By 2018, it has been estimated that $217 billion worth of originator products will have lost patent protection, with $150 billion of this figure predicted to be lost between 2010 and 2017¹. Although the number of blockbuster drugs coming off patent year-on-year is set to slowly decrease up to 2017-2018, drug innovators are picking up the deficit and growing revenues by expanding their established portfolios in all markets—both mature and emerging ones.

This article will discuss the patient safety challenges that both innovators and generics manufacturers face in today’s expanding global market.  It will explore a more proactive approach to pharmacovigilance, focused on prevention, and achievable through better stakeholder communication, data, analytical tools, and interpretation.

The Evolving Global Market
Emerging markets, once viewed as risky, are now seen as attractive propositions for growth, due to vigorous economic growth and growing consumer spending power in the region. Government health reform, population growth and changing disease profiles have led to a significant increase in demand for pharmaceuticals and healthcare products and services. Approximately 20% of global spending on pharmaceuticals is estimated to come from emerging markets, according to IMS data. Growth in these markets is expected to be the most dramatic, with China leading, followed by Brazil² . Over the next five years emerging markets are set to grow by 15%-20% compared with 8%-10% in mature markets³. In fact, it is expected that “Pharmerging” markets will be responsible for over half of the growth in the global pharmaceutical markets.

Strategic partnerships have been critical in allowing both branded and generic pharmaceutical companies to expand their businesses in the regions.  These deals create and foster synergistic partnerships across multiple stakeholders, and involve data exchange agreements and data hand-offs.

Typical partnerships involve a mixed portfolio of innovative and generic products, where even the marketing is being undertaken between several companies across different global geographies with different regulatory requirements. However, this new business model increases operational complexities, and may result in enhanced exposure to safety and regulatory risks, leading to potential threats to bringing products safely and successfully into new markets and maintaining brand integrity.

Increased Regulatory Expectations from Innovators and Generics
Lines are blurring with respect to regulatory expectations around safety and risk management of new and established products. This is partly due to the fact that established products are being introduced more aggressively into emerging markets, where scant prior safety data is typically available.

A recently proposed regulation by the U.S. FDA would allow generics manufacturers to change product labels based on their own safety monitoring findings⁴. This means that both innovators and generics companies will now have to focus, proactively, on the safety and risk management of established products, and develop data, rather than simply relying on previous published material.
Regulators themselves are also being more proactive about product safety. Following a number of high-profile cases, such as the 2010 recall of Cylert, a central nervous system stimulant to treat ADHD/ADD, and the 2011 recall of Xigris, a treatment for severe sepsis and septic shock that was found to give patients no survival benefit, there is increased pressure to guarantee that pharmaceutical formulations are safe to use. In addition, all the information available on any drug must be accurate, clear and comprehensive.

How can these diverse requirements be met? The key is enforcing strict pharmacovigilance (PV) standards during the development and post-approval stages.

Initially, pharmacovigilance was all about collecting spontaneous reports of suspected adverse drug reactions (ADRs) in the post-marketing phase and using these to identify previously unrecognized hazards of medications during clinical use. When a drug reaches this stage, relatively little is known about its safety in clinical use because only about 1,500 patients are likely to have been exposed to it⁵. Therefore it is crucial that these ADRs be well documented and reported in order to further advance the knowledge about any drug.

However, recently there has been a movement away from this “reactive” approach to safety oversight, to a more practical approach that is more clinically relevant⁶. Proactive safety and risk management will also be especially critical as biological advances improve our understanding of disease mechanism and of the effect of medicines on individual patient responses, especially as more biosimilars are developed for global markets.

Proactive Pharmacovigilance
The main goal of pharmacovigilance is to identify any hazards associated with pharmaceutical products and to minimize the risk of harm to patients. In order to meet expectations of prescribers and patients that all approved medicines are safe, it is important to focus on safety during clinical development. The past few years have seen a great deal of progress in the advancement and standardization of methodology for collecting, analyzing, evaluating and reporting information on product safety during clinical trials.

Furthermore, the methods and tools used in post-approval PV are being increasingly adapted for use in early and late stages of pre-approval development. The Council for International Organizations of Medical Sciences (CIOMS) Working Group VI has made significant contributions in this area.

Safety assessment and evaluation is thus increasingly based on seamless analysis of integrated pre-approval and post-approval data. Pharmacovigilance should involve product input from all stakeholders, from biopharmaceutical companies to regulators, prescribers, and patients as well as data safety monitoring boards and ethics review committees.

The guiding principles for establishing the proactive management of safety data, effective use of analytical tools, and interpretation and communication of results, are discussed below. 

Data
From its initial generation, complete and validated data is a fundamental requirement of successful pharmacovigilance.

1. Generation
Data generation starts at the clinical development stage, after which relatively large volumes of safety data are collected in the post-marketing phase, especially from the developed regions. This additional information gets added to the clinical trial data and the safety profile of the medicinal product becomes clearer.

Conducting epidemiology studies and recruiting patient registries is vital in producing sound baseline data. With little data for several medical conditions available in developing regions, it is important to encourage the reporting of ADRs. This reporting may take place through national programs, such as the Pharmacovigilance Program of India (PVPI), or through individual programs driven by hospitals, medical associations and patient advocacy groups. Programs should spread awareness about the importance of reporting of ADRs as well as make the required tools and training available.

Furthermore, electronic health record (EHR) data is becoming increasingly common in developed countries and is also on the rise in emerging markets. If captured and maintained methodically, EHR data can be of huge worth to facilitating proactive pharmacovigilance.

