What is History? An Echo of the Past in the Future; A Reflex From the Future on the Past

In the January 2020 issue of Clinical Pharmacology and Therapeutics (CPT), as the incoming Editors, we coauthored an Editorial entitled “Clinical Pharmacology and Therapeutics, 2030.”1 The goals of the Editorial, which appeared in the inaugural issue under our leadership, were to introduce the editorial team and highlight (over the next 10 years) our expectations for the expanding field of clinical pharmacology. The quote in the title, attributed to Victor Hugo, could not have been more fitting as we cataloged the transformational areas of growth in clinical pharmacology that we expected over the next 10 years (Figure 1). As the new leaders of the journal, we appointed an editorial team to guide its content for the next 5 years. Building upon the expert editorial group of the previous Editors, Scott Waldman and Andre Terzic, we reappointed several Associate Editors and appointed new ones, ensuring that major subject matter experts in clinical pharmacology, including pharmacogenomics, pharmacometrics, and regulatory sciences, were well-represented on the editorial team. Our new team included individuals from the United States (US) and around the world with PharmD, MD, and PhD degrees representing academia, industry, healthcare systems, and regulatory agencies. The team reflected the multiple sectors that are part of the ecosystem of clinical pharmacology. In addition to our Associate Editors, we introduced a new type of editor, Editor-in-Training (EiT) for the journal. The goal was to appoint two early-career editors, who would work with the team to advance the journal. The EiTs were involved in peer review and decision making, under the mentorship of experienced members of the editorial team. The role provided a unique training opportunity for outstanding young researchers to get closely involved in the running of a top peer-reviewed journal. Collectively, and with an outstanding editorial staff, our editorial team mentored 10 EiTs over our 6-year tenure and in turn received much, including social media posts, analyses of data, considerable enthusiasm, and new ideas for clinical pharmacology.2 As we reflect on the last 6 years, we must acknowledge that the COVID-19 pandemic, which took us and the world by surprise, had an enormous impact on the content and indeed some of the practices of the journal. Our inaugural issue preceded the pandemic by just a few months, and in 6 years, the journal published nearly 100 articles and received about 350 manuscripts focused on various aspects of COVID-19, which catalyzed research in clinical pharmacology. Notably, articles published during this era described the experiences of regulators in the rapid development of COVID-19 vaccines and therapeutics3 and the use of real-world data (RWD) and real-world evidence (RWE) for transitioning in vitro diagnostics for SARS-CoV-2 approved under the Emergency Use Authorization to full market authorization.4 Though the pandemic catalyzed great innovations, there were also missteps in the literature as the scientific community raced to perform research and publish articles to address disease prevention and treating seriously ill patients. Hydroxychloroquine in the treatment of COVID-19 became a poster story for hastily applied science. Though major articles on the use of hydroxychloroquine for treatment of COVID-19 were published elsewhere,5, 6 and were subsequently retracted, the entire publishing community including our editorial team learned many lessons. It reinforced that speed to publish should not compromise the quality of our reviews and that we as journal editors and indeed all readers require access to the original or raw data.7 For example, one manuscript, which was published in our journal, used information from the erroneous hydroxychloroquine articles to derive dosing regimens.8 These lessons motivated changes in our editorial policies, which now require registration of clinical trials and data in public registries to ensure the integrity of the research published in our journals.9 This decade will be the era when precision medicine and personalized therapeutics transition from concepts to routine clinical practice and clinical pharmacologists will play a leading role in not only driving this innovation but also translating it into patient benefit. In January and September of 2021, we published themed issues focusing on precision and personalized medicines and highlighting implementation sciences.10, 11 The January themed issue was entitled “Precision Dosing” and featured a range of articles which encouraged practitioners to move from a one-size-fits-all approach to drug dosing to precise dosing based on factors such as age, disease diagnosis, and genetic information.10 A key Tutorial, which illustrates the transitioning of “concepts to routine clinical practice,” provided a guide for healthcare systems and others on how to implement pharmacogenomic testing.12 The article included advice on laboratory and technical infrastructure as well as on flexible clinical decision support systems needed to support pharmacogenomic testing and adapt to the discovery of new actionable alleles in the future. Importantly, it highlighted the critical need for guidelines such as those developed by the Clinical Pharmacogenetics