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Pharmacovigilance: Challenges in Getting From Here to There

      Rafael Luna has written an insightful book on how to prepare scientific manuscripts, The Art of Scientific Storytelling,
      • Luna R.E.
      The Art of Scientific Storytelling.
      in which he uses storytelling as a paradigm for thinking about, preparing for, organizing, and writing a scientific manuscript. He begins with the title: “The Title serves as a guideline for your entire manuscript, which helps you focus your research around a hypothesis. Leaving the Title for the end is a major mistake which fuels procrastination and prevents you from keeping the big picture in mind while fashioning your research story.”
      In applying this concept, I believe the big picture for this special section on pharmacovigilance (PV) is about change. My title, which was inspired by Marshall Goldsmith's What Got You Here Won't Get You There,
      • Goldsmith M.
      What Got You Here Won't Get You There.
      focuses on the guest authors' descriptions of uncertainty and accompanying angst in the PV community about the present state of affairs and their varying perspectives of what a future might look like. Thus, my editorial's title, “Pharmacovigilance: Challenges in Getting From Here to There,” reflects the overarching theme of this month's Specialty Update on Pharmacovigilance.
      One way to characterize the issues raised by these authors is as growing pains, the substantial challenges that organizations face when they undergo dramatic growth to address the multiple, near-simultaneous, substantive changes taking place in their wide-ranging environments, compacted relatively short periods of time. The challenges run the gamut of organizational theory: frequent, new, and widely variable regulatory demands from multiple jurisdictions; tightening human resource availability with limited skill sets; greater competition from originator and generic manufacturers on an increasingly global basis; accelerated introduction of new and more sophisticated enabling technologies; greater demands from a better informed and growing list of stakeholders; and, finally, all of these factors leading to spiraling costs in the face of greater cost pressures and societal challenges to pricing associated with stagnant product development failure rates and continuing product output uncertainty. Although this description characterizes the overall drug development enterprise, it is of particular relevance to PV.
      Beginning with “Pharmacovigilance in Crisis: Drug Safety at a Crossroads,” Price
      • Price J.
      Pharmacovigilance in crisis: drug safety at a crossroads.
      presents an impassioned discussion of these issues from a business perspective, noting in particular the shortage of trained talent and the potential risks and consequences of a general failure to invest in PV. Boerstoel-Streefland
      • Boerstoel-Streefland M.
      Why are we still creating individual case safety reports (ICSRs)?.
      focuses attention on another critical issue in her commentary, “Why Are We Still Creating Individual Case Safety Reports (ICSRs)?”; this subject is increasingly perceived as an inadequate, if not also outdated, mechanism for collecting patient drug-event information. Donzanti
      • Donzanti B.
      Pharmacovigilance is everyone's concern: let's work it out together.
      examines a third factor in “Pharmacovigilance Is Everyone's Concern: Let's Work It Out Together”; this article describes the increasing global heterogeneity of the regulatory environment and the ploddingly slow progress in collaborative activities to address the ever-increasing divergence in regulations. In the last commentary, “Deconstructing the Pharmacovigilance Hype Cycle,” Hauben et al
      • Hauben M.
      • Reynolds R.
      • Caubel P.
      Deconstructing the pharmacovigilance hype cycle.
      offer an important warning against overpromising on the advances from novel and innovative technologies by placing the topic in the context of the Gartner technology hype cycle. Finally, I provide an overview of PV as an evolving discipline with many and varied responsibilities.
      • Beninger P.
      Pharmacovigilance: an overview.
      Two fundamental themes can be drawn from the perspectives expressed by these experienced PV professionals regarding the current state of their industry. These themes are 1) that PV regulation is showing its age and 2) that talent is inadequate to fulfill the industry's expectations for sufficient numbers of highly trained medical and operational professionals.
      • 1.
        Regulatory Gap. As the oldest of the comprehensive national/regional regulatory systems, the US Food and Drug Administration uses concepts and tools that came together over decades in an ad hoc way to deal with the exigencies posed by tragedies and disasters over the 20th century up until the quinquennial statutory reauthorizations of the user fee act, beginning in 1992 with the Prescription Drug User Fee Act.

        Woodcock J, Junod S. PDUFA Lays the Foundation: Launching Into the Era of User Fee Acts. https://www.fda.gov/AboutFDA/History/FOrgsHistory/EvolvingPowers/ucm593391.htm. Updated February 1, 2018. Accessed October 23, 2018.

        In addition to creating a sustainable payment mechanism to provide for the timely review of applications, it is important to recognize that this statutory mechanism also initiated a prospective, stakeholder–collaborative, interventionist approach to addressing simmering issues that has largely succeeded in heading off new tragedies and disasters. Examples include the development and access of new drugs for pediatrics through renewed, then permanent, legislation (Pediatric Research Equity Act and Best Pharmaceuticals for Children Act

        FDA. Best Pharmaceuticals for Children Act and Pediatric Research Equity Act. https://www.fda.gov/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/ucm509707.htm. Updated March 22, 2018. Accessed October 23, 2018.

        ) and the multifaceted, expedited regulatory tracks for serious conditions. The user fee mechanism has further been applied to biologics, medical devices, generic drugs, and veterinary products, primarily to secure adequate regulatory talent to provide timely review of product applications. However, several additional areas remain in need of attention: the regulatory gap between release of a manufactured product and reporting of an adverse event following patient exposure,
        • Beninger P.
        Pharmacovigilance: work in progress.
        the long-neglected regulation of food additives,

        Hamblin J. Why Vitamins and Other ‘Dietary Supplements’ Can Contain Anything. https://www.theatlantic.com/health/archive/2016/06/supplements-make-tobacco-look-easy/488798/. Accessed October 21, 2018.

        the troublingly inadequate regulation of nutritional supplements,

        Hamblin J. Why Vitamins and Other ‘Dietary Supplements’ Can Contain Anything. https://www.theatlantic.com/health/archive/2016/06/supplements-make-tobacco-look-easy/488798/. Accessed October 21, 2018.