In this way, regulatory agencies have been collating a large bank of information. For example, the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP) comprises over 170 research centers and healthcare providers, with a comprehensive, searchable database and a registry of data sources for post-authorisation studies. This provides an extensive and valuable supply of information that can benefit those undertaking PV.

2. Availability
After the data has been generated and validated, it can be accessed in real-time using advanced databases and other computing infrastructure. Ideally, all data is pooled through various sources in a way that makes it freely available for analysis, which requires basic standardization in data collection and databases. Rather than conducting large and long-term trials, such pooled data is used—this is not only more practical, but much more cost effective. With the standards and methods used for post-marketing PV being increasingly adapted to clinical trial safety, it’s also easier to pool pre-approval and post-approval data.

3. Quality
When the bulk of the data on established products is captured through voluntary reporting of spontaneous ADRs, data quality must be assured, at all costs. Data quality can be improved by using carefully designed data capture forms and well thought-out data management processes. Employing an effective quality management system (QMS) for PV is essential to ensure quality at all stages.

Analytical Tools
Improved and easy-to-use pattern recognition and data-mining tools are becoming available on the commercial market, allowing analysts and professionals within the industry to access advanced scientific and statistical methodologies and tools.⁷ Using these packages, data can be pooled and analyzed in a meaningful manner to gain further insight into the safety of products.Improved signal detection methods, with superior performance with respect to, for example, false discovery rates, are being developed and made available for use⁸.

Interpretation
Once data has been collected and analyzed, the benefit-risk profile can be generated for proactive safety management of the product. This is possible, provided that the definitions, terminologies and measures of benefit-risk are standardized.
Validated standards and tools enable translation of analysis outcomes into determination of clinical benefits and risks. Benefit-risk profiles are subjective and may vary between patient groups. Accurate interpretation is a key requisite for determination of comparative effectiveness of treatments and their application.

Communication
At the end of this process, stakeholders should be able to understand and balance the benefits and risks of treatments, easily and effectively. To make this possible, carefully planned, customized communication has to be ensured across all parties, from healthcare providers to patients. By providing these stakeholders with access to reliable and actionable clinical information—through product labels and product literature, for example—it becomes easier for them to make informed therapeutic choices.
Industry players and regulatory agencies take enormous care to ensure that product labels are regularly updated with new safety material data and therapeutic benefits. Additionally, product literature is made available to prescribers by manufacturing companies. Completeness and accuracy of this information makes it a reliable source, and it is vital that caregivers pay close attention to the information they are provided.

When any safety data is reported in the U.S. and EU, it becomes publicly available. Regulatory agencies’ public websites list on-going clinical trials, while some sponsor organizations are working with regulators to make summary clinical trial data widely available. Deliberations of the Pharmacovigilance Risk Assessment Committee and the FDA’s on-going evaluation of unconfirmed safety signals are posted on the internet.

Finally, a large amount of information on clinical trials is published in the media. Although useful, these reports have to be communicated in an accurate, meaningful manner by those who are able to understand and correctly interpret the results.

Looking forward
Thanks to increased scrutiny of potential patient health risks and the increasing involvement in emerging markets, pharmaceutical manufacturers’ priorities and approaches are shifting. In the not-so-distant future, it seems that comparative benefit-risk assessment will become the primary driver of clinical decision-making. Huge advances in biology and the life sciences have deepened and improved our understanding of disease mechanisms, and, with stakeholders becoming increasingly aware of the challenges being faced by the healthcare industry, there is an increasing opportunity and need for change. Along with this increased awareness comes a greater need to understand the effect of medicines on individual patient responses, and ensuring that all therapies are acting in a safe, efficient manner.

In order to deliver this level of safety, proactive risk management is becoming ever more critical. By improving the capture, analysis and dissemination of medical, clinical and epidemiological data, pharmaceutical manufacturers can implement proactive management of safety and benefit-risk balance of new and established healthcare products. 

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Chitra Lele is Chief Scientific Officer at Sciformix Corporation, with over 20 years of experience in the healthcare industry. She has been part of the company’s leadership from its inception and has been instrumental in establishing and growing the organisation. Prior to Sciformix, Chitra was Executive Director responsible for Indian operations of Pfizer Global R&D. With a PhD in Statistics from Stanford University, her prior experience includes work as a biostatistician in cancer epidemiology at both Stanford and University of California.

References

1. McKinsey & Company (2013). ‘Insights into pharmaceuticals and medical products – Generating value in generics: finding the next five years of growth.’ McKinsey & Company, published May 2013.
2. IMS – Meteos, (December 2012). Pharma’s New Productivity Challenge: Perspectives from Emerging Markets. PharmaFutures
3. Frost & Sullivan (2013). ‘Global generic pharmaceutical market – qualitative and quantitative analysis.’ Frost & Sullivan, presented at Pharma Tech Conference, 2013. Available at http://www.slideshare.net/AiswariyaChidambaram/pharma-tech-2013-aiswariya-chidambaram-fs Accessed 29/05/14
4. FDA (2013). ’Supplemental applications proposing labeling changes for approved drugs and biological products.’ Federal Register, November 2013. Available at https://www.federalregister.gov/articles/2013/11/13/2013-26799/supplemental-applications-proposing-labeling-changes-for-approved-drugs-and-biological-products Accessed 28/05/14
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7. Lele, C. (2013). ‘A successful path to fulfilling pharmacovigilance obligations.’ Manufacturing Chemist, 84(7/8),pp. 24-26
8. Huang, J., Zalkikar, J. and Tiwari, R. (2013). ‘Likelihood ratio test-based method for signal detection in drug classes using FDA’s AERS database.’ J Biopharm Stat, 23(1), pp. 178-200