Implementation Consortium (CPIC) to translate genetic variants into drug selection and dosing recommendations.13 In fact, CPIC has published many articles in our journal on using genetic information for dosing a range of medications and has been one of the major catalysts for implementation of pharmacogenomic testing.14, 15 Importantly, many of the guidelines go beyond genotyping for drug metabolizing enzymes and include receptors and transporters such as SLCO1B1, ABCG2, and SLC6A4.13-15 CPIC, which has been involved in advancing pharmacogenomic testing since 2009, has recently published an article in our journal reviewing their history, which began simply as developing guidelines for interpretation of genetic information into drug dosing and selection but has advanced to a global leader in pharmacogenomic implementation, standardization, and sustainable integration of genetic testing for drug and dosage selection.13 Together with PharmVar, a more recent initiative focused on standardization of nomenclature of pharmacogenomic variants,16, 17 CPIC has greatly advanced pharmacogenomic testing worldwide. Also appearing in the themed issue was an article by Powell et al.,18 reminding the reader that most drug labels do not contain dosing recommendations for real-world patients. The article provides recommendations for how to design, predict, confirm and continuously improve drug dosing for real patients. Their recommendations include using real-world data to both learn and confirm doses that may be required for particular populations of patients. Our 2021 September themed issue, entitled “Pharmacogenetics and Pharmacogenomics” extended the “Precision Dosing” themed issue by focusing more specifically on genetic polymorphisms and drug response.11 Once again, progress in clinical implementation of genetic testing was showcased. The review of Luzum et al. on “Moving Pharmacogenetics Into Practice: It’s All About the Evidence!” begins with two patient cases that illustrate how pharmacogenomic testing affected their case and reminds the readers of the fact that therapeutic decisions for dosing often rely on data generated in randomized clinical trials. Such clinical trials are not available for pharmacogenomic-based dosing, where evidence may come from other sources such as real-world data.19 A white paper from Whirl-Carrillo et al.20 provides more information on pharmacogenetics evidence, as the Pharmacogenomics Knowledgebase (PharmGKB) has developed a scoring system to provide a more standardized transparent assessment of the level of evidence for drug–gene pairs. Data science, which continues to transform many disciplines and indeed society as a whole, will have a major impact on clinical pharmacology and health care in general…. and by bringing together scientists ….in areas like artificial intelligence, machine learning, real-world data, integration of multi-omics, and imaging data in pharmacology models… Data science has transformed many disciplines and has continued to transform the discovery, development and therapeutic use of drugs and other therapeutic agents. Three themed issues highlighted the impact of data science including most recently, artificial intelligence, in clinical pharmacology. The first themed issue, published in April of 2020, entitled “Data Science” explored how the rapidly evolving field of data science was affecting all aspects of clinical pharmacology.22 The issue introduced a broad range of topics that were beginning to affect research in clinical pharmacology ranging from data generated in traditional clinical trials, which though limited, are controlled and allow for careful examination of some factors on drug response to real-world data, captured outside traditional boundaries, allow for examination of many more factors and real-world settings. In the Editorial, we described how deep or machine learning and artificial intelligence were being applied to healthcare before 2020, which was largely focused on pattern recognition, but not generative tasks, and highlighted the enormous potential of generative AI “on clinical data science in the coming years.”22 In January of 2022, we focused data science on the real world by creating an entire themed issue focused on RWE. Peter Honig wrote a landmark commentary on RWE highlighting how it was used in informing critical clinical questions during the COVID-19 pandemic.23 Questions included how durable vaccine protection was, how frequently vaccines need to be administered to prevent transmission of the virus, and how frequent rare vaccine adverse events were. His commentary pointed out the importance of using RWE by drug developers and regulators alike and provided historical context to the use of RWE in clinical pharmacology. He described several articles in the themed issue and in particular highlighted reviews by Purpura et al. on the use of RWE by the FDA in making regulatory decisions,24 and reviews by Bakker et al.25 and Asano et al.,26 who describe the use of RWE in regulatory decisions made by the European Medical Agency, EMA, and Japan’s Pharmaceutical and Medical Device Agency, PMDA, respectively. This forward-looking themed issue focused on the major area of data science, RWE, and described its past, current, and future use in clinical pharmacology including regulatory sciences. CPT will increasingly emphasize therapeutics, as the revolution in modalities results in a spectrum of novel treatment options, which requires clinical pharmacologists and educators to adapt and develop a new set of skills, knowledge, and expertise in areas like cell-based and gene-based therapies, and immune and combination therapies, as well as delivery technology. Rare diseases and global health have been largely ignored for too long but there are encouraging signs that we will witness a significant shift in this decade This decade will be the era when precision medicine and personalized therapeutics transition from concepts to routine clinical practice and clinical pharmacologists will play a leading role in not only driving this innovation, but also translating it into patient benefit. In 2020, we predicted that in this decade, clinical pharmacologists would play a leading role in driving innovations in precision and personalized medicine as well as in translating that into patient benefit. As planned, a themed issue in 2023 applied the concept of “diversity, equity and inclusion” to clinical pharmacology to include a broad range of factors that may affect drug disposition and response for all patients including patients of different races and ethnicities, patients living in diverse geographical locations, patients with different disease diagnoses and male and female patients of all ages.39 Several articles focused on pharmacogenomic factors were included in the journal, with one perspective highlighting the need to study the genetically diverse populations of Africa in order to understand the totality of genetic polymorphisms and their effects on drug response.40 Other articles focused on the need to build community trust in order to recruit and enroll diverse populations including pediatric and ethnically diverse populations into clinical trials.41, 42 Hughes et al. highlighted our increasing ability to harness multi-modal data to translate population sources of variability to precision dosing for all patients.43 Finally, Mohan and Freedman review three distinct clinical trials in diverse therapeutic areas—coronavirus disease 2019 (COVID-19), multiple sclerosis, and diabetic macular edema—where an emphasis on inclusion of underrepresented racial and ethnic groups was a key focus of the trials.44 In their article, they describe strategies for community engagement and selection of clinical sites and provide recommendations for enhancing diversity in clinical trials. Clinical pharmacologists continue to be leaders in translating our discoveries into clinical therapies for the diverse patient populations of the world. “If diversity is defined as the inclusion of a range of many people that are different from each other, then it is obviously a core principle guiding best practices in clinical pharmacology and the foundation for personalized medicine and precision dosing.”45 As we end our 6-year tenure, we find ourselves again in uncharted territory. Recent changes in the political leadership in the United States are having effects on multiple stakeholders in clinical pharmacology. For example, the US Food and Drug Administration (FDA) has experienced a 20% reduction in its workforce, increasing the workload of individual medical product reviewers and potentially reducing the time for regulatory review and research. The use of animal models is increasingly being discouraged by both the National Institutes of Health and the FDA; therefore, those involved in drug development need to develop new ways for predicting drug disposition, response, and toxicity. Thus, there are new research opportunities for the development of predictive models using, for example, organoids, organ-on-a-chip, physiology-based pharmacokinetic and pharmacodynamic models, and AI.46 Finally, clinical pharmacology research in academia may be reduced with the possibility of reductions in federal grants. These potential cuts open up the possibility of new collaborations in research, for example, partnerships between academia and industry, and perhaps new models for funding graduate students. In just half a decade, with the world-changing COVID-19 pandemic, the tremendous advances in generative AI and data sciences, the increasing translation of research results to patient care, especially in pharmacogenomic testing, novel therapeutic modalities, and a focus on rare and neglected disease, the field of clinical pharmacology has undergone sweeping changes. Our flagship journal, CPT, has reflected these changes in its content and its policies. We, as the current and soon past editors-in-chief, are very grateful for our outstanding associate editors, editors-in-training, editorial board and editorial staff at the American Society for Clinical Pharmacology and Therapeutics (ASCPT), who with us guided the journal for the last 6 years. It has been a unique privilege to be part of such a purpose-driven team of exceptionally talented and dedicated people. We look forward to the next period for our journal under its new leadership. If indeed history is “an echo of the past in the future,” then Clinical Pharmacology and Therapeutics will remain a record of the best science in clinical pharmacology and with some surprises, a vision for its future. No funding was received for this work. The authors declared no competing interests for this work.