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21st century pharmacovigilance: efforts, roles, and responsibilities
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Drug safety 1 21st century pharmacovigilance: efforts, roles, and responsibilities Peter J Pitts, Hervé Le Louet, Yola Moride, Rena M Conti
In an era when the number of expedited and conditional review pathways for newly available brand-name drugs and biosimilar medicines to treat serious and life-threatening diseases is increasing, defining pharmacovigilance has never been more crucial. 21st century pharmacovigilance is not merely about uncovering, reporting, and addressing adverse events associated with already approved and marketed agents, but can be described as the systematic monitoring of the process of pre-market review and post-market surveillance, which includes the use of medicines in everyday practice. Pharmacovigilance identifies previously unrecognised adverse events or changes in the patterns of these effects, the quality and adequacy of drug supply, and should ensure effective communication with the public, health-care professionals, and patients about the optimum safety and effective use of medicines. In this paper, the first in a Series of three about drug safety in oncology, we discuss evolving challenges in the purview, roles, and responsibilities of the US Food and Drug Administration and the European Medicines Agency with respect to pharmacovigilance efforts, with a special emphasis on oncology treatment.
Introduction The goal of pharmacovigilance is to assess the risk of adverse events for patients taking drugs—bearing in mind that no medicine is completely safe—at the time of approval for sale and throughout the product’s lifecycle. Although pharmacovigilance is essential to both patients’ safety and clinical outcomes, there are some disease states for which early, accurate, and detailed reporting is crucial. Oncology treatments—with high toxicity and narrow therapeutic windows—fall into this priority category. However, studies on pharmacovigilance and post-marketing surveillance of cancer drugs are scarce.1 Although pharmacovigilance is defined in many ways by different systems, ultimately, its aims are to enhance patients’ care and safety and to provide reliable and balanced information for effective assessment of the risks and benefits of medical drugs. WHO sets the global standard, defining pharmacovigilance as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem”.2 In 2010, 134 countries were part of WHO’s pharmacovigilance programme, which is promoted through collaboration between the Programme for International Drug Monitoring and the Collaborating Centre for International Drug Monitoring. In the USA, the term post-marketing surveillance refers to monitoring of the safety, effectiveness, and quality of marketed drugs, whereas within the European Union (EU), the term post-marketing activities is used, giving regulators a wider range of authority over a broader number of factors. In both the USA and the EU, proactive pharmacovigilance efforts by both regulators and pharmaceutical companies have escalated in recent times, most notably by increased collection of data after a medicine has been approved, across multiple sources, including by the regulator, industry, and patients.3 www.thelancet.com/oncology Vol 17 November 2016
Countries within the EU have moved towards greater harmonisation of pharmacovigilance systems to simplify funders’ activities and increase the effectiveness of these efforts.4 Generally, systems in EU member countries now use a common methodology to measure pharmacovigilance based on a regulatory body, post-marketing surveillance, risk management, post-approval research, and enforcement—even though the operative definitions of pharmacovigilance vary by agency. New pharmacovigilance legislation came into effect in the EU in 2012,5 introducing a range of tasks, a pathway for citizens to report side-effects and adverse events, more frequent and extensive monitoring and reporting by the pharmaceutical industry, and expanded and streamlined existing responsibilities for regulators. In the USA, pharmacovigilance activities have gone further than EU efforts and have been strengthened substantially by the Modernization Act of the US Food and Drug Administration (FDA) in 2007 and subsequent agency guidance.6 These rules mandate that the FDA must engage in high-frequency screening of the adverse event database and publicly post quarterly reports of any new safety information or potential signals of serious risk. Furthermore, the FDA has the authority to request that pharmaceutical companies submit Risk Evaluation Mitigation Strategies (REMS) when there is uncertainty about whether the benefits of a medicine outweigh the risks, submit post-approval studies and trials to assess known risks or signals of serious risk, and identify unexpected risks emerging from available data. Finally, the FDA has the authority to sanction industry members that violate the responsibilities and requirements or post-approval study conduct and submission of REMS. These surveillance activities underscore the point that 21st century pharmacovigilance is not merely about the uncovering, reporting, and addressing of adverse events
Lancet Oncol 2016; 17: e486–92 This is the first in a Series of three papers about drug safety Center for Medicine in the Public Interest, New York, NY, USA (P J Pitts BA); École Supérieure des Sciences Économiques et Commerciales, Paris, France, and Singapore (P J Pitts); Pharmacovigilance Department, Henri Mondor/ Assistance Publique Hôpitaux de Paris Université Paris est Créteil, Paris, France (H Le Louet MD); Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada (Prof Y Moride PhD); International Society of Pharmacovigilance, Créteil, France (H Le Louet, Prof Y Moride); and Health Economics and Policy Departments of Pediatrics Hematology/Oncology and Public Health Sciences, University of Chicago, Chicago, IL, USA (R M Conti PhD) Correspondence to: Mr Peter J Pitts, Center for Medicine in the Public Interest, New York, NY 10024, USA [email protected]
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associated with already approved and marketed prescription medicines; rather, pharmacovigilance can be best described as the systematic monitoring of the process of pre-market review and post-market surveillance, which are linked through study design, product labelling, therapeutic outcomes, adverse events, hospital and clinician reporting systems, the pharmacy interface, compliance, and a complete understanding of realworld evidence. Guidance from the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) states that pharmacovigilance should not only include monitoring the use of drugs to identify adverse events but also consist of an assessment of a medicine’s risks and benefits to establish how safe use can be improved, include the provision of information to clinicians and patients to augment safe and effective use of medicines, and monitor the outcomes of any action taken.7 In this paper, the first in a Series of three about drug safety in oncology, we look at issues regarding the purview, roles, and responsibilities of both national and international pharmacovigilance activities. Should pharmacovigilance address evolving bioequivalence issues for products with a narrow therapeutic index and drugs with a critical dose? For example, the traditional 80–125% criteria state that the confidence interval for the difference in mean values between treatments should fall within 80–125% for area under the curve (AUC) and maximum concentration (Cmax) after log transformation.8 Are these criteria appropriate for all products or should there be more narrow formalised requirements? Moreover, as the European Medicines Agency (EMA) and FDA develop pharmacovigilance guidance, we discuss how quality should be measured and results shared. In the 21st century, pharmacovigilance cannot only be about the finished product but must include post-marketing risk-based investigations into the sourcing of active pharmaceutical ingredients and excipients and look for potential associations with unanticipated adverse events based on components other than a medicine’s active pharmaceutical ingredient. Furthermore, we describe how 21st century pharmacovigilance must also include efforts to record suboptimum therapeutic outcomes systematically, as is now common practice in advanced systems for oncology drugs, such as the FDA, Health Canada, and the EMA. Finally, we discuss the emerging roles of real-world data as the successful foundation of pharmacovigilance activities, issues related to attribution and indeterminancy, and interactive effects of pharmacovigilance in both the USA and the EU, and in other regions such as Asia.
