repository of all AEs reported worldwide and can seamlessly report as per local requirements of each country.
The result is that today’s safety monitoring requirements of manufacturers of established products are comparable, in scope and complexity, to those of the innovator companies. Pharmacovigilance capabilities required by generics manufacturers, large and small, have seen exponential growth.
Because of the complexity, a common trend is that these companies are seeking strategic alliances with service partners who can manage either a specifi c part of the pharmacovigilance process or, in some instances, the end-to-end process.
Implementation of Safety Systems
Business realities of the current healthcare environment are leading to an evolution of the ecosystem. Both innovator companies and generics manufacturers are facing challenges with the traditional operating models being pushed to the point of breaking due to cost pressures, government and political demands, and the weight of supporting global distribution channels. Innovator companies are moving towards a mixed portfolio of innovative and generic products. As the marketing of pharmaceutical products is being driven more by partnerships between two or more companies, there has been a substantial increase in the number of licensing and supply partnerships between generics manufacturers and large or mid-sized global pharmaceutical companies. The increase in regulatory vigilance and government pressures means that the responsibility for safety reporting has to be clearly outlined and closely monitored in such relationships. This adds to the already challenging drug safety environment. Operational effi ciency is of crucial importance in ensuring compliance with safety monitoring and adverse event reporting requirements.
Figure 1. Safety and Risk Management ProcessThe complexity of end-to-end PV makes it attractive for companies to outsource these activities. Drug safety, or PV, is an area where alliances have literally ‘paid-off ’ signifi cantly. Generics manufacturers are typically not as conversant with the regulatory requirements or legal obligations, and are relatively inexperienced in managing safety reporting compliance. They have limited access to expertise and to resources such as safety databases. Consultancy and implementation need to drive companies to outsource PV to a neutral third party for its successful management.
There are three main strategic imperatives to consider when adopting a model to ensure a successful path to PV outsourcing:
- Capability – Access to PV and regulatory knowledge to ensure compliance.
- Capacity – Access to scalable and resilient sources of talent and infrastructure.
- Cost – Ability to establish global PV centers in a low-cost destination.
With regard to the above imperatives, various sourcing models may be considered. The fully outsourced model, at one end of the spectrum, is an immensely attractive option for some of the generics manufacturing companies that are on a steep growth path, especially if adequate controls are defined and implemented. The outsourcing partner is competent and is also sufficiently flexible to accommodate requirements arising from future partnerships of the MAH. At the other end of the spectrum would be a fully captive model and the approaches in between would involve outsourcing of select activities in the PV process. The hybrid model for manufacturers of established products was described in ‘A successful path to fulfilling pharmacovigilance obligations’ [4].
PV-in-a-Box: Effective Safety Monitoring
PV-in-a-box refers to a fully integrated end-to-end safety solution which comprises of database, services, and automation. An alternate interpretation could pertain to the automation envelope, which can serve as a box for any PV system the company may choose to employ.
The first step is the needs analysis, driven by the safety reporting obligations of the company as outlined in the Safety Data Exchange Agreement (SDEA) and other documents and by the business model including future plans of expansion with respect to products, geographies, and alliances. Subsequent to the needs analysis, the PV partner will make the appropriate safety database available as the PV platform of the company. The partner also manages all modalities related to installation, validation, and any other technical support that may be needed. If the company had processed a few cases on paper in the past, these can be easily migrated into the database. If the company was working with another PV partner in a different partnership model in the past and has chosen a different partner for the PV-in-a-box model, the data is migrated from the previous database into the new one. The migration activity can be extremely challenging in some situations and the PV partner should have the expertise and prior experience in managing migration of safety data, including an understanding of the impact on/of aggregate reporting, dictionary version upgrades, etc.
Another important element of the safety system is the set of applicable procedures. A robust set of SOPs which apply to the specific needs of the company are created by the PV partner. The partner should also have all the required resources to implement the safety system for the client. Human resource requirements include personnel with expertise and experience in case processing, aggregate reporting, signal detection, and risk management, including a Qualified Person in Pharmacovigilance (QPPV).
The ability to quickly adapt and continually ensure proactive patient safety and regulatory compliance necessitates efficiency and scalability in operations and consistency in quality. Unpredictable case volumes or sudden spurts in Individual Case Safety Reports (ICSRs) can be diffi cult to manage and sub-processes like assessment of seriousness, causality, and reportability of adverse events can be time consuming. Moreover, parallel routing and reporting of adverse events to all internal and external recipients to ensure timely compliance with multiple regulatory requirements, locally and globally, further increases the complexity. While quality controls are enforced through independent teams, making submissions of ICSRs, and other related documents to the regulatory agency on time, require collaboration of multiple resources across time zones. All handoff s increase complexity, cost, and eff ort. In spite of technology being an integral part of pharmacovigilance, there are multiple challenges that need to be addressed to optimize along the dimensions of eff ort, time, quality, compliance, and cost.
