key: cord-0912028-8ahk7f4m
authors: Kugener, Veronique F.; Freedland, Eric S.; Maynard, Kenneth I.; Aimer, Omar; Webster, Peggy S.; Salas, Maribel; Gossell-Williams, Maxine
title: Enhancing Pharmacovigilance from the US Experience: Current Practices and Future Opportunities
date: 2021-05-15
journal: Drug Saf
DOI: 10.1007/s40264-021-01078-8
sha: dcb01c3f7019c51d33acfb6c263cbae258f490b5
doc_id: 912028
cord_uid: 8ahk7f4m

This review is intended to present perspectives from the US experience in enhancing pharmacovigilance on current practices and future opportunities. Best practices concepts could be applied worldwide through the presentation of how three pillars of pharmacovigilance: (1) medical and scientific excellence, (2) operational and compliance excellence, and (3) knowledge sharing and experts development in the field could serve as a framework for the establishment of an efficient and successful global pharmacovigilance system.

Pharmacovigilance (PV) is an important function with the mission of primarily ensuring the safety of patients with the use of pharmaceuticals, including biologics, such as vaccines, plasma-derived therapies and/or medical devices, which are in clinical development or in the post-marketing setting. Pharmacovigilance functions work collaboratively with highly skilled clinical experts from various disciplines (e.g., medicine, pharmacy, pharmaceutical sciences, biostatistics, informatics, epidemiology) and other cross functions worldwide.

Pharmacovigilance has to constantly adapt to a rapidly evolving regulatory landscape and to the dizzying pace of advancement of new therapies and technologies. These demands require ongoing awareness and training of not only current PV experts, but also behoove the recruitment and training of experts for the future.

Most PV practices are guided by local and regional healthcare systems and regulations, as well as international regulations. These share the objectives of continuously and timely collecting, assessing, monitoring, and reporting safety data for compounds and products either in clinical development or in the post-marketing setting.

The PV community maintains a collaborative and harmonizing spirit to share best practices worldwide. This review is intended to present current PV practices and future opportunities from the US experience. These best practices concepts could be applied worldwide through the presentation of how three pillars of PV: (1) medical and scientific excellence; (2) operational and compliance excellence; and (3) knowledge sharing and experts development in the field could serve as a framework for the establishment of an efficient and successful global PV system (Fig. 1 ).

The convergence of medical science, data science, and technology has accelerated the pace of transformative scientific discoveries that are helping medical practice rewrite the script for detecting, preventing, and treating diseases in our society. Precision medicine is now possible with the advent of groundbreaking therapies that harness the human genome or immune system, and we have witnessed an inflection point in our ability to treat and potentially cure diseases that were previously thought to be outside the reach of medicine. Advances in translational medicine have fostered the discovery of new biomarkers that allow for enhanced prediction and monitoring of target organ toxicities, and novel uses of existing datasets can enrich safety evidence generation. The following examples further illustrate how constant advances in medicine and science challenge PV to continue to uphold an efficient and successful framework.

Gene therapy products are now being studied in many diseases and conditions, including genetic disorders, autoimmune diseases, heart disease, cancer, diabetes mellitus, and human immunodeficiency virus/acquired immunodeficiency syndrome [1] . Recognizing the traditional phase I-IV clinical trial process is unsuitable for the development of these emerging therapies has led to not only regulators developing guidelines specifically focused on expediting the approval process, but also raises concerns about the reliability of benefit-risk assessment processes [2] [3] [4] . These evolving challenges, which apply to safety assessment, have prompted the active updating of regulatory guidelines for human gene therapy products [5] . With the advancement of potential new therapies giving hope to millions of patients, all parties involved in the healthcare system must continue to develop a proactive approach to ensure the continuous benefit-risk assessment for innovative medicines and contribute to carefully plan and monitor drug development and the post-marketing phase of these new therapies. Gene therapy products are designed to provide benefit through a long-acting or permanent mechanism of action, and the resulting longterm exposure may place subjects of investigational studies at increased risk for delayed adverse effects requiring additional PV activities. Patients may therefore need to be followed up for 15 years for genome editing products [6] . There are also options of enrolling patients from phase III randomized controlled trials into observational open-label Fig. 1 Proposed three-pillar model of an optimized, fully integrated, global pharmacovigilance system extension studies or to create a global registry of treated patients [7, 8] ; such studies are currently active for US Food and Drug Administration (FDA)-approved gene therapy [6] .