Pharmacovigilance and substandard medicines Pharmaceutical quality is both a pre-licensure and post-licensure endeavour. Similar to safe use, assessment of quality is a scientific and educational enterprise that requires close coordination with many stakeholders over the effective lifecycle of the product. This process will not come easily or inexpensively and will require a substantial e487
shift in engagement by agencies, manufacturers, and health-care providers. Moreover, the pharmaceutical industry must be responsible for quality and be able to measure it. The FDA has led efforts to define the centrality of data for 21st century pharmacovigilance activities. In 2011, shortages were reported in many essential medicines used to treat leukaemia, lymphoma, and testicular cancer,9 largely because of constrained supply among manufacturers engaged in poor-quality production,10 leading the FDA to become increasingly engaged in pharmacovigilance efforts.11 In 2014, the FDA opened the Office of Pharmaceutical Quality to oversee the safety, efficacy, and quality of medicinal products.12 Since there is no such thing as a safe substandard product, the FDA is sourcing active pharmaceutical ingredients and excipients to develop a risk-based approach that includes data gathered from manufacturing inspections, adverse event reporting, and substandard pharmaceutical events.13 This policy has already helped to resolve bioequivalence issues related to bupropion in 2012, for which the FDA recalled a generic product after reports of subtherapeutic outcomes,14 metoprolol in 2014 (also for subtherapeutic outcomes), and methylphenidate in 2015.15 Many shortages of essential medicines have also been averted as a result of the FDA ensuring the adequacy of quality manufacturing and supply.10,16 Although bioequivalence problems are the exception rather than the norm, a strategic risk-management approach must be taken to identify where problems exist—eg, in modified-release formulations. Difficulties in using traditional bioequivalence testing for the regulation of generic methylphenidate hydrochloride extended-release tablets have proven especially problematic in this case,17 reflecting the controversy around the ability of companies to produce generic extended-release drugs, which require technical expertise to manufacture. The FDA has said it is looking more closely at extended-release generic drugs and has set aside US$20 million to test these medicines for safety and quality;18 attention-deficit drugs were among the agency’s initial targets. An immediate result of this work by the FDA is a new paradigm for inspections and reports that will advance pharmaceutical quality (panel 1). Furthermore, the FDA has outlined its aims for regulation of drug quality (panel 2).19 The agency’s efforts underscore the urgency of a regular and risk-based approach to changes in active pharmaceutical ingredients and excipient sourcing, and more systematic monitoring of bioequivalence. The key issue is that both the product itself and the supplier are viewed as having quality dimensions that must be monitored routinely.20 The FDA’s new respect for quality will influence their views on both the review and post-marketing surveillance of brand-name small molecules and biological agents, generic drugs, biosimilar agents, and non-biological complex drugs. www.thelancet.com/oncology Vol 17 November 2016
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Panel 1: Standardised approach to manufacturer inspections
Panel 2: Aims of regulation of drug quality by the US Food and Drug Administration11
• Data gathering to inform quality intelligence of sites and products • Risk-based and rule-based process, using expert questions • Semi-quantitative scoring to allow for comparisons within and between sites • More common inspection report structure • Positive behaviours recognised and rewarded where facilities exceed basic compliance
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The FDA’s policy was launched only a few months before the US General Accounting Office issued a report detailing the agency’s shortcomings in tracking drug safety issues, including incomplete, outdated, inaccurate, and opaque information about the safety of the product, including its base ingredients, and the identity of the manufacturer responsible for its supply.21 At the same time, the FDA made relevant use of mechanisms to streamline its reviews, particularly for new drugs to treat cancer, and to clear the backlog of applications for manufacturers of generic drugs.21 The Director-General of the Jordan Food and Drug Administration, Hayel Mohammad Obeidat, believes that 21st century pharmacovigilance must also include tighter and more regularly monitored post-approval bioequivalence measures, with validated methods for both data collection and signal prioritisation.22 Moreover, he says that national agencies must take the lead and educate stakeholders about the importance of phase 4 monitoring and interventions. Safety is a relative concept and can only be defined in relation to risk and benefit. There is no medicine that is completely safe. In 2014, recognising this delicate balance, Canada enacted the Protecting Canadians from Unsafe Drugs Act,23 which called for stronger surveillance of medicines, including mandatory adverse drug reaction reporting by health-care institutions and recall of unsafe therapeutic products. Although the law is helpful in raising awareness, stronger post-marketing surveillance is already a requirement in developed regulatory systems (eg, in the USA, Canada, Mexico, Brazil, the EU, Japan, Australia, Singapore, South Korea, and Taiwan). The Canadian law also compelled drug companies to revise labels to reflect health risk information clearly, including potential updates to health warnings for children. Yet, these changes cannot be made without direct approval of Health Canada; moreover, the legislation did not address the issue of safety concerns generated by generic drugs. Of growing concern are substandard therapeutic outcomes driven not by traditional adverse event reports but by substandard pharmaceutical events. These events occur when a product does not perform as expected, perhaps because of issues with the active pharmaceutical ingredient or excipient or low-quality manufacturing www.thelancet.com/oncology Vol 17 November 2016
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Put patients first by balancing risk and availability Ensure clinically relevant quality standards Integrate review and inspection across product lifecycle Maximise efficiency by applying risk-based approaches Strengthen lifecycle management by using team-based processes Apply staff expertise effectively to enhance quality regulation Encourage innovation by advancing new technology and manufacturing science Enhance cross-disciplinary interaction, shared accountability, and joint problem-solving Build collaborative relationships by communicating openly, honestly, and directly
practices.24 Substandard pharmaceutical events are especially important with respect to cancer drugs and other medicines that treat immunological conditions because their therapeutic benefits are both costly and urgent. Nowhere are these matters more urgent than beyond the traditional boundaries of safety and surveillance. Does this mean there is an epidemic of unsafe substandard medicines? Not when a functioning regulatory authority exists. However, as for all issues of quality, the last stage is always the most difficult. To this end, the FDA, the EMA, and other regulatory authorities have designed and implemented programmes to increase and better understand how the products they license function in a non-randomised, real-world environment. Yet, assessment of the effectiveness of approved medicines is almost impossible for clinicians, particularly in therapeutic specialties such as oncology. For example, a patient’s response to cancer treatment is typically mitigated by the extreme nature of the disease. As a result, poor clinical outcomes are generally ascribed to the nature of the malignant disease and not the quality or appropriateness of the pharmaceutical intervention. This focus underscores the fact that post-marketing risk management of medicines cannot exist without a holistic understanding and acceptance of the responsibilities of risk. Pharmacovigilance activities have relied traditionally on clinicians and pharmaceutical manufacturers as the two main pillars of reporting, with the overwhelming volume of data coming from industry and a small but significant contribution coming directly from patients and health-care providers. This situation is clearly changing. For example, consensus is growing that patients and other individuals have a role in 21st century pharmacovigilance activities. Patient-reported outcomes have become increasingly important aspects of data collection in the conduct of clinical trials for first marketing approval of medicines in the USA, but what is e488
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the role of these outcomes in the post-market setting? The emerging idea of pharmacovigilance as a postmarketing system—requiring input from regulators (quality oversight of active pharmaceutical ingredients, excipient sourcing, and manufacturing), clinicians, pharmacists (both storefront and hospital based), payers, academics, and manufacturers—begs the inclusion of patients and caregivers as actors with roles and responsibilities similar to regulators and the pharmaceutical industry. In 2009, the FDA announced its Safe Use of Drugs Initiative,25 with the aim of making medicines safer to ensure that they are used as directed. The main strategy is education, and the agency’s efforts are aimed at clinicians, nurses, pharmacists, and patients.
