The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the Treatment of Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma.

Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming one of the most promising approaches in the treatment of cancer. On June 28, 2018, the Committee for Advanced Therapies (CAT) and the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Kymriah for pediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse after transplant, or in second or later relapse and for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Kymriah became one of the first European Union-approved CAR T therapies. The active substance of Kymriah is tisagenlecleucel, an autologous, immunocellular cancer therapy that involves reprogramming the patient's own T cells to identify and eliminate CD19-expressing cells. This is achieved by addition of a transgene encoding a CAR. The benefit of Kymriah was its ability to achieve remission with a significant duration in patients with ALL and an objective response with a significant duration in patients with DLBCL. The most common hematological toxicity was cytopenia in both patients with ALL and those with DLBCL. Nonhematological side effects in patients with ALL were cytokine release syndrome (CRS), infections, secondary hypogammaglobulinemia due to B-cell aplasia, pyrexia, and decreased appetite. The most common nonhematological side effects in patients with DLBCL were CRS, infections, pyrexia, diarrhea, nausea, hypotension, and fatigue. Kymriah also received an orphan designation on April 29, 2014, following a positive recommendation by the Committee for Orphan Medicinal Products (COMP). Maintenance of the orphan designation was recommended at the time of marketing authorization as the COMP considered the product was of significant benefit for patients with both conditions. IMPLICATIONS FOR PRACTICE: Chimeric antigen receptor (CAR)-engineered T-cell therapy is becoming the most promising approach in cancer treatment, involving reprogramming the patient's own T cells with a CAR-encoding transgene to identify and eliminate cancer-specific surface antigen-expressing cells. On June 28, 2018, Kymriah became one of the first EMA approved CAR T therapies. CAR T technology seems highly promising for diseases with single genetic/protein alterations; however, for more complex diseases there will be challenges to target clonal variability within the tumor type or clonal evolution during disease progression. Products with a lesser toxicity profile or more risk-minimization tools are also anticipated.

A review of clinical pharmacology deficiencies of European centralised drug marketing authorisation applications.

The aim of this observational review was to review trends in deficiencies in clinical pharmacology dossiers by analysing the frequency and characteristics of major objections (MOs) related to clinical pharmacokinetics and dose-exposure-response (DER) relationships in assessment reports for medicinal products submitted in centralised procedures to the European Medicines Agency (EMA). Initial Assessor (Day 120) assessment reports between 2013 and 2018 were reviewed MOs and characterised with regards to ATC code, orphan status, legal basis and type of molecule, major objection topic and if scientific advice had been sought during development. 23% of the 551 identified Day 120 assessments contained at least one major objection related to clinical pharmacology. Most common topics identified were related to the pharmacokinetics in the target populations, analytical methods, dose-exposure-response relationships, absorption, distribution, metabolism, excretion, comparative bioavailability, and bioequivalence issues. The importance of a robust clinical PK dossier in the assessment of marketing authorisation applications was highlighted by the high frequency of major objections. This review should provide valuable insights to ensure that aspects of bioanalytical methods, comparative bioavailability, PK in the target population and DER relationships are thoroughly addressed in future marketing authorisation applications.

Casgevy: Innovative Medicinal Products Require Innovative Approaches to Regulatory Assessment.

Casgevy (exa-cel) is an autologous cellular therapy modified ex vivo by a CRISPR-Cas9-mediated gene-editing technology. For Casgevy to be granted the indication in transfusion-dependent ß-thalassemia, one single-arm trial was submitted which was not amenable to conventional statistical analysis of 'effect of cause'. Therefore, an analysis was conducted on the basis of 'cause of effect' making use of the scheme described by Toulmin coupled to an analysis of causal inference. Based on the current data within the submitted study: subjects with transfusion-dependent ß-thalassemia no longer needed a red blood cell transfusion with a 93-percent probability if and only if administered Casgevy; PNS = 93%. It is acknowledged that unknown elements of safety may yet be revealed by long-term follow-up of recipients of Casgevy. Its durability of efficacy is, at present, also an unknown that may also be ascertained by long-term follow-up of recipients. The limitations of a causal analysis are related to assumptions of the proposed causal structure which may not capture the complexity of the real world. Overall, the claim that Casgevy is indicated to treat people with transfusion-dependent ß-thalassemia is considered to be supported by the results of the submitted study; the benefit-risk evaluation of Casgevy is found to be positive.

Covariate modeling in pharmacometrics: General points for consideration.