        • Tucker J.
        • Fischer T.
        • Upjohn L.
        • Mazzera D.
        • Kumar M.
        Unapproved pharmaceutical ingredients included in dietary supplements associated with US Food and Drug Administration warnings.
        and the near absent regulation of personal care products.
        • Feinstein D.
        • Collins S.
        The personal care products safety act.
        There is also the issue of harmonization. In the 1980s and 1990s, there were tremendous advancements through cross-cutting global collaborations under the Council for International Organizations of Medical Sciences (CIOMS) and the International Conference (later to be changed to Council) on Harmonisation. However, the last decade has seen these efforts stall, with much at risk of loss: continued improvements in the efficient use of resources; greater speed and continued standardization of processes; and high public confidence in the collaborative, multilateral leadership that gained these achievements.
      • 2.
        PV Talent Gap: The dramatic growth in PV regulatory drivers over the past 2 decades has had the unintended consequence of creating a pressing shortage of well-trained, professional talent, both medical and operational. It is not a problem for any one company to solve; it is a collective problem that is in a stand-off. Any individual company's effort to train a cadre of professionals from scratch invariably leads to recruitment overtures from other companies in need of similar talent, to the detriment of the first company. The European Union has found success in addressing this issue by creating the European Programme in Pharmacovigilance and Pharmacoepidemiology (EU2P) in 2009, a consortium of regulatory agencies, industry companies, and universities to provide training that leads to certificates as well as master and doctoral degrees.

        European Programme in Pharmacovigilance and Pharmacoepidemiology. https://www.eu2p.org/. Accessed October 21, 2018.

        It is reasonable to anticipate that there will also be an eventual need for documentation of competency.
      What can be done to address these gaps? The answer to this question is less about solutions per se and more about institutionalizing processes that can lead to solutions. Many structural and operational pieces are in place: the range of stakeholders and their organizations (eg, industry, regulatory agencies, academia, patient representation, cross-cutting organizations) and the enacting statutory mechanisms (eg, the 5-year cycle for User Fee Acts legislation). However, these are more like jigsaw puzzle reflective of a century-long history of legislation in need of more pieces and a lot more work to create a comprehensive and seamless picture of what a well-honed pharmaceutical enterprise could look like.
      Here are 5 considerations, including suggestions by our guest authors, that could set the stage to help us get from here to there:
      • 1.
        Seek executive level support for an extended commitment. Stakeholders can explicitly engage their respective senior managements to plan for and commit the necessary long-term resources (primarily talent, time, and money in varying proportions) concerning the issues covered in both of these themes.
      • 2.
        Expand stakeholder involvement. There are additional stakeholders who would welcome engagement, including other academic and professional organizations (eg, the National Academy of Medicine, CIOMS, the International Society of Pharmacoepidemiology, the International Society of Pharmacovigilance), patient-based organizations (eg, the Patient-Centered Outcomes Research Institute), other industries with experience in managing risk (eg, airlines, financial institutions), information technology, and congressional interests.
      • 3.
        Develop a road map for creating a collaborative vision. Use existing cross-cutting organizations (eg, CIOMS, International Council on Harmonisation) or develop other mechanisms to convene informal meetings to re-imagine the overall process through presentation of white papers, deliberation of topics, creation of agendas, and publication of findings and proposals.
      • 4.
        Build the necessary infrastructure. With the EU2P model in mind, all stakeholders can collaborate to build the academic infrastructure for ongoing continuing professional education that can be shared among all interested parties to develop and expand the skill sets of present PV professionals and to provide a pipeline for newly trained talent. Success of this model with PV could be usefully applied to other areas.
      • 5.
        Start the conversation. Submit a commentary to expand and/or critique the ideas presented in this Special Section with the goal of building momentum.
      I look forward to hearing from you.

      Conflicts of Interest

      The author was employed by Genzyme, a Sanofi company, which provided salary, bonus and stock options during his employment, until his retirement in April 2017. He otherwise received no financial support from industry. No one else influenced choice of content during the preparation the manuscript.

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        What Got You Here Won't Get You There.
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        • Price J.
        Pharmacovigilance in crisis: drug safety at a crossroads.
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      1. Woodcock J, Junod S. PDUFA Lays the Foundation: Launching Into the Era of User Fee Acts. https://www.fda.gov/AboutFDA/History/FOrgsHistory/EvolvingPowers/ucm593391.htm. Updated February 1, 2018. Accessed October 23, 2018.

      2. FDA. Best Pharmaceuticals for Children Act and Pediatric Research Equity Act. https://www.fda.gov/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/ucm509707.htm. Updated March 22, 2018. Accessed October 23, 2018.

      3. FDA. Expedited Programs for Serious Conditions – Drugs and Biologics - ucm358301.pdf. Accessed October 23, 2018.

        • Beninger P.
        Pharmacovigilance: work in progress.
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      4. Hamblin J. Why Vitamins and Other ‘Dietary Supplements’ Can Contain Anything. https://www.theatlantic.com/health/archive/2016/06/supplements-make-tobacco-look-easy/488798/. Accessed October 21, 2018.

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        The personal care products safety act.
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