Dosage Optimization: A Regulatory Perspective for Developing Oncology Drugs.

Optimized dosages provide a secure foundation for the development of well-tolerated and effective oncology drugs. Project Optimus, an initiative within the Oncology Center of Excellence, strives to reform the dosage optimization and dosage selection paradigm in oncology. This initiative stems from the availability of targeted drugs and from the demand for more tolerable dosages from patients, caregivers, and advocates. Reforming dosage optimization for oncology drugs requires a paradigm shift from the one employed for cytotoxic chemotherapy to one that understands and considers the unique attributes of targeted therapy, immunotherapy, and cellular therapy. Limited characterization of dosage during drug development may result in (1) patients not staying on a therapy long-term due to poor tolerability, (2) failure to establish positive benefit-risk in clinical trials for regulatory approval (3) withdrawal of drugs from the market (4) removal of indications of drugs from the market. Timely access to drugs is important for all patients with cancer, so it is vital to iteratively analyze all nonclinical and clinically relevant data at each stage of development and leverage quantitative approaches, innovative trial designs, and regulatory support to arrive at dosages with favorable benefit-risk. This review highlights the key challenges and opportunities to embracing this new paradigm and realizing the full potential of new oncology therapies.

Paediatric Drug Development in China: Current Status and Future Prospects.

For more than two decades, regulatory agencies throughout the world released guidelines, rules and laws to stimulate and assist in paediatric drug development. In 2014, the National Health and Family Planning Commission (now known as the National Health Commission, NHC) and five other departments in China jointly issued 'Several Opinions on Safeguarding Medication for Children', after which several policies and regulations were issued to implement the priority review and approval of paediatric medicinal products and support the development of new drugs, including new dosage forms and strengths, for children. A total of 172 special medicinal products for children were approved from 2018 to 2022. Since 2016, the NHC, together with relevant administrative departments, has formulated and issued four paediatric drug lists containing 129 medicinal products to encourage research and development. At present, approximately 25 of these drugs (at exactly the same dosage forms and strengths as on the lists) have been approved for marketing, including antitumour drugs and immunomodulators, nervous system drugs, drugs for mental disorders and drugs for rare diseases. In this review, we analysed the regulations issued for promoting paediatric drug development in China, including the priority review and approval system, technical guidelines, data protection and financial support policies and general profiles of paediatric drug approval, clinical trials and the addition of information for children in the labels of marketed medicinal products. Finally, we discussed the challenges and possible strategies in the research and development of paediatric drugs in China.

Navigating the Regulatory Landscape to Develop Pediatric Oncology Drugs: Expert Opinion Recommendations.

Regulatory changes have been enacted in the United States (US) and European Union (EU) to encourage the development of new treatments for pediatric cancer. Here, we review some of the factors that have hampered the development of pediatric cancer treatments and provide a comparison of the US and EU regulations implemented to address this clinical need. We then provide some recommendations for each stage of the oncology drug development pathway to help researchers maximize their chance of successful drug development while complying with regulations. A key recommendation is the engagement of key stakeholders such as regulatory authorities, pediatric oncologists, academic researchers, patient advocacy groups, and a Pediatric Expert Group early in the drug development process. During drug target selection, sponsors are encouraged to consult the Food and Drug Administration (FDA), European Medicines Agency (EMA), and the FDA target list, in addition to relevant US and European consortia that have been established to characterize and prioritize oncology drug targets. Sponsors also need to carefully consider the resourcing requirements for preclinical testing, which include ensuring appropriate access to the most relevant databases, clinical samples, and preclinical models (cell lines and animal models). During clinical development, sponsors can account for the pharmacodynamic (PD)/pharmacokinetic (PK) considerations specific to a pediatric population by developing pediatric formulations, selecting suitable PD endpoints, and employing sparse PK sampling or modeling/simulation of drug exposures where appropriate. Additional clinical considerations include the specific design of the clinical trial, the potential inclusion of children in adult trials, and the value of cooperative group trials.

In the last few decades, great progress has been made in developing new treatments for adult cancers. However, development of new treatments for childhood cancers has been much slower. To encourage drug companies (sponsors) to develop effective treatments for childhood cancer, authorities in the United States (US) and Europe have made new rules for drug development. Under these new rules, sponsors developing drugs for specific cancers in adults have to consider whether the target of that drug also causes cancers in children. If this is the case, sponsors have to carry out clinical studies of their drug in children who have cancer that is caused by the same drug target. In this article, we describe some reasons for why drug development for childhood cancers has been slow and the rules created to address this problem in the US and Europe. We share some recommendations to help sponsors maximize their chances of developing an effective drug in children while satisfying the new rules. Specifically, sponsors need to be aware of the differences between studying drugs in adults versus children and how these influence the way the drug is tested. We make several recommendations for each stage of the development process, beginning with what is needed even before human studies begin. Finally, we highlight some issues that sponsors need to think about during drug development, from the preclinical stage (testing drugs in cells and animals) through to clinical testing in adults and pediatric patients with cancer