Modeling the relationships between covariates and pharmacometric model parameters is a central feature of pharmacometric analyses. The information obtained from covariate modeling may be used for dose selection, dose individualization, or the planning of clinical studies in different population subgroups. The pharmacometric literature has amassed a diverse, complex, and evolving collection of methodologies and interpretive guidance related to covariate modeling. With the number and complexity of technologies increasing, a need for an overview of the state of the art has emerged. In this article the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee presents perspectives on best practices for planning, executing, reporting, and interpreting covariate analyses to guide pharmacometrics decision making in academic, industry, and regulatory settings.

Use of Physiologically Based Pharmacokinetic Modeling for Hepatically Cleared Drugs in Pregnancy: Regulatory Perspective.

Physiologically based pharmacokinetic modeling could be used to predict changes in exposure during pregnancy and possibly inform medicine use in pregnancy in situations in which there is currently limited or no available clinical PK data. The Medicines and Healthcare Product Regulatory Agency has been evaluating the available models for a number of medicines cleared by hepatic clearance mechanisms. Models were evaluated for metoprolol, tacrolimus, clindamycin, ondansetron, phenytoin, caffeine, fluoxetine, clozapine, carbamazepine, metronidazole, and paracetamol. The hepatic metabolism through cytochrome P450 (CYP) contributes significantly to the elimination of these drugs, and available knowledge of CYP changes during pregnancy has been implemented in the existing pregnancy physiology models. In general, models were able to capture trends in exposure changes in pregnancy to some extent, but the magnitude of pharmacokinetic change for these hepatically cleared drugs was not captured in each case, nor were models always able to capture overall exposure in the populations. A thorough evaluation was hampered by the lack of clinical data for drugs cleared by a specific clearance pathway. The limited clinical data, as well as complex elimination pathways involving CYPs, uridine 5'-diphospho-glucuronosyltransferase and active transporter for many drugs, currently limit the confidence in the prospective use of the models. Pregnancy-related changes in uridine 5'-diphospho-glucuronosyltransferase and transport functions are emerging, and incorporation of such changes in current physiologically based pharmacokinetic modeling software is in progress. Filling this gap is expected to further enhance predictive performance of models and increase the confidence in predicting PK changes in pregnant women for hepatically cleared drugs.

Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy.

Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocrit; this may lead to increased free concentrations, tissue distribution, and clearance during pregnancy. In this paper we highlight the importance and challenges of considering changes in total and free concentrations during pregnancy. For medicines highly bound to plasma proteins, such as tacrolimus, efavirenz, clindamycin, phenytoin, and carbamazepine, differential changes in concentrations of free drug during pregnancy may be clinically significant and have important implications for dose adjustment. Therapeutic drug monitoring usually relies on the measurement of total concentrations; this can result in dose adjustments that are not necessary when changes in free concentrations are considered. We explore the potential of physiologically based pharmacokinetic (PBPK) models to support the understanding of the changes in plasma proteins binding, using tacrolimus and efavirenz as example drug models. The exposure to either drug was predicted to be reduced during pregnancy; however, the decrease in the exposure to the total tacrolimus and efavirenz were significantly larger than the reduction in the exposure to the free drug. These data show that PBPK modelling can support the impact of the changes in plasma protein binding and may be used for the simulation of free concentrations in pregnancy to support dosing decisions.

Demystifying physiologically based pharmacokinetic modelling among non-modelers towards model-informed medicine use in under-served populations.

Physiologically based pharmacokinetic (PBPK) models represent computational technology to characterize drug behavior within the context of detailed human physiology. Today, PBPK is routinely used in drug development and regulatory approval to support decisions on how a medicine can be used under certain clinical conditions. As such, PBPK has the potential to enhance medicine use for populations that are often under-served globally in drug development and clinical care, namely pediatric patients, pregnant and lactating women. To facilitate broader applications of PBPK for these populations, we joined force and organized five hands-on workshops primarily to non-modelers on the principles of PBPK and its potential applications in pediatric and obstetric pharmacology in 2021 and 2022. In this open letter, we report learning objectives and content of such workshops and to highlight the significant value of these educational efforts.

The Use of Pregnancy Physiologically Based Pharmacokinetic Modeling for Renally Cleared Drugs.