Role of new media and patients In a world driven increasingly by social media, more real-time data from individual consumers is not always synonymous with better information. Despite the frustrating increase in the signal-to-noise ratio, social media is becoming an ever more important source of potentially valuable pharmacovigilance information. Social media efforts have, in some important and measurable circumstances, revolutionised safety concerns for rare diseases (eg, myelodysplastic syndrome) and documented adverse drug reactions (eg, fluoroquinolone-associated disability).26 These cases highlight the point that regulatory agencies might not have sufficient knowledge of new media and the technological and human resources to extract important and relevant data relative to drug safety. There are fears that current systems could be overwhelmed with poorquality information.27 With these worries in mind, what level of staffing and training is needed to adequately and appropriately handle modern-day demands for pharmacovigilance? In May, 2014, the European Commission published a report on the tasks the agency undertook during the first year of the new legislation, together with regulatory medicines authorities in EU member states and the European Commission.28 During the period from July, 2012, to July, 2013, patients’ reports of suspected adverse drug reactions increased by more than 9000; changes to product information were made as a result of assessment of signals of new or changing safety issues with specific medicines; major public health reviews were initiated, including combined hormonal contraceptives and venous thromboembolism, medicines containing cyproterone acetate or ethinylestradiol and venous thromboembolism, and codeine-containing products used for pain relief and overdose in children; and thousands of patients underwent training in pharmacovigilance. In many respects, pharmacovigilance efforts by both US and EU regulatory agencies suggest 21st century pharmacovigilance should be based on the notion of design thinking.29 Unlike critical thinking, which is a process of analysis, design thinking is creative and based e489
around formation of action-oriented ideas. This approach requires intense cross-examination of the filters used in defining a problem and revision of the opportunity before embarking on its creation and execution. Design thinking also needs cross-functional insight into each problem by varied perspectives and constant and relentless questioning—observation takes centre stage. Design has also been defined as transformation of existing conditions into preferred ones.30
Biosimilar and generic drug safety: post-marketing indetermination A key issue driving the development of 21st century regulatory pharmacovigilance activities is the need for updated post-marketing surveillance of biosimilar drugs. Issues related to the particularities of biological agents (ie, sources, processes, quality requirements, and new safety profiles) need advanced regulatory science for both increased and enhanced oversight of pre-market randomised data and post-approval real-world clinical outcomes. Fundamentally, all players in the pharmacovigilance process will have difficulties characterising issues with biosimilar agents because we do not have existing, validated, predictive models of potential hotspot products, base ingredients, or suppliers. Thus, biosimilar pharmacovigilance will have to evolve when new medicines are launched. Small numbers and novelty of products and their safety profiles alone and in combination with other medicines will render monitoring of biosimilar agents a challenge for manufacturers, medical providers, and patients. We are in an era of post-marketing indetermination, and the first step should be to develop epidemiological approaches that are based on better understanding the differences between generic and biosimilar drugs. For example, generic drugs can have different safety profiles from biological agents because of variable bioequivalence ranges and sources of excipients and active pharmaceutical ingredients. With respect to biosimilar pharmacovigilance activities, however, concerns arise over variable iatrogenic effects, differences between batches by multiple manufacturers, and the elastic definition of similarity, which are all important aspects of safety. For example, between 1998 and 2004, the number of cases of antibody-mediated pure redcell aplasia increased because of a manufacturing change that augmented the immunogenicity of an erythropoiesis-stimulating agent;31 however, with three similar agents on the market, the challenge was to identify which agent was causing the problem.32 Nowhere is this issue more profound (for patients) and urgent (relative to health-care technology assessment) than in the development of 21st century strategies for post-marketing surveillance of generic drugs and biosimilar agents in oncology.33 What do we know about pharmacovigilance when it is applied to medicines with highly toxic potential effects on www.thelancet.com/oncology Vol 17 November 2016
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Risk minimisation in Asia Existing methods for risk minimisation used in the USA and the EU might not be applicable to some national systems and medical care settings—eg, those in Asian countries. For instance, risk-minimisation interventions are typically based on effect analyses in a few patients from selected populations. Thus, identification of high-risk small-molecule medicines and biological agents in the USA and the EU might not be generalisable to specific subpopulations within Asian countries or in countries other than those in Europe and North America.37,38 US and EU approaches to pharmacovigilance have gained widespread uptake in many regions around the world and have become global models since the FDA and the EMA have released regulation and guidance documents that are more extensive than those released in smaller countries. In parallel, the multinational pharmaceutical industry develops global pharmacovigilance and risk www.thelancet.com/oncology Vol 17 November 2016
16 000 14 000 12 000 Adverse event reports (n)
patients, such as cancer drugs? In the USA, many cancer medicines approved for sale since 1995 have REMS attached to them,34 and a significant increase in adverse event reports has been noted among this therapeutic class (figure). The FDA defines adverse drug events as any undesirable experience associated with the use of a drug, including serious drug side-effects, product use errors, product quality problems, and therapeutic failures. The FDA maintain an online system for adverse event reports related to generic and branded drugs. Analysis of data from this system shows that, in the first three quarters (Q1, Q2, and Q3) of 2015, most adverse event reports among cancer drugs (>80%) were related to brand-name cancer medicines. This finding is unusual because many generic cancer medicines have entered the market in recent years and use of generic versions of the innovator product seems to increase after launch.35 It is possible that attribution of an adverse event to generic versions (typically, multiple generic products are available) is difficult because of the high prevalence of combination regimens in which generic drugs act as the backbone for brand-name drug-based treatment for metastatic disease. It is also important to note that reports of therapeutic failure typically increase immediately after initial generic entry into the marketplace.36 What does the increasing trend in adverse event reports among cancer medicines overall tell us? Does it indicate a safety problem or more aggressive reporting? Has the rise in adverse events led to increased actions by agencies? The answer, at least to date, is that no brand-name or generic drug treatments for cancer have been recalled or relabelled between 2012 and the first quarter of 2016. So, what is the value of adverse event reporting? Success cannot be measured in report volume alone. Perhaps a more germane question is whether or not the increase in adverse events matches up with a decrease in positive therapeutic outcomes. However, scant data are available with which to draw legitimate conclusions.
10 000 8000 6000 4000 2000 0
2012 2012 2012 2012 2013 2013 2013 2013 2014 2014 2014 2014 2015 2015 2015 (Q1) (Q2) (Q3) (Q4) (Q1) (Q2) (Q3) (Q4) (Q1) (Q2) (Q3) (Q4) (Q1) (Q2) (Q3) Year (quarter)
Figure: Number of adverse events reported to the FDA’s adverse event reporting system for cancer medicines Data shown are from the first quarter (Q1) of 2012 to the third quarter (Q3) of 2015. Data were obtained on Feb 15, 2016, from the FDA’s open adverse event reporting system. FDA=US Food and Drug Administration.