An overarching automation layer is an important technology solution (see Figure 2), which can be easily applied to any PV process of any client. Automation encapsulating PV operations has to work without changes of codes in the underlying call center, case processing, and allied systems already in use and work with minimalistic changes to the operational SOPs. This needs to be an agnostic system based on robust technology with a multi-tier architecture that is highly configurable and customizable, and enables LEAN processes to be implemented without changing the code base. Such an automation layer will allow the client to continue working seamlessly across multiple underlying safety applications (databases and tools).
Figure 2. SciVigilance – Base ArchitectureThe automation layer integrates proactive case management, quality management, and project management of PV process into a compliant and structurally validated system with inherent traceability and audit trail. The bi-directional data fl ow between underlying systems and the automation layer minimizes process time by traversing process blocks and synchronizing data. It increases eff ective case management through active tracking, strategic alerts, and notifi cations that allows personnel to focus on core business objectives. Consulting and services in all areas of drug safety with structured processes, along with access to database and automation in a compliant manner, is the PV-in-a-box solution which is attractive to many organizations that manufacture and sell healthcare products.
Conclusion
Eff ective safety and risk management is a result of a multi-tiered eff ort from all stakeholders - sponsors, payers, health personnel, and patients – to ensure safety of the products for patients and to mitigate fi nancial risk for the company. Pharmacovigilance requires informed decisions regarding the safety and risk of the product, while meeting targets of quality, time, and cost. This area has evolved in its importance for the innovators, as well as generics manufacturers. In the context of their business model, the integrated PV-in-a-box solution is an attractive option for manufacturers to ensure compliance and proactiveness in safety and risk management. The automation layer is an attractive option for the innovator companies as well. Choosing the right vendor with all facets of capabilities and being able to eff ectively partner with them are the key requirements. There are three main strategic imperatives to consider when adopting a model to ensure a successful path to PV outsourcing: capability, capacity, and cost. The vendors also need to fully understand the diff erences in the business priorities of generic manufacturers versus innovator companies, and implement a robust, fi t-for-purpose safety solution. Eff ective combination of domain expertise, agile process and robust technology leads to time savings, high quality, cost reductions, increased effi ciency, and absolute compliance.
References
- DeRuiter, J. and Holston, P. L. (2012). ‘Drug patent expirations and the ‘patent cliff .’ U.S. Pharm, 37(6), pp.12-20.
- The Burrill Report (2012) ‘Patent Expirations Help Cut Drug Spending in 2012’.
- Evaluate Pharma (2012). ‘Patent expirations put more than $290 billion in prescription drug sales at risk through 2018.’ Available at http://www.evaluategroup.com/public/PressReleases/Patent-Expirations-Put-More-Than-$290-Billion-in-Prescription-Drug-Salesat-Risk-Through-2018.aspx Accessed 20/05/13
- Lele, C. (2013). ‘A successful path to fulfi lling pharmacovigilance obligations.’ Manufacturing Chemist, 84 (7/8), pp. 24-26
- Reuters (2013). ‘FDA new drug approvals hit 16-year high in 2012.’ Available at http://www.reuters.com/article/2012/12/31/uspharmaceuticals-fda-approvals-idUSBRE8BU0EK20121231 Accessed 20/05/13
Chitra Lele has been part of the Sciformix leadership from its inception and has been instrumental in establishing the pharmacovigilance practice at Sciformix. Sciformix Corporation is a world leading Scientific Process Organization (SPO), providing scientific knowledge-based services to pharmaceutical and biopharmaceutical, generics, consumer products, medical devices and other healthcare companies - in the areas of Safety and Risk Management, Clinical Research & Post-Approval Support and Regulatory Affairs. Prior to Sciformix, as Executive Director responsible for India operations of Pfizer Global R&D, Chitra established India's first Biometrics Center providing services in clinical data management, statistics, programming and medical writing, and successfully grew it to a size of over 400 staff. Chitra has a Ph.D in Statistics from Stanford University and her prior experience includes work as a biostatistician in cancer epidemiology at Stanford University and University of California, San Francisco and as a faculty member at the School of Statistics at the University of Minnesota and Indian Institute of Technology.