In August 2017, the FDA approved the first gene therapy, tisagenlecleucel, followed by the approval of axicabtagene ciloleucel in October 2017. Both are chimeric antigen receptor (CAR) T-cell therapies for lymphoblastic leukemia [3, 4, 9] . A third CAR T-cell therapy, brexucabtagene autoleucel, was approved for the treatment of mantle cell lymphoma in July 2020 [10] . Chimeric antigen receptor T-cell therapy is a customized treatment that uses the patient's own T lymphocytes, which are then genetically modified ex vivo with a gene that encodes a chimeric antigen receptor to direct the patient's T cells against the malignancy. The T cells are expanded in a production facility prior to being infused back into the patient [11] . All three approved CAR T-cell therapies target the CD19 protein on B cells and have shown promise in achieving remission with some patients needing no further therapy for at least 3 years [9, 12] . However, the overall durability of these responses is yet to be determined. Furthermore, major safety issues have been observed across all indications. For example, cytokine release syndrome is reported in most treated patients [6, 13] . Although the detection of safety risks during development provides a framework for effective mitigation, the full range of long-term adverse effects of CAR T-cell therapies remain undefined at the time of regulatory approval [14] . The FDA has provided gene therapy guidelines for industry on long-term follow-up [15] . Currently, the approved CAR T-cell therapies are only available in the USA through a risk evaluation and mitigation strategy drug safety program [15, 16] , which restricts the distribution of these drugs to select treatment centers required to have special certification. Staff must be trained to recognize and manage defined adverse events. Agents such as tocilizumab must be available for immediate administration in the case of cytokine release syndrome.

Drug-induced cardiovascular toxicities cannot always be entirely characterized during clinical development, and an additional post-approval assessment may be required. Cardiovascular safety studies have been performed across a variety of therapeutic areas, e.g., arthritis, coronary artery disease, diabetes, obesity, and pulmonary disease. The Cardiac Safety Research Consortium, which supports research by engaging stakeholders from the pharmaceutical industry, academia, and government to collaborate and share data and expertise, is a public private partnership that was formed in 2016 [17] . This consortium acts as a think tank and shares work with electrocardiogram data, as well as other areas of cardiac safety evaluation from the preclinical, through to the post-marketing setting.

A wide range of new cardiac biomarkers are constantly being developed and evaluated to further drive efficiencies in clinical trials and drug safety evaluations with biomarkers often being interpreted as surrogates for objective outcomes. For example, while most available data pertaining to cardiotoxicity in cancer therapy come from anthracyclinebased therapies, the long-term effects of new treatments, e.g., immune therapy remain mostly unknown. Furthermore, cancer is an independent risk factor with direct effects on the cardiovascular system. Both cardiac troponin and B-type natriuretic peptide have been shown to detect subclinical cardiotoxicity during cancer treatment. Monitoring these cardio-specific biomarkers should be strongly considered and could predict which patients are at risk of developing cardiotoxicities even before the start of therapy [17] .

Regulators have often mandated specific post-approval requirements for evaluating the long-term cardiovascular safety of newly approved medications. This has been most evident for novel therapies aimed at treating type 2 diabetes. In 2007, controversy about the cardiovascular safety of the medication rosiglitazone led the FDA to establish new guidance for evaluating the long-term cardiovascular safety of such therapies, which stated that developers should demonstrate that new antidiabetic drugs and biologics would not result in an unacceptable increase in cardiovascular risk [18] . As a result, every novel antidiabetic agent approved since 2008 has undergone post-marketing cardiovascular outcome trials (CVOTs). Opinions on the overall effectiveness of these CVOTs in better characterizing the long-term cardiovascular benefit-risk profile, however, highlighted limitations of the approach [19, 20] . In 2018, the Endocrinologic and Metabolic Drugs Advisory Committee reviewed the Agency's 2008 guidelines and narrowly supported continuation of CVOTs to exclude unacceptable increases in cardiovascular risk for all new glucose-lowering therapies, but with general agreement that modification of the 2008 guidance was needed [21] .