management activities with local adaptations and country-specific appendices when needed. Complete harmonisation of post-marketing activities and strategies might not always be warranted, or possible, particularly when labelling is not identical. Moreover, differences in cultures, health-care systems, and patients’ management practices might not be conducive to such pharmacovigilance concordance. For example, in several Asian countries, new biological agents are typically launched in the private hospital setting,39 which provides opportunities for pharmacovigilance that differ from the broader distribution channels observed in Europe and North America, because private hospitals have more advanced pharmacy-based pharmacovigilance processes and procedures, and data can be gathered and reported with greater speed and accuracy. Furthermore, private Asian hospitals usually cover only a small proportion of the population in any given country, resulting in very small sample sizes for undertaking post-marketing activities—eg, cohort event monitoring. A special interest group of the International Society of Pharmacovigilance was created in 2015 with the goal of designing novel risk-minimisation methods applied in a manner proportionate to risk in specific populations.40 In keeping with the theoretical underpinnings of design thinking, this initiative—namely, the Post-Approval Vigilance Program—aims to develop a customisable decision aid yielding four levels of stringency of riskminimisation interventions, ranging from level 0 (no risk-minimisation intervention beyond the label) to level III (most stringent risk-minimisation intervention). A level IV has also been created, which corresponds with the requirement for a post-approval study. Because riskminimisation interventions and post-approval studies are
For the FDA’s adverse event reporting system see https://open.fda.gov/data/faers
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Search strategy and selection criteria We did a systematic PubMed search between January, 2005, and January, 2016, using the terms: “pharmacovigilance”, “cancer”, “oncology”, “pharmacoepidemiology”, “drug quality”, “medicines”, “prescription drugs”, “adverse events”, “biosimilars”, “substandard pharmaceutical events”, “safe use of medicines”, “clinical outcomes”, “regulatory harmonization”, and “regulatory convergence”. We restricted our search to reports written in English and French and to peer-reviewed papers. Bibliographies of identified articles, guidelines, and conference proceedings were reviewed for additional references. Moreover, we spoke with senior medicines regulators, hospital pharmacy departments, clinicians, innovator and generic pharmaceutical manufacturers, and patient organisations from around the world. The final reference list was generated on the basis of originality and relevance to the broad scope of this Series paper.
two distinct risk-management activities, level IV can be viewed as a stand-alone requirement or as a supplement to level I, II, or III. Fundamental tenets of the PostApproval Vigilance Program criteria have been put forward by some members of the special interest group. Before testing and implementing this strategy, it is necessary to establish the criteria and scoring system using a robust and validated approach.40 This process will lead to efficient, practical, and transparent planning of risk-minimisation activities in Asia. We believe dangers are inherent in recommending harmonisation of Asian processes with European and US best practices. We must be wary of the uncertainties of regulatory imperialism. Indeed, pharmacovigilance is as much a management problem as a public health issue. Convergence into best European and US practices will probably be pointless in view of profound differences in regulatory staffing levels, overall budgetary limitations, and education of clinicians, pharmacists, and patients. Expecting other nations with less experience and resources to harmonise with the FDA or the EMA is not the right approach.
Future directions Regular and creative risk-management plans and diligent efforts are needed to understand issues surrounding safety and surveillance of cancer drugs. One way of improving pharmacovigilance efforts is to utilise a pharmacovigilance database to accrue data for known effects and identify new ones.41 Epidemiological studies and collaborations with cancer registries might also be useful. Most importantly, we must investigate how pharmacovigilance activities can be used to identify and correct issues that affect the ability for licensed medicines and medical devices to maximise positive therapeutic outcomes. Such an effort will require a new three-dimensional approach that includes not only identification of traditional adverse events but also a more e491
dedicated focus on substandard outcomes and on why a product’s safety profile has evolved differently from the predictive (and rarefied) clinical trial environment used for initial product approval and market launch.
Conclusion Under-reported, inaccurate, delayed, and non-salient data are major shortcomings for pharmacovigilance activity in every country, and all must be addressed with new and existing methods and strategies to make 21st century pharmacovigilance a reality. This need is especially relevant and urgent for medicines used to treat cancer, for which better knowledge can save lives and ensure more cost-effective use of precious health-care resources. No easy answers are available. For 21st century pharmacovigilance of cancer treatments and across other therapeutic classes, we should seek regulatory convergence and a pathway to improvement— with the first step being identification of specific procedural asymmetries that can be addressed and corrected.42 We view pharmacovigilance as a management problem as much as a public health issue. Contributors PJP wrote the report and contributed to its design, data analysis, and data interpretation. HLL and YM contributed to design and writing of the report and data analysis. RMC did the literature search, contributed to design and writing of the report, and data interpretation. Declaration of interests We declare no competing interests. Acknowledgments RMC was funded by an award from the National Cancer Institute to the University of Chicago (K07-CA138906). The statements, findings, conclusions, views, and opinions contained and expressed herein are not necessarily those of the institutions with whom the authors are affiliated. References 1 Baldo P, De Paoli P. Pharmacovigilance in oncology: evaluation of current practice and future perspectives. J Eval Clin Pract 2014; 20: 559–69. 2 WHO. Essential medicines and health products: pharmacovigilance. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/ pharmvigi/en/ (accessed May 20, 2016). 3 Wilson A, Milne CP. FDA’s risk evaluation and mitigation strategies (REMS): effective and efficient safety tools or process poltergeist? Food Drug Law J 2011; 66: 569–85. 4 Borg JJ, Aislaitner G, Pirozynski M, Mifsud S. Strengthening and rationalizing pharmacovigilance in the EU: where is Europe heading to? A review of the new EU legislation on pharmacovigilance. Drug Saf 2011; 34: 187–97. 5 Callréus T. The new EU legislation on pharmacovigilance and changing models for drug development. Drug Saf 2011; 34: 529–30. 6 Senate and House of Representatives of the United States of America in Congress. Food and Drug Administration Modernization Act of 1997: United States Senate Bill 830. Jan 7, 1997. http://www.fda.gov/downloads/RegulatoryInformation/ Legislation/SignificantAmendmentstotheFDCAct/FDAMA/ FullTextofFDAMAlaw/UCM089145.pdf (accessed March 20, 2016). 7 Medicines and Healthcare products Regulatory Agency. Medicines, medical devices and blood regulation and safety: guidance—good pharmacovigilance practice (GPvP). Dec 18, 2014. https://www.gov. uk/guidance/good-pharmacovigilance-practice-gpvp (accessed Feb 15, 2016). 8 US Food and Drug Administration. Product-specific recommendations for generic drug development. Aug 29, 2016. http://www.fda.gov/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm075207.htm (accessed Sept 19, 2016).
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Kaur K, Fayad R, Saxena A, et al, on behalf of the Southern Network on Adverse Reactions (SONAR) project. Fluoroquinolone-related neuropsychiatric and mitochondrial toxicity: a collaborative investigation by scientists and members of a social network. J Community Support Oncol 2016; 14: 54–65. Pitts PJ, Therese D. Social media and post marketing surveillance: signal vs noise. Your Encore blog, Dec 16, 2015. http://blog. yourencore.com/postmarketing-surveillance-and-social-media (accessed Feb 15, 2016). European Commission. Study on the regulation of advanced therapies in selected jurisdictions. http://ec.europa.eu/health/ documents/new_en.htm (accessed Sept 19, 2016). Fast Company. Design thinking . . . what is that? March 20, 2006. http://www.fastcompany.com/919258/design-thinking-what (accessed Feb 15, 2016). Simon HA. The sciences of the artificial. Cambridge: The MIT Press, 1996. Rossert J, Maroni B, Aljama P, et al, for the Pure Red Cell Aplasia Global Scientific Advisory Board (GSAB). Erythropoietin-induced, antibody-mediated pure red cell aplasia. Eur J Clin Invest 2005; 35: 95–99. Ahmed I, Kaspar B, Sharma U. Biosimilars: impact of biologic product life cycle and European experience on the regulatory trajectory in the United States. Clin Ther 2012; 34: 400–19. Kaltenboeck A, Long G, Hayes-Larson E, de Lima Lopes G. Assessing the impact of substandard copy medicines in developing countries: the experience with imatinib copies. Expert Rev Clin Pharmacol 2013; 6: 691–701. US Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies (REMS). http://www.accessdata.fda.gov/ scripts/cder/rems/index.cfm?event=RemsData.page (accessed July 12, 2016). Conti RM, Berndt ER. Specialty drug prices and utilization after loss of US patent exclusivity, 2001–2007: National Bureau Of Economic Research (NBER) working paper 20016. Aug 8, 2014. http://www.nber.org/papers/w20016.pdf (accessed July 12, 2016). Dunne S, Shannon B, Dunne C, Cullen W. A review of the differences and similarities between generic drugs and their originator counterparts, including economic benefits associated with usage of generic medicines, using Ireland as a case study. BMC Pharmacol Toxicol 2013; 14: 1. Bennett CL, Chen B, Hermanson T, et al. Regulatory and clinical considerations for biosimilar oncology drugs. Lancet Oncol 2014; 15: e594–605. Renwick MJ, Smolina K, Gladstone EJ, Weymann D, Morgan SG. Postmarket policy considerations for biosimilar oncology drugs. Lancet Oncol 2016; 17: e31–38. Tarn Y-H, Hu S, Kamae I, et al. Health-care systems and pharmacoeconomic research in Asia-Pacific region. Value Health 2008; 11 (suppl 1): S137–55. Bahri P, Dodoo AN, Edwards BD, et al. The ISoP CommSIG for improving medicinal product risk communication: a new special interest group of the International Society of Pharmacovigilance. Drug Saf 2015; 38: 621–27. Durrieu G, Mazau B, Jégu J, Lapeyre-Mestre M, Delord JP, Montastruc JL, and the French network of Regional Pharmacovigilance Centers. Drugs and cancer: an analysis of the French Pharmacovigilance Database. Therapie 2013; 68: 149–54. Pitts PJ. The globetrotting regulator. J Commer Biotechnol 2015; 21: 5.
