Considerations for Industry-Preparing for the FDA Model-Informed Drug Development (MIDD) Paired Meeting Program.

A recent industry perspective published in this journal describes the benefits received by drug companies from participation in the MIDD Pilot Program. Along with the primary objectives of supporting good decision-making in drug development, there were substantial savings in time and development costs. Furthermore, many sponsors reported qualitative benefits such as new learnings and clarity on MIDD strategies and methodology that could be applied to other development programs.

Anaphylatoxin signaling activates macrophages to control intracellular proliferation.

Pathogenic species are extremely dangerous bacteria that grow within the cytoplasm of host mammalian cells. In most cases, these bacteria are able to overpower the host cell and grow within the protected environment of the cytoplasm. However, a dramatic conflict occurs when encounter innate immune cells; the bacteria can "win" by taking over the host, or the bacteria can "lose" if the host cell efficiently fights the infection.

Ensuring diversity in clinical trials: The role of clinical pharmacology.

Increasing the diversity of participants in clinical trials is important as it allows further examination of drug effects in all subgroups of patients who will be prescribed an approved medicine. It also gives patients more confidence in the medicine when they know that individuals similar to themselves have participated in pivotal efficacy and safety trials. Pfizer recently committed to ensuring that its clinical trials reflect racial and ethnic demographics of the patient populations in the countries and communities in which the trials are conducted.

Clinical Relevance of Hepatic and Renal P-gp/BCRP Inhibition of Drugs: An International Transporter Consortium Perspective.

The role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in drug-drug interactions (DDIs) and limiting drug absorption as well as restricting the brain penetration of drugs with certain physicochemical properties is well known. P-gp/BCRP inhibition by drugs in the gut has been reported to increase the systemic exposure to substrate drugs. A previous International Transporter Consortium (ITC) perspective discussed the feasibility of P-gp/BCRP inhibition at the blood-brain barrier and its implications.

Exposure-Response Characterization of Tofacitinib Efficacy in Moderate to Severe Ulcerative Colitis: Results From Phase II and Phase III Induction and Maintenance Studies.

Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis. Relationships between plasma tofacitinib concentration and efficacy were characterized using exposure-response (E-R) models, with demographic and disease covariates evaluated as potential predictors of efficacy. Data were from phase II and III (OCTAVE Induction 1 and 2) induction studies, and a phase III maintenance study (OCTAVE Sustain).

To blind or not to blind first in human and exploratory clinical trials: Acceleration of development vs. risk of bias.

An IQ consortium working group (WG) conducted a survey across multiple biopharmaceutical companies to gain information about the level of blinding commonly utilized for early clinical development trials. The main objectives were: (1) to understand blinding practices between healthy volunteer (HV) and early explorative patient trials in all therapeutic areas except oncology where early clinical trials are commonly open-label; (2) to understand the rationale for blinding/unblinding practices; (3) to understand the groups and personnel involved in unblinding; and (4) strategic considerations around blinding/unblinding options in early clinical development trials-risk of bias vs. potential for acceleration.

Contribution of classical complement activation and IgM to the control of Rickettsia infection.

Pathogenic Rickettsia are obligate intracellular bacteria and the etiologic agents of many life-threatening infectious diseases. Due to the serious nature of these infections, it is imperative to both identify the responsive immune sensory pathways and understand the associated immune mechanisms that restrict Rickettsia proliferation. Previous studies have demonstrated that the mammalian complement system is both activated during Rickettsia infection and contributes to the immune response to infection.

Roadmap to 2030 for Drug Evaluation in Older Adults.

Changes that accompany older age can alter the pharmacokinetics (PK), pharmacodynamics (PD), and likelihood of adverse effects (AEs) of a drug. However, older adults, especially the oldest or those with multiple chronic health conditions, polypharmacy, or frailty, are often under-represented in clinical trials of new drugs. Deficits in the current conduct of clinical evaluation of drugs for older adults and potential steps to fill those knowledge gaps are presented in this communication.

Harnessing formulation and clinical pharmacology knowledge for efficient pediatric drug development: Overview and discussions from M-CERSI pediatric formulation workshop 2019.

A pediatric formulation workshop entitled "Pediatric Formulations: Challenges of Today and Strategies for Tomorrow" was held to advance pediatric drug product development efforts in both pre-competitive and competitive environments. The workshop had four main sessions discussing key considerations of Formulation, Analytical, Clinical and Regulatory. This paper focuses on the clinical session of the workshop.

Correction to: Integrated Multi-stakeholder Systems Thinking Strategy: Decision-making with Biopharmaceutics Risk Assessment Roadmap (BioRAM) to Optimize Clinical Performance of Drug Products.

A Correction to this paper has been published: https://doi.org/10.1208/s12248-020-00534-0.

Model-Informed Precision Dosing: Background, Requirements, Validation, Implementation, and Forward Trajectory of Individualizing Drug Therapy.

Model-informed precision dosing (MIPD) has become synonymous with modern approaches for individualizing drug therapy, in which the characteristics of each patient are considered as opposed to applying a one-size-fits-all alternative. This review provides a brief account of the current knowledge, practices, and opinions on MIPD while defining an achievable vision for MIPD in clinical care based on available evidence. We begin with a historical perspective on variability in dose requirements and then discuss technical aspects of MIPD, including the need for clinical decision support tools, practical validation, and implementation of MIPD in health care.

The Weight of Evidence From Electrophysiology, Observational, and Cardiovascular End Point Studies Demonstrates the Safety of Azithromycin.