In March 2020, the FDA released new draft guidance based upon more than a decade of data from CVOTs that indicated no increased risk of ischemic cardiovascular events with anti-diabetic therapies. The updated guidance no longer includes a recommendation that companies conduct CVOTs to demonstrate cardiovascular safety of type 2 diabetes medications and instead proposes an updated approach to evaluating the broader safety profile of new drugs and biologics to improve glycemic control [22] .

It is incontrovertible that the CVOTs provide valuable long-term cardiac safety information that will help diabetologists, cardiologists, endocrinologists, nephrologists, and general practitioners weigh the benefits and risks of treatment with antidiabetic medications. The pharmaceutical industry and its PV function played a critical role in collecting and providing the essential data that led to these advancements [23] .

Real-world evidence (RWE) and real-world data (RWD) have become key components of clinical development and healthcare decisions. The 21st Century Cures Act, passed in 2016, places an additional focus on the use of these types of data to support regulatory decision making, including approval of new indications for approved drugs. A 2017 White Paper produced by the Duke Margolis Center for Health Policy describes RWD as data relating to patient health status and/or the delivery of healthcare routinely collected from a variety of sources, e.g., electronic health record, payer claims data, registries, and mobile apps and digital technologies; while RWE is defined as evidence derived from RWD through the application of research methods. For regulatory applications, RWE can further be defined as clinical evidence regarding the use and potential benefits or risks of a medical product derived from analysis of RWD [24] .

Real-world evidence is broader than simple observational data and retrospective analysis; it involves data validation and standardization along with thoughtful study designs to assess the effects of the treatments on the outcomes of interest, and an understanding of the context in which the treatments are used [24] . In the Second Annual Duke-Margolis Conference on Real-World Data and Evidence in 2018, use of RWD was further explored, including in oncology and rare diseases where ethical considerations may make randomized controlled trials difficult to conduct [25] . An additional workshop and White Paper further explored the role of RWE, as part of a total evidence package. Real-world evidence can help evaluate marketed product effectiveness along with the benefit-risk profile and possibly contribute to a labeling change [26] .

The contributions of RWD and RWE to clinical trials continue to evolve through partnerships that support medical and scientific excellence. The Clinical Trials Transformation Initiative, started as a public private partnership between Duke University and the FDA, currently comprises more than 80 member organizations representing academia, clinical investigators, government and regulatory agencies, industry, institutional review boards, patient advocacy groups, and other stakeholders. Their multi-stakeholder project teams use various research methods to gain an objective understanding of evidence and promote the adoption of recommendations to improve the design of clinical trials [27] . The Multi-Regional Clinical Trials Center at Brigham and Women's Hospital and Harvard Medical School has collaborated with Optum Labs to determine the limitations of RWE from various data sources (e.g., claims, electronic health records) and whether observational studies using RWE can replicate randomized controlled trials submitted for regulatory decision making and help our understanding of the effectiveness for on-label indications in approved populations [28] .

Real-world evidence has implications for PV, as data mining from RWD can provide valuable information regarding adverse effects and drug interactions. The COVID-19 outbreak has augmented the importance of the integration and the interpretation of this type of data in benefit-risk assessments of the many therapies explored, such as azithromycin, hydroxychloroquine, and chloroquine [29] . Additionally, RWD from patients with COVID-19 have supported the risk assessment for hypertensive patients receiving angiotensin system modulation drugs [30] . Pharmacovigilance must now balance the risk from treatment delay vs harm from COVID-19, minimize negative effects of social distancing during the delivery of care, and appropriately allocate limited healthcare resources.

The examples below indicate why optimal PV function requires an all-time inspection-readiness PV system with dedicated and highly trained medical, scientific, and operationally technical and tactical professionals, who are proactive to ensure that commitments to various regulations worldwide are met.