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Drug safety 1 21st century pharmacovigilance: efforts, roles, and responsibilities Peter J Pitts, Hervé Le Louet, Yola Moride, Rena M Conti
In an era when the number of expedited and conditional review pathways for newly available brand-name drugs and biosimilar medicines to treat serious and life-threatening diseases is increasing, defining pharmacovigilance has never been more crucial. 21st century pharmacovigilance is not merely about uncovering, reporting, and addressing adverse events associated with already approved and marketed agents, but can be described as the systematic monitoring of the process of pre-market review and post-market surveillance, which includes the use of medicines in everyday practice. Pharmacovigilance identifies previously unrecognised adverse events or changes in the patterns of these effects, the quality and adequacy of drug supply, and should ensure effective communication with the public, health-care professionals, and patients about the optimum safety and effective use of medicines. In this paper, the first in a Series of three about drug safety in oncology, we discuss evolving challenges in the purview, roles, and responsibilities of the US Food and Drug Administration and the European Medicines Agency with respect to pharmacovigilance efforts, with a special emphasis on oncology treatment.
Introduction The goal of pharmacovigilance is to assess the risk of adverse events for patients taking drugs—bearing in mind that no medicine is completely safe—at the time of approval for sale and throughout the product’s lifecycle. Although pharmacovigilance is essential to both patients’ safety and clinical outcomes, there are some disease states for which early, accurate, and detailed reporting is crucial. Oncology treatments—with high toxicity and narrow therapeutic windows—fall into this priority category. However, studies on pharmacovigilance and post-marketing surveillance of cancer drugs are scarce.1 Although pharmacovigilance is defined in many ways by different systems, ultimately, its aims are to enhance patients’ care and safety and to provide reliable and balanced information for effective assessment of the risks and benefits of medical drugs. WHO sets the global standard, defining pharmacovigilance as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem”.2 In 2010, 134 countries were part of WHO’s pharmacovigilance programme, which is promoted through collaboration between the Programme for International Drug Monitoring and the Collaborating Centre for International Drug Monitoring. In the USA, the term post-marketing surveillance refers to monitoring of the safety, effectiveness, and quality of marketed drugs, whereas within the European Union (EU), the term post-marketing activities is used, giving regulators a wider range of authority over a broader number of factors. In both the USA and the EU, proactive pharmacovigilance efforts by both regulators and pharmaceutical companies have escalated in recent times, most notably by increased collection of data after a medicine has been approved, across multiple sources, including by the regulator, industry, and patients.3 www.thelancet.com/oncology Vol 17 November 2016
Countries within the EU have moved towards greater harmonisation of pharmacovigilance systems to simplify funders’ activities and increase the effectiveness of these efforts.4 Generally, systems in EU member countries now use a common methodology to measure pharmacovigilance based on a regulatory body, post-marketing surveillance, risk management, post-approval research, and enforcement—even though the operative definitions of pharmacovigilance vary by agency. New pharmacovigilance legislation came into effect in the EU in 2012,5 introducing a range of tasks, a pathway for citizens to report side-effects and adverse events, more frequent and extensive monitoring and reporting by the pharmaceutical industry, and expanded and streamlined existing responsibilities for regulators. In the USA, pharmacovigilance activities have gone further than EU efforts and have been strengthened substantially by the Modernization Act of the US Food and Drug Administration (FDA) in 2007 and subsequent agency guidance.6 These rules mandate that the FDA must engage in high-frequency screening of the adverse event database and publicly post quarterly reports of any new safety information or potential signals of serious risk. Furthermore, the FDA has the authority to request that pharmaceutical companies submit Risk Evaluation Mitigation Strategies (REMS) when there is uncertainty about whether the benefits of a medicine outweigh the risks, submit post-approval studies and trials to assess known risks or signals of serious risk, and identify unexpected risks emerging from available data. Finally, the FDA has the authority to sanction industry members that violate the responsibilities and requirements or post-approval study conduct and submission of REMS. These surveillance activities underscore the point that 21st century pharmacovigilance is not merely about the uncovering, reporting, and addressing of adverse events
Lancet Oncol 2016; 17: e486–92 This is the first in a Series of three papers about drug safety Center for Medicine in the Public Interest, New York, NY, USA (P J Pitts BA); École Supérieure des Sciences Économiques et Commerciales, Paris, France, and Singapore (P J Pitts); Pharmacovigilance Department, Henri Mondor/ Assistance Publique Hôpitaux de Paris Université Paris est Créteil, Paris, France (H Le Louet MD); Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada (Prof Y Moride PhD); International Society of Pharmacovigilance, Créteil, France (H Le Louet, Prof Y Moride); and Health Economics and Policy Departments of Pediatrics Hematology/Oncology and Public Health Sciences, University of Chicago, Chicago, IL, USA (R M Conti PhD) Correspondence to: Mr Peter J Pitts, Center for Medicine in the Public Interest, New York, NY 10024, USA [email protected]
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associated with already approved and marketed prescription medicines; rather, pharmacovigilance can be best described as the systematic monitoring of the process of pre-market review and post-market surveillance, which are linked through study design, product labelling, therapeutic outcomes, adverse events, hospital and clinician reporting systems, the pharmacy interface, compliance, and a complete understanding of realworld evidence. Guidance from the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) states that pharmacovigilance should not only include monitoring the use of drugs to identify adverse events but also consist of an assessment of a medicine’s risks and benefits to establish how safe use can be improved, include the provision of information to clinicians and patients to augment safe and effective use of medicines, and monitor the outcomes of any action taken.7 In this paper, the first in a Series of three about drug safety in oncology, we look at issues regarding the purview, roles, and responsibilities of both national and international pharmacovigilance activities. Should pharmacovigilance address evolving bioequivalence issues for products with a narrow therapeutic index and drugs with a critical dose? For example, the traditional 80–125% criteria state that the confidence interval for the difference in mean values between treatments should fall within 80–125% for area under the curve (AUC) and maximum concentration (Cmax) after log transformation.8 Are these criteria appropriate for all products or should there be more narrow formalised requirements? Moreover, as the European Medicines Agency (EMA) and FDA develop pharmacovigilance guidance, we discuss how quality should be measured and results shared. In the 21st century, pharmacovigilance cannot only be about the finished product but must include post-marketing risk-based investigations into the sourcing of active pharmaceutical ingredients and excipients and look for potential associations with unanticipated adverse events based on components other than a medicine’s active pharmaceutical ingredient. Furthermore, we describe how 21st century pharmacovigilance must also include efforts to record suboptimum therapeutic outcomes systematically, as is now common practice in advanced systems for oncology drugs, such as the FDA, Health Canada, and the EMA. Finally, we discuss the emerging roles of real-world data as the successful foundation of pharmacovigilance activities, issues related to attribution and indeterminancy, and interactive effects of pharmacovigilance in both the USA and the EU, and in other regions such as Asia.
