Paul Beninger

Pharmacovigilance and Biomedical Informatics: A Model for Future Development

PURPOSE The discipline of pharmacovigilance is rooted in the aftermath of the thalidomide tragedy of 1961. It has evolved as a result of collaborative efforts by many individuals and organizations, including physicians, patients, Health Authorities, universities, industry, the World Health Organization, the Council for International Organizations of Medical Sciences, and the International Conference on Harmonisation. Biomedical informatics is rooted in technologically based methodologies and has evolved at the speed of computer technology. The purpose of this review is to bring a novel lens to pharmacovigilance, looking at the evolution and development of the field of pharmacovigilance from the perspective of biomedical informatics, with the explicit goal of providing a foundation for discussion of the future direction of pharmacovigilance as a discipline. METHODS For this review, we searched [publication trend for the log10 value of the numbers of publications identified in PubMed] using the key words [informatics (INF), pharmacovigilance (PV), phar-macovigilance þ informatics (PV þ INF)], for [study types] articles published between [1994-2015]. We manually searched the reference lists of identified articles for additional information. IMPLICATIONS Biomedical informatics has made significant contributions to the infrastructural development of pharmacovigilance. However, there has not otherwise been a systematic assessment of the role of biomedical informatics in enhancing the field of pharmacovigilance, and there has been little cross-discipline scholarship. Rapidly developing innovations in biomedical informatics pose a challenge to pharmacovigilance in finding ways to include new sources of safety information, including social media, massively linked databases, and mobile and wearable wellness applications and sensors. With biomedical informatics as a lens, it is evident that certain aspects of pharmacovigilance are evolving more slowly. However, the high levels of mutual interest in both fields and intense global and economic external pressures offer opportunities for a future of closer collaboration.

Opportunities for Collaboration at the Interface of Pharmacovigilance and Manufacturing

A case can be made that much common ground exists between pharmacovigilance and pharmaceutical manufacturing. Of the 8 major US statutes that shaped the pharmaceutical industry since early in the 20th Century, 7 followed fatally catastrophic events related to the use of a manufactured product, and 1 followed the discovery of a counterfeit product. To facilitate an understanding of the interplay between pharmacovigilance and manufacturing, it is convenient to divide manufacturing into 3 categories: (1) upstream sourcing of materials: pharmacovigilance plays an important role when adverse event clusters are seen during routine vigilance detection processes and the suspicion turns to possibly contaminated source material, (2) the manufacturing process itself: pharmacovigilance may be called on to conduct a health hazard evaluation if a manufacturing deviation is detected after product release (the assessment can inform the depth of a recall), and (3) downstream distribution and product use: there is only light regulation of the interval between product distribution after manufacturing release and just before administration to patients, a time during which product may be subject to an out-of-specification determination for environmental controls or subject to malfeasant activities, such as counterfeit substitution or product diversion. Recently introduced statutory remedies, including the FDA Safety and Innovation Act and the Drug Supply Chain Security Act in the United States and the Falsified Medicines Directive (directive 2011/62/EC) in the European Union, can provide capabilities to support pharmacovigilance signal management activities that have the potential to reduce the risk to patients of experiencing adverse events caused by counterfeit, diverted, or tampered product.

Risk Communication in a Pharmacovigilance Environment

Communication, in particular risk communication in the pharmaceutical realm, is the theme for this Specialty Update on pharmacovigilance. This is an underappreciated, yet critical frontier: Who communicates, what is communicated, to whom, how it is received and acted upon, and the degree to which it results in changes in behavioral outcomes. So many of our misunderstandings, missed opportunities, and disasters across the span of business, academic, and political sectors come back to failures in executing on this critical discipline. Whether it is a reflection of a lack of interest, weakness in understanding, poor planning, or something else, it is also an opportunity to shine a light on this topic and make progress.

Theranos Experience Exposes Weaknesses in FDA Regulatory Discretion

Beginning in late 2015, the Wall Street Journal published a series of articles on the American biotech startup company, Theranos.1–13 Founded in 2003, Theranos promised fingerstick and small volume blood-testing technology that would revolutionize the way small blood samples could be tested for a myriad of diagnostic applications. At its pinnacle 10 years later, Theranos was valued at

Regulatory agencies of the ICH: Authorities, structures, and functions

9 billion. Theranos succeeded in exploiting the Food and Drug Administration (FDA)’s regulatory enforcement discretion, which allowed it to delay FDA review of its technology; it gained Centers for Medicare & Medicaid Services (CMS) certification for its laboratories; and it secured retail shelf space at Walgreens. All of this would eventually be undone: (1) Theranos was cited by FDA inspectors for misclassifying its nanotainer blood-collecting technology and for deficiencies in documentation of manufacturing compliance; (2) it was sanctioned by CMS, including revocation of its certification; and (3) it was forced to close down its laboratory and retail operations to concentrate on a single miniature testing machine. What did Theranos hope to accomplish, and how did the FDA’s regulatory enforcement discretion help to make it happen? The goal that had been articulated by senior Theranos management to a wide audience was that Theranos would be the first to commercialize a laboratory testing platform that could accurately test a small volume of blood on site: in a drugstore, a doctor’s office, or another convenient location.14 Hospital managers and investors were intrigued by claims that 30 tests could be rapidly run on a single droplet of blood.15 Consumers would have direct access to technological breakthroughs that make it “possible to quickly process the full range of laboratory tests from a few drops of blood.”3 In a race to be first in a highly competitive market, Theranos attracted high-profile, albeit primarily nonscientific, investors to sit on its board, and it exploited regulatory ambiguities to find its way into this

Pharmacovigilance: An Overview

75 billion-a-year commercial market.1 Eschewing a traditional, thorough, project management-driven, science-focused development program, Theranos appeared to presume that its technology would eventually be able to do what it promised and develop the necessary test results to prove its capability. Regrettably, that is not how the story unfolded.