Benefit-risk assessment involves a set of activities and methodologies to determine whether there are new or changed risks associated with active substances or medicinal products based on various sources of data, including risk minimization programs, which vary across regulatory agencies [31] [32] [33] . Comparing elements of benefit-risk frameworks reveals the variability in how sponsors and marketing authorization holders provide these assessments. Inconsistencies could result in distinctive interactions with regulatory authorities and the final implementation of non-harmonized risk minimization programs in different territories for the same products. For example, the comparison of prasugrel and certolizumab pegol on US and European Union risk minimization program legislation showed a difference in risk minimization timeline update requirements and to whom the updates are communicated [34] . Most recently, with the emergence of the COVID-19 pandemic, there is an example of the use of the Benefit-Risk Action Team framework to assess the overall benefit-risk profile of the use of remdesivir as a treatment for COVID-19 compared with standard of care, placebo, or other treatments [35] . The need for global harmonization of benefit-risk legislation continues to evolve [36] , including the 2016 International Council for Harmonisation revision of the content of Common Technical Document ICH M4E(R2) Section 2.5.6 "Benefits and Risks Conclusions" [37] . The revision includes division into sections on therapeutic context, benefit, risk, and the benefit-risk assessment, which must now succinctly and critically communicate the benefits and risks of the product. The focus should be on key benefits and risks while describing and interpreting the data. Regulators are recognizing that benefit-risk assessment is a rapidly evolving field and are open to flexibility with different approaches. While PV primarily has a focus on safety risks, it considers efficacy in the assessment of the benefit-risk profile of products.

The increasing volumes of reported adverse events can be overwhelming for both the industry as the reporter and the FDA as the receiver. Solutions must address the tremendous challenge of balancing the timely expedited regulatory reporting of meaningful adverse events, while ensuring prompt detection and management of safety-related medical matters. The agency had issued the Safety Assessment for Investigational New Drug (IND) Safety Reporting Draft Guidance for Industry in October 2015, a guidance to sponsors on developing a systematic approach for investigational new drug application safety reporting for human drugs and biological products [32, 38] . The guidance includes recommendations on how to identify and evaluate important safety information; the establishment of a Safety Assessment Committee; the aggregate analysis for comparison of adverse event rates across treatment groups; the planned unblinding of safety data; reporting thresholds for IND safety reporting; and the development of a safety surveillance plan. An FDAsponsored public workshop was held in 2018 to engage in discussions and share feedback about this draft guidance. Multiple efforts have been made to ensure that companies are ready for the implementation of that guidance.

Approaches can vary and harmonization needs to be addressed toward achieving a meaningful regulatory reporting of safety data. In 2020, TransCelerate, a non-profit entity composed of many global drug companies, published their assessment on how sponsors can address the principles of the 2015 draft guidance [39] .

Healthcare professionals with training and experience in clinical medicine are key contributors within PV functions in regulatory agencies, academia, and the pharmaceutical industry. Their medical and scientific expertise is essential for adverse events to be accurately characterized and assessed within the context of a product's benefits and risks, and their knowledge of patient care and healthcare delivery is invaluable for developing effective risk mitigation strategies. It is therefore essential that the knowledge of professionals practicing PV keeps pace. As important as being effective, approved medications should have an advantageous benefit-risk assessment in the patient populations they are intended to treat. Consequently, it is critical that medical, scientific, and other professionals are highly trained in the specialized area of PV (i.e., drug safety) and the associated various regulations that control both the development and post-marketing approval of medications.

Both degree (Diploma and Masters of Science, see Table 1 ) and non-degree (online course or private certification, see Table 2 ) training programs are available for students and healthcare professionals in the USA and are sponsored by academia and professional organizations in the USA and Canada. Non-degree training comes with multiple approaches such as stand-alone courses and workshops, professional conferences, and other venue training. The benefits of such programs ensure that the expertise of PV professionals remains at a high level and is current. They also help to refresh the current personnel and, in the longer term, support and encourage the future influx to the field by physicians, nurses, pharmacists, and regulators. Thus, PV professionals rely on internal training and especially external programs to supplement their learning and keep up with rapidly changing demands. Many of these are supported by the pharmaceutical companies.