Pharmacovigilance and substandard medicines Pharmaceutical quality is both a pre-licensure and post-licensure endeavour. Similar to safe use, assessment of quality is a scientific and educational enterprise that requires close coordination with many stakeholders over the effective lifecycle of the product. This process will not come easily or inexpensively and will require a substantial e487
shift in engagement by agencies, manufacturers, and health-care providers. Moreover, the pharmaceutical industry must be responsible for quality and be able to measure it. The FDA has led efforts to define the centrality of data for 21st century pharmacovigilance activities. In 2011, shortages were reported in many essential medicines used to treat leukaemia, lymphoma, and testicular cancer,9 largely because of constrained supply among manufacturers engaged in poor-quality production,10 leading the FDA to become increasingly engaged in pharmacovigilance efforts.11 In 2014, the FDA opened the Office of Pharmaceutical Quality to oversee the safety, efficacy, and quality of medicinal products.12 Since there is no such thing as a safe substandard product, the FDA is sourcing active pharmaceutical ingredients and excipients to develop a risk-based approach that includes data gathered from manufacturing inspections, adverse event reporting, and substandard pharmaceutical events.13 This policy has already helped to resolve bioequivalence issues related to bupropion in 2012, for which the FDA recalled a generic product after reports of subtherapeutic outcomes,14 metoprolol in 2014 (also for subtherapeutic outcomes), and methylphenidate in 2015.15 Many shortages of essential medicines have also been averted as a result of the FDA ensuring the adequacy of quality manufacturing and supply.10,16 Although bioequivalence problems are the exception rather than the norm, a strategic risk-management approach must be taken to identify where problems exist—eg, in modified-release formulations. Difficulties in using traditional bioequivalence testing for the regulation of generic methylphenidate hydrochloride extended-release tablets have proven especially problematic in this case,17 reflecting the controversy around the ability of companies to produce generic extended-release drugs, which require technical expertise to manufacture. The FDA has said it is looking more closely at extended-release generic drugs and has set aside US$20 million to test these medicines for safety and quality;18 attention-deficit drugs were among the agency’s initial targets. An immediate result of this work by the FDA is a new paradigm for inspections and reports that will advance pharmaceutical quality (panel 1). Furthermore, the FDA has outlined its aims for regulation of drug quality (panel 2).19 The agency’s efforts underscore the urgency of a regular and risk-based approach to changes in active pharmaceutical ingredients and excipient sourcing, and more systematic monitoring of bioequivalence. The key issue is that both the product itself and the supplier are viewed as having quality dimensions that must be monitored routinely.20 The FDA’s new respect for quality will influence their views on both the review and post-marketing surveillance of brand-name small molecules and biological agents, generic drugs, biosimilar agents, and non-biological complex drugs. www.thelancet.com/oncology Vol 17 November 2016
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Panel 1: Standardised approach to manufacturer inspections
Panel 2: Aims of regulation of drug quality by the US Food and Drug Administration11
• Data gathering to inform quality intelligence of sites and products • Risk-based and rule-based process, using expert questions • Semi-quantitative scoring to allow for comparisons within and between sites • More common inspection report structure • Positive behaviours recognised and rewarded where facilities exceed basic compliance
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The FDA’s policy was launched only a few months before the US General Accounting Office issued a report detailing the agency’s shortcomings in tracking drug safety issues, including incomplete, outdated, inaccurate, and opaque information about the safety of the product, including its base ingredients, and the identity of the manufacturer responsible for its supply.21 At the same time, the FDA made relevant use of mechanisms to streamline its reviews, particularly for new drugs to treat cancer, and to clear the backlog of applications for manufacturers of generic drugs.21 The Director-General of the Jordan Food and Drug Administration, Hayel Mohammad Obeidat, believes that 21st century pharmacovigilance must also include tighter and more regularly monitored post-approval bioequivalence measures, with validated methods for both data collection and signal prioritisation.22 Moreover, he says that national agencies must take the lead and educate stakeholders about the importance of phase 4 monitoring and interventions. Safety is a relative concept and can only be defined in relation to risk and benefit. There is no medicine that is completely safe. In 2014, recognising this delicate balance, Canada enacted the Protecting Canadians from Unsafe Drugs Act,23 which called for stronger surveillance of medicines, including mandatory adverse drug reaction reporting by health-care institutions and recall of unsafe therapeutic products. Although the law is helpful in raising awareness, stronger post-marketing surveillance is already a requirement in developed regulatory systems (eg, in the USA, Canada, Mexico, Brazil, the EU, Japan, Australia, Singapore, South Korea, and Taiwan). The Canadian law also compelled drug companies to revise labels to reflect health risk information clearly, including potential updates to health warnings for children. Yet, these changes cannot be made without direct approval of Health Canada; moreover, the legislation did not address the issue of safety concerns generated by generic drugs. Of growing concern are substandard therapeutic outcomes driven not by traditional adverse event reports but by substandard pharmaceutical events. These events occur when a product does not perform as expected, perhaps because of issues with the active pharmaceutical ingredient or excipient or low-quality manufacturing www.thelancet.com/oncology Vol 17 November 2016
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Put patients first by balancing risk and availability Ensure clinically relevant quality standards Integrate review and inspection across product lifecycle Maximise efficiency by applying risk-based approaches Strengthen lifecycle management by using team-based processes Apply staff expertise effectively to enhance quality regulation Encourage innovation by advancing new technology and manufacturing science Enhance cross-disciplinary interaction, shared accountability, and joint problem-solving Build collaborative relationships by communicating openly, honestly, and directly
practices.24 Substandard pharmaceutical events are especially important with respect to cancer drugs and other medicines that treat immunological conditions because their therapeutic benefits are both costly and urgent. Nowhere are these matters more urgent than beyond the traditional boundaries of safety and surveillance. Does this mean there is an epidemic of unsafe substandard medicines? Not when a functioning regulatory authority exists. However, as for all issues of quality, the last stage is always the most difficult. To this end, the FDA, the EMA, and other regulatory authorities have designed and implemented programmes to increase and better understand how the products they license function in a non-randomised, real-world environment. Yet, assessment of the effectiveness of approved medicines is almost impossible for clinicians, particularly in therapeutic specialties such as oncology. For example, a patient’s response to cancer treatment is typically mitigated by the extreme nature of the disease. As a result, poor clinical outcomes are generally ascribed to the nature of the malignant disease and not the quality or appropriateness of the pharmaceutical intervention. This focus underscores the fact that post-marketing risk management of medicines cannot exist without a holistic understanding and acceptance of the responsibilities of risk. Pharmacovigilance activities have relied traditionally on clinicians and pharmaceutical manufacturers as the two main pillars of reporting, with the overwhelming volume of data coming from industry and a small but significant contribution coming directly from patients and health-care providers. This situation is clearly changing. For example, consensus is growing that patients and other individuals have a role in 21st century pharmacovigilance activities. Patient-reported outcomes have become increasingly important aspects of data collection in the conduct of clinical trials for first marketing approval of medicines in the USA, but what is e488
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the role of these outcomes in the post-market setting? The emerging idea of pharmacovigilance as a postmarketing system—requiring input from regulators (quality oversight of active pharmaceutical ingredients, excipient sourcing, and manufacturing), clinicians, pharmacists (both storefront and hospital based), payers, academics, and manufacturers—begs the inclusion of patients and caregivers as actors with roles and responsibilities similar to regulators and the pharmaceutical industry. In 2009, the FDA announced its Safe Use of Drugs Initiative,25 with the aim of making medicines safer to ensure that they are used as directed. The main strategy is education, and the agency’s efforts are aimed at clinicians, nurses, pharmacists, and patients.