Data Sharing in the Pharmaceutical Enterprise: The Genie's Out of the Bottle

Abstract This chapter has as its focus the three major jurisdictions and agencies of the initial International Conference on Harmonization (ICH) that regulate medicinal and medical device products for human use: United States Food and Drug Administration (FDA), the European Union European Medicines Agency (EMA), and Japan’s Pharmaceutical and Medical Device Agency (PMDA). Although they attain the same goal of making safe and effective medical products available for their respective populations, the three jurisdictions have charted their own paths through strikingly different historical contexts to construct regulatory authorities, structures, and processes to attain their common goal. Over the years, other agencies around the world have matured and expanded their reach, with many, like those of China and South Korea becoming more prominent globally.

Medical Schools’ Competition for Clinical Training Sites

PURPOSE Pharmacovigilance (PV) is a relatively new discipline in the pharmaceutical industry. Having undergone rapid growth over the past 2 decades, PV now touches many other disciplines in the research and development enterprise. With its growth has come a heightened awareness and interest in the medical community about the roles that PV plays. This article provides insights into the background and inner workings of PV. METHODS This narrative review covers the core PV activities and other major areas of the pharmaceutical enterprise in which PV makes significant contributions. FINDINGS Drug safety monitoring activities were organized by the US Food and Drug Administration and academic medical centers in the early 1950s in response to growing concern over the occurrence of aplastic anemia and other blood dyscrasias associated with the use of chloramphenicol. This experience was codified in the 1962 Kefauver-Harris Amendments to the Federal Food, Drug and Cosmetic Act as adverse event evaluation and reporting requirements. The ensuing decades have seen the development of core PV functions for pharmaceutical companies: case management, signal management, and benefit-risk management. A broader scope of PV has developed to include the following major activities: support of patient safety during the conduct of clinical trials through assuring proper use of informed consent and institutional review boards (ethics committees); selection of the first safe dose for use in humans, based on pharmacologic data obtained in animal studies; development of the safety profile for proper use of a new molecular entity and appropriate communication of that information to the range of relevant stakeholders; attendance to surveillance activities through a set of signal management processes; monitoring the manufactured product itself through collaborative activities with manufacturing professionals; management of benefit-risk to assure appropriate use in medical care after marketing; and maintenance of inspection readiness as a corporate cultural process. IMPLICATIONS The extent and pace of change promise to accelerate with the integration of biomedical informatics, analytics, artificial intelligence, and machine learning. This progress has implications for the development of the next generation of PV professionals who will need to be trained in entirely new skill sets to lead continued improvements in the safe use of pharmaceuticals.

Pharmacovigilance: Work in Progress

OBJECTIVE This Commentary shows that the present emphasis on the sharing of data from clinical trials can be extended to the entire pharmaceutical enterprise. METHODS The authors constructed a Data Sharing Dashboard that shows the relationship between all of the life-cycle domains of the pharmaceutical enterprise from discovery to obsolescence and the domain-bridging disciplines, such as target credentialing, structure-activity relationships, and exposure-effect relationships. FINDINGS The published literature encompassing the pharmaceutical enterprise is expansive, covering the major domains of discovery, translation, clinical development, and post-marketing outcomes research, all of which have even larger, though generally inaccessible, troves of legacy data bases. Notable exceptions include the fields of genomics and bioinformatics. IMPLICATIONS We have the opportunity to broaden the present momentum of interest in data sharing to the entire pharmaceutical enterprise, beginning with discovery and extending into health technology assessment and post-patent expiry generic use with the plan of integrating new levels and disciplines of knowledge and with the ultimate goal of improving the care of our patients.

Pharmacovigilance in the New Millennium.

Medical Schools’ Competition for Clinical Training Sites To the Editor: Why would a prominent medical school in New York send its thirdand fourth-year students to Texas for clinical training, while an offshore medical school sends its students to the New York hospital that once trained the New York school’s students? Medical schools have increased class size dramatically over the past decade, and more than two dozen new medical schools have been accredited. The numbers of physician assistant, nurse practitioner, osteopathic, and other educational programs have grown even more. Today there are upwards of 33% more students requiring clinical training than there were 10 years ago. Since enrollment is constrained primarily by the number of clinical teaching slots available, it is not surprising that high-quality training sites are coveted, and schools find themselves competing for clinical space by acquiring sites from one another. While medical schools that own hospitals have greater control over clinical training capacity, those that do not may find themselves competing vigorously for clinical teaching venues, and sometimes having to “outbid” other medical schools. The moment has come for a national dialogue about how to realign medical schools with local clinical teaching sites so that schools throughout the country can train their students in reasonable proximity to their schools.