Degree training comes by integrating PV concepts into existing continuing education and is available for PV professionals who have a broad healthcare or pharmaceuticals background. For even the formally and well-trained PV expert, there is a need to continuously expand their knowledge in PV to continuously adapt to a rapidly changing scientific and regulatory landscape [40] .

Traditional curricula in medical, public health, and pharmacy schools do not emphasize drug safety and PV. This deficiency not only impacts the understanding of reporting obligations, but also diminishes the potential talent pipeline and the importance of patient safety, in addition to efficacy, as a critical aspect of drug development. While formal PV training programs exist, most PV specialists gain their expertise through at least a baseline understanding of statistical methods and analytical problem solving combined with a broad knowledge of pharmacology and clinical medicine. Often this is followed by a hierarchy of training experiences that involve increasing exposure and responsibilities in an apprenticeship environment. The pharmaceutical industry has already committed to attract and develop potential talents through various pathways by investing in future generations of PV professionals and providing Courses on good PV operations, pharmaco-epidemiology, regulatory and legal basis of PV, risk management and safety signaling, and post-marketing safety surveillance opportunities for them to learn more about the pharmaceutical industry [41, 42] .

Internship programs can be offered to undergraduate college students to provide an opportunity to learn about PV. During a summer internship, a student might be assigned a short-term, e.g., 12- week project that provides an opportunity to work within a PV department and interact with PV experts and key stakeholders. The student intern benefits from mentorship and provides valuable contributions, including selecting a project of interest and presenting his/ her perspectives at the end of the program. Applications and opportunities for PV internship programs are found on relevant pharmaceutical company websites as applicable and by searching for the phrase "pharmacovigilance internships" using any internet search engine. Rotation programs have been established between schools of pharmacy and the pharmaceutical industry offering for the pharmacy student to be fully immersed in a PV department as part of his/her educational curriculum [43] .

Fellowship programs represent a longer term (e.g., 2 years) commitment, i.e., usually a post-doctoral program targeted toward recent Doctor of Pharmacy graduates and coordinated by both the pharmaceutical company and a sponsoring university. Through offering real-world, hands-on, and in-depth specialized training, the PV fellowship provides healthcare professionals an opportunity within a corporation to develop skills, knowledge, and experience to further explore a potential career as a PV expert. Fellowship opportunities have been increasingly offered by pharmaceutical companies to graduate students. These programs have been established between the pharmaceutical industry and academia, where, for example, recent graduates from a school of pharmacy or school of public health may apply for fellowship positions in the pharmaceutical industry. The focus of a fellowship curriculum may vary somewhat, but the primary objectives for these positions are to educate the fellow on how to evaluate the safety profile of products throughout the life cycle of development, approval, and post-marketing setting, offering in some instances to contribute with implementing and evaluating risk management strategies and with conducting postauthorization safety studies. After the completion of their program, fellows could have the opportunity to apply for available PV subject matter expert positions [43] .

A comprehensive and compliant PV system of regulated processes and tools worldwide is mandated and critical to ensure patient safety through a set of multiple and complex PV activities. The proposed approach of a three-pillar model for PV is intended to help the PV professional to establish functions that will foster robust scientific and medical excellence, implement operational and compliant PV capabilities, and foster the commitment to the hiring, retention, and continuous development of strong PV experts. In the spirit of strengthening a community of PV experts, the sharing of experiences and the continued collaboration and education among PV colleagues will ensure that best practices are implemented.

We describe a model of three pillars as the tenets that support an efficient and successful PV framework, i.e., (1) medical and scientific excellence, (2) operational and compliance excellence, and (3) knowledge sharing and experts development in the field. The authors elaborate on these concepts and demonstrate how this model helps the PV expert organize the discipline. Using examples of cutting-edge science in clinical drug development and new technologies and methods for assessing safety, the authors shed light on how these essential components come together from the US experience with universal implications. In addition, the authors emphasize the importance of promoting formal training and continued education to ensure PV excellence now and in the future.

Funding No funding was received for the preparation of this article. 

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