Role of new media and patients In a world driven increasingly by social media, more real-time data from individual consumers is not always synonymous with better information. Despite the frustrating increase in the signal-to-noise ratio, social media is becoming an ever more important source of potentially valuable pharmacovigilance information. Social media efforts have, in some important and measurable circumstances, revolutionised safety concerns for rare diseases (eg, myelodysplastic syndrome) and documented adverse drug reactions (eg, fluoroquinolone-associated disability).26 These cases highlight the point that regulatory agencies might not have sufficient knowledge of new media and the technological and human resources to extract important and relevant data relative to drug safety. There are fears that current systems could be overwhelmed with poorquality information.27 With these worries in mind, what level of staffing and training is needed to adequately and appropriately handle modern-day demands for pharmacovigilance? In May, 2014, the European Commission published a report on the tasks the agency undertook during the first year of the new legislation, together with regulatory medicines authorities in EU member states and the European Commission.28 During the period from July, 2012, to July, 2013, patients’ reports of suspected adverse drug reactions increased by more than 9000; changes to product information were made as a result of assessment of signals of new or changing safety issues with specific medicines; major public health reviews were initiated, including combined hormonal contraceptives and venous thromboembolism, medicines containing cyproterone acetate or ethinylestradiol and venous thromboembolism, and codeine-containing products used for pain relief and overdose in children; and thousands of patients underwent training in pharmacovigilance. In many respects, pharmacovigilance efforts by both US and EU regulatory agencies suggest 21st century pharmacovigilance should be based on the notion of design thinking.29 Unlike critical thinking, which is a process of analysis, design thinking is creative and based e489
around formation of action-oriented ideas. This approach requires intense cross-examination of the filters used in defining a problem and revision of the opportunity before embarking on its creation and execution. Design thinking also needs cross-functional insight into each problem by varied perspectives and constant and relentless questioning—observation takes centre stage. Design has also been defined as transformation of existing conditions into preferred ones.30
Biosimilar and generic drug safety: post-marketing indetermination A key issue driving the development of 21st century regulatory pharmacovigilance activities is the need for updated post-marketing surveillance of biosimilar drugs. Issues related to the particularities of biological agents (ie, sources, processes, quality requirements, and new safety profiles) need advanced regulatory science for both increased and enhanced oversight of pre-market randomised data and post-approval real-world clinical outcomes. Fundamentally, all players in the pharmacovigilance process will have difficulties characterising issues with biosimilar agents because we do not have existing, validated, predictive models of potential hotspot products, base ingredients, or suppliers. Thus, biosimilar pharmacovigilance will have to evolve when new medicines are launched. Small numbers and novelty of products and their safety profiles alone and in combination with other medicines will render monitoring of biosimilar agents a challenge for manufacturers, medical providers, and patients. We are in an era of post-marketing indetermination, and the first step should be to develop epidemiological approaches that are based on better understanding the differences between generic and biosimilar drugs. For example, generic drugs can have different safety profiles from biological agents because of variable bioequivalence ranges and sources of excipients and active pharmaceutical ingredients. With respect to biosimilar pharmacovigilance activities, however, concerns arise over variable iatrogenic effects, differences between batches by multiple manufacturers, and the elastic definition of similarity, which are all important aspects of safety. For example, between 1998 and 2004, the number of cases of antibody-mediated pure redcell aplasia increased because of a manufacturing change that augmented the immunogenicity of an erythropoiesis-stimulating agent;31 however, with three similar agents on the market, the challenge was to identify which agent was causing the problem.32 Nowhere is this issue more profound (for patients) and urgent (relative to health-care technology assessment) than in the development of 21st century strategies for post-marketing surveillance of generic drugs and biosimilar agents in oncology.33 What do we know about pharmacovigilance when it is applied to medicines with highly toxic potential effects on www.thelancet.com/oncology Vol 17 November 2016
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Risk minimisation in Asia Existing methods for risk minimisation used in the USA and the EU might not be applicable to some national systems and medical care settings—eg, those in Asian countries. For instance, risk-minimisation interventions are typically based on effect analyses in a few patients from selected populations. Thus, identification of high-risk small-molecule medicines and biological agents in the USA and the EU might not be generalisable to specific subpopulations within Asian countries or in countries other than those in Europe and North America.37,38 US and EU approaches to pharmacovigilance have gained widespread uptake in many regions around the world and have become global models since the FDA and the EMA have released regulation and guidance documents that are more extensive than those released in smaller countries. In parallel, the multinational pharmaceutical industry develops global pharmacovigilance and risk www.thelancet.com/oncology Vol 17 November 2016
16 000 14 000 12 000 Adverse event reports (n)
patients, such as cancer drugs? In the USA, many cancer medicines approved for sale since 1995 have REMS attached to them,34 and a significant increase in adverse event reports has been noted among this therapeutic class (figure). The FDA defines adverse drug events as any undesirable experience associated with the use of a drug, including serious drug side-effects, product use errors, product quality problems, and therapeutic failures. The FDA maintain an online system for adverse event reports related to generic and branded drugs. Analysis of data from this system shows that, in the first three quarters (Q1, Q2, and Q3) of 2015, most adverse event reports among cancer drugs (>80%) were related to brand-name cancer medicines. This finding is unusual because many generic cancer medicines have entered the market in recent years and use of generic versions of the innovator product seems to increase after launch.35 It is possible that attribution of an adverse event to generic versions (typically, multiple generic products are available) is difficult because of the high prevalence of combination regimens in which generic drugs act as the backbone for brand-name drug-based treatment for metastatic disease. It is also important to note that reports of therapeutic failure typically increase immediately after initial generic entry into the marketplace.36 What does the increasing trend in adverse event reports among cancer medicines overall tell us? Does it indicate a safety problem or more aggressive reporting? Has the rise in adverse events led to increased actions by agencies? The answer, at least to date, is that no brand-name or generic drug treatments for cancer have been recalled or relabelled between 2012 and the first quarter of 2016. So, what is the value of adverse event reporting? Success cannot be measured in report volume alone. Perhaps a more germane question is whether or not the increase in adverse events matches up with a decrease in positive therapeutic outcomes. However, scant data are available with which to draw legitimate conclusions.