Physiologically based pharmacokinetic modeling (PBPK) could be used to predict changes in exposure during pregnancy and possibly inform medicine use in pregnancy in situations where there are currently no available clinical data. The Medicines and Healthcare Product Regulatory Agency has been evaluating the available models for a number of medicines cleared by the kidney. Models were evaluated for ceftazidime, cefuroxime, metformin, oseltamivir, and amoxicillin. Because the passive renal process contributes significantly to the renal elimination of these drugs and changes of the process during pregnancy have been implemented in existing pregnancy physiology models, simulations using these models can reasonably describe the pharmacokinetics of ceftazidime changes during pregnancy and appears to generally capture the changes in the other medicines; however, there are insufficient data on drugs solely passively cleared to fully qualify the models. In addition, in many cases, active transport processes are involved in a drug's renal clearance. Knowledge of changes in renal transport functions during pregnancy is emerging, and incorporation of such changes in current physiologically based pharmacokinetic modeling software is a work in progress. Filling this gap is expected to further enhance predictive performance of the models and increase the confidence in predicting pharmacokinetic changes in pregnant women for other renally cleared drugs.

Pharmacokinetic data in pregnancy: A review of available literature data and important considerations in collecting clinical data.

Pregnancy-related physiological changes can alter the absorption, distribution, metabolism and excretion of medicines which may affect the safety and efficacy of the medicines administered in pregnancy. Pharmacokinetic data can thus be instrumental in supporting dose adjustments required in this population. This review considers the availability of published pharmacokinetic data for over 200 medicines of interest for use in pregnancy in the UK, to identify whether sufficient data currently exists, in principle, for any medicine or group of medicines to support dose adjustments to maintain maternal health through pregnancy. Very limited data was found for many of the medicines of interest. Nevertheless, well documented, large changes of exposure for some drugs, where data is available, highlights the urgent need to collect more data of good quality to inform appropriate doses, when needed, in this population. In addition, clinical study methodology can have an impact on the usefulness of the data and key clinical design aspects are highlighted for consideration in future clinical study design.

Physiologically Based Pharmacokinetics Model in Pregnancy: A Regulatory Perspective on Model Evaluation.

Physiologically based pharmacokinetics (PBPK) modelling is widely used in medicine development and regulatory submissions. The lack of clinical pharmacokinetic data in pregnancy is widely acknowledged; therefore, one area of current interest is in the use of PBPK modelling to describe the potential impact of anatomical and physiological changes during pregnancy on the medicine's pharmacokinetics. PBPK modelling could possibly represent a predictive tool to support the medicine benefit-risk decision and inform dose adjustment in this population and also to investigate medicine levels in the foetus to support the risk assessment to the foetus. In the context of regulatory application, there are, however, a number of considerations around model evaluation, and this should be tailored to the model purpose, in order to inform the confidence in the model for the intended application. A number of gestational age-related physiological changes are expected to alter the pharmacokinetics of medicines during pregnancy, and there are uncertainties on some parameters; therefore, well-qualified models are needed to improve assurance in the model prediction before this approach can be used to inform with confidence high-impact decisions as part of regulatory submissions.

A summary of the current drug interaction guidance from the European Medicines Agency and considerations of future updates.

The current EMA drug interaction guideline was published in 2012. This guideline gives important recommendations on the information required to elucidate the interaction potential of an investigational drug, both as effects of the investigational drug on the PK of other drugs and effects of other medicinal products on the PK of the investigational drug. Additional information on the use of PBPK modelling to inform drug interaction information, is also available in the guideline on the reporting of physiologically based modelling and simulation (2018). Some points of clarification on the drug interaction guideline, particularly in the area of enzyme induction screening, have been published as the EMA questions and answers (2014) and these points and further additional points, were proposed to be incorporated into a new update of the guideline, for which a concept paper was published in 2017. This update, which is still in progress, was to include new recommendations in line with relevant emerging scientific data (e.g. in the area of drug transporters). It is also intended to harmonise requirements on drug interactions with other Regulatory Agencies and this will be facilitated by the recently announced ICH initiative.

Commentary on the MID3 Good Practices Paper.

During the last 10 years the European Medicines Agency (EMA) organized a number of workshops on modeling and simulation, working towards greater integration of modeling and simulation (M&S) in the development and regulatory assessment of medicines. In the 2011 EMA - European Federation of Pharmaceutical Industries and Associations (EFPIA) Workshop on Modelling and Simulation, European regulators agreed to the necessity to build expertise to be able to review M&S data provided by companies in their dossier. This led to the establishment of the EMA Modelling and Simulation Working Group (MSWG). Also, there was agreement reached on the need for harmonization on good M&S practices and for continuing dialog across all parties. The MSWG acknowledges the initiative of the EFPIA Model-Informed Drug Discovery and Development (MID3) group in promoting greater consistency in practice, application, and documentation of M&S and considers the paper is an important contribution towards achieving this objective.