Increased use of azithromycin (AZ) in treating infections associated with coronavirus disease 2019 (COVID-19) and reports of increased incidence of prolonged corrected QT (QTc) interval associated with AZ used with hydroxychloroquine prompted us to review the latest evidence in the literature, present additional analyses of human cardiovascular (CV) electrophysiology studies, and to describe sequential steps in research and development that were undertaken to characterize the benefit-risk profile of AZ. Combined QTc findings from electrocardiograms taken during oral and i.v.

Integrated Multi-stakeholder Systems Thinking Strategy: Decision-making with Biopharmaceutics Risk Assessment Roadmap (BioRAM) to Optimize Clinical Performance of Drug Products.

Decision-making in drug development benefits from an integrated systems approach, where the stakeholders identify and address the critical questions for the system through carefully designed and performed studies. Biopharmaceutics Risk Assessment Roadmap (BioRAM) is such a systems approach for application of systems thinking to patient focused and timely decision-making, suitable for all stages of drug discovery and development. We described the BioRAM therapy-driven drug delivery framework, strategic roadmap, and integrated risk assessment instrument (BioRAM Scoring Grid) in previous publications (J Pharm Sci 103:3377-97, 2014; J Pharm Sci 105:3243-55, 2016).

Pharmacokinetics and Pharmacological Properties of Chloroquine and Hydroxychloroquine in the Context of COVID-19 Infection.

Chloroquine and hydroxychloroquine are quinoline derivatives used to treat malaria. To date, these medications are not approved for the treatment of viral infections, and there are no well-controlled, prospective, randomized clinical studies or evidence to support their use in patients with coronavirus disease 2019 (COVID-19). Nevertheless, chloroquine and hydroxychloroquine are being studied alone or in combination with other agents to assess their effectiveness in the treatment or prophylaxis for COVID-19.

Drug Dosing Recommendations for All Patients: A Roadmap for Change.

Most drug labels do not contain dosing recommendations for a significant portion of real-world patients for whom the drug is prescribed. Current label recommendations predominately reflect the population studied in pivotal trials that typically exclude patients who are very young or old, emaciated or morbidly obese, pregnant, or have multiple characteristics likely to influence dosing. As a result, physicians may need to guess the correct dose and regimen for these patients.

A Real-World Evidence Framework for Optimizing Dosing in All Patients With COVID-19.

Potential treatments for coronavirus disease 2019 (COVID-19) are being investigated at unprecedented speed, and successful treatments will rapidly be used in tens or hundreds of thousands of patients. To ensure safe and effective use in all those patents it is essential also to develop, at unprecedented speed, a means to provide frequently updated, optimal dosing information for all patient subgroups. Success will require immediate collaboration between drug developers, academics, and regulators.

ICH M9 Guideline in Development on Biopharmaceutics Classification System-Based Biowaivers: An Industrial Perspective from the IQ Consortium.

In October 2016, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) ICH began efforts to provide recommendations to harmonize guidances for biopharmaceutics classification system (BCS)-based biowaivers. Topics to be addressed included consideration of the dose used to classify solubility, tests, and criteria for establishing highly permeable, dissolution conditions, the influence of excipients, and aspects of product strength. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) is a technically focused organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators, and the broader R&D community.

ITC Commentary on Metformin Clinical Drug-Drug Interaction Study Design That Enables an Efficacy- and Safety-Based Dose Adjustment Decision.

Metformin drug-drug interaction (DDI) studies are conducted during development of drugs that inhibit organic cation transporters and/or multidrug and toxin extrusion proteins (OCTs/MATEs). Monitoring solely changes in systemic exposure, the typical DDI study endpoint appears inadequate for metformin, which is metabolically stable, has poor passive membrane permeability, and undergoes transporter-mediated tissue distribution and clearance. Evaluation of renal clearance, antihyperglycemic effects, and potentially lactate as an exploratory safety marker, can support rational metformin dose adjustment.

Driving Access to Medicines With a Totality of Evidence Mindset: An Opportunity for Clinical Pharmacology.

Access to Medicine (AtM) initiatives have traditionally focused on enabling continuous availability and affordability of medicines for patients in the developing world. A more holistic view of AtM across the discovery-development-regulation-utilization continuum would also include participation in the development and timely access to emerging therapies in diverse populations in the era of precision therapeutics, built upon foundational clinical pharmacology principles, leveraging a Totality of Evidence (ToE) mindset.

Optimizing Clinical Drug Product Performance: Applying Biopharmaceutics Risk Assessment Roadmap (BioRAM) and the BioRAM Scoring Grid.

The aim of Biopharmaceutics Risk Assessment Roadmap (BioRAM) and the BioRAM Scoring Grid is to facilitate optimization of clinical performance of drug products. BioRAM strategy relies on therapy-driven drug delivery and follows an integrated systems approach for formulating and addressing critical questions and decision-making (J Pharm Sci. 2014,103(11): 3777-97).

Utility of Model-Based Approaches for Informing Dosing Recommendations in Specific Populations: Report From the Public AAPS Workshop.

This report summarizes the discussions and recommendations of the workshop titled "Specific Population Drug Dosing Recommendations: Shifting from Clinical Studies to Predict and Confirm," which preceded the 2015 American Association of Pharmaceutical Scientists annual meeting. Participants from the pharmaceutical industry, regulatory agencies (FDA and EMA), and academia discussed the current state, challenges, opportunities, and future direction of utilizing model-based approaches to inform dosing recommendations in specific populations.