10 000 8000 6000 4000 2000 0
2012 2012 2012 2012 2013 2013 2013 2013 2014 2014 2014 2014 2015 2015 2015 (Q1) (Q2) (Q3) (Q4) (Q1) (Q2) (Q3) (Q4) (Q1) (Q2) (Q3) (Q4) (Q1) (Q2) (Q3) Year (quarter)
Figure: Number of adverse events reported to the FDA’s adverse event reporting system for cancer medicines Data shown are from the first quarter (Q1) of 2012 to the third quarter (Q3) of 2015. Data were obtained on Feb 15, 2016, from the FDA’s open adverse event reporting system. FDA=US Food and Drug Administration.
management activities with local adaptations and country-specific appendices when needed. Complete harmonisation of post-marketing activities and strategies might not always be warranted, or possible, particularly when labelling is not identical. Moreover, differences in cultures, health-care systems, and patients’ management practices might not be conducive to such pharmacovigilance concordance. For example, in several Asian countries, new biological agents are typically launched in the private hospital setting,39 which provides opportunities for pharmacovigilance that differ from the broader distribution channels observed in Europe and North America, because private hospitals have more advanced pharmacy-based pharmacovigilance processes and procedures, and data can be gathered and reported with greater speed and accuracy. Furthermore, private Asian hospitals usually cover only a small proportion of the population in any given country, resulting in very small sample sizes for undertaking post-marketing activities—eg, cohort event monitoring. A special interest group of the International Society of Pharmacovigilance was created in 2015 with the goal of designing novel risk-minimisation methods applied in a manner proportionate to risk in specific populations.40 In keeping with the theoretical underpinnings of design thinking, this initiative—namely, the Post-Approval Vigilance Program—aims to develop a customisable decision aid yielding four levels of stringency of riskminimisation interventions, ranging from level 0 (no risk-minimisation intervention beyond the label) to level III (most stringent risk-minimisation intervention). A level IV has also been created, which corresponds with the requirement for a post-approval study. Because riskminimisation interventions and post-approval studies are
For the FDA’s adverse event reporting system see https://open.fda.gov/data/faers
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Search strategy and selection criteria We did a systematic PubMed search between January, 2005, and January, 2016, using the terms: “pharmacovigilance”, “cancer”, “oncology”, “pharmacoepidemiology”, “drug quality”, “medicines”, “prescription drugs”, “adverse events”, “biosimilars”, “substandard pharmaceutical events”, “safe use of medicines”, “clinical outcomes”, “regulatory harmonization”, and “regulatory convergence”. We restricted our search to reports written in English and French and to peer-reviewed papers. Bibliographies of identified articles, guidelines, and conference proceedings were reviewed for additional references. Moreover, we spoke with senior medicines regulators, hospital pharmacy departments, clinicians, innovator and generic pharmaceutical manufacturers, and patient organisations from around the world. The final reference list was generated on the basis of originality and relevance to the broad scope of this Series paper.
two distinct risk-management activities, level IV can be viewed as a stand-alone requirement or as a supplement to level I, II, or III. Fundamental tenets of the PostApproval Vigilance Program criteria have been put forward by some members of the special interest group. Before testing and implementing this strategy, it is necessary to establish the criteria and scoring system using a robust and validated approach.40 This process will lead to efficient, practical, and transparent planning of risk-minimisation activities in Asia. We believe dangers are inherent in recommending harmonisation of Asian processes with European and US best practices. We must be wary of the uncertainties of regulatory imperialism. Indeed, pharmacovigilance is as much a management problem as a public health issue. Convergence into best European and US practices will probably be pointless in view of profound differences in regulatory staffing levels, overall budgetary limitations, and education of clinicians, pharmacists, and patients. Expecting other nations with less experience and resources to harmonise with the FDA or the EMA is not the right approach.
Future directions Regular and creative risk-management plans and diligent efforts are needed to understand issues surrounding safety and surveillance of cancer drugs. One way of improving pharmacovigilance efforts is to utilise a pharmacovigilance database to accrue data for known effects and identify new ones.41 Epidemiological studies and collaborations with cancer registries might also be useful. Most importantly, we must investigate how pharmacovigilance activities can be used to identify and correct issues that affect the ability for licensed medicines and medical devices to maximise positive therapeutic outcomes. Such an effort will require a new three-dimensional approach that includes not only identification of traditional adverse events but also a more e491
dedicated focus on substandard outcomes and on why a product’s safety profile has evolved differently from the predictive (and rarefied) clinical trial environment used for initial product approval and market launch.
Conclusion Under-reported, inaccurate, delayed, and non-salient data are major shortcomings for pharmacovigilance activity in every country, and all must be addressed with new and existing methods and strategies to make 21st century pharmacovigilance a reality. This need is especially relevant and urgent for medicines used to treat cancer, for which better knowledge can save lives and ensure more cost-effective use of precious health-care resources. No easy answers are available. For 21st century pharmacovigilance of cancer treatments and across other therapeutic classes, we should seek regulatory convergence and a pathway to improvement— with the first step being identification of specific procedural asymmetries that can be addressed and corrected.42 We view pharmacovigilance as a management problem as much as a public health issue. Contributors PJP wrote the report and contributed to its design, data analysis, and data interpretation. HLL and YM contributed to design and writing of the report and data analysis. RMC did the literature search, contributed to design and writing of the report, and data interpretation. Declaration of interests We declare no competing interests. Acknowledgments RMC was funded by an award from the National Cancer Institute to the University of Chicago (K07-CA138906). The statements, findings, conclusions, views, and opinions contained and expressed herein are not necessarily those of the institutions with whom the authors are affiliated. References 1 Baldo P, De Paoli P. Pharmacovigilance in oncology: evaluation of current practice and future perspectives. J Eval Clin Pract 2014; 20: 559–69. 2 WHO. Essential medicines and health products: pharmacovigilance. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/ pharmvigi/en/ (accessed May 20, 2016). 3 Wilson A, Milne CP. FDA’s risk evaluation and mitigation strategies (REMS): effective and efficient safety tools or process poltergeist? Food Drug Law J 2011; 66: 569–85. 4 Borg JJ, Aislaitner G, Pirozynski M, Mifsud S. Strengthening and rationalizing pharmacovigilance in the EU: where is Europe heading to? A review of the new EU legislation on pharmacovigilance. Drug Saf 2011; 34: 187–97. 5 Callréus T. The new EU legislation on pharmacovigilance and changing models for drug development. Drug Saf 2011; 34: 529–30. 6 Senate and House of Representatives of the United States of America in Congress. Food and Drug Administration Modernization Act of 1997: United States Senate Bill 830. Jan 7, 1997. http://www.fda.gov/downloads/RegulatoryInformation/ Legislation/SignificantAmendmentstotheFDCAct/FDAMA/ FullTextofFDAMAlaw/UCM089145.pdf (accessed March 20, 2016). 7 Medicines and Healthcare products Regulatory Agency. Medicines, medical devices and blood regulation and safety: guidance—good pharmacovigilance practice (GPvP). Dec 18, 2014. https://www.gov. uk/guidance/good-pharmacovigilance-practice-gpvp (accessed Feb 15, 2016). 8 US Food and Drug Administration. Product-specific recommendations for generic drug development. Aug 29, 2016. http://www.fda.gov/Drugs/GuidanceComplianceRegulatory Information/Guidances/ucm075207.htm (accessed Sept 19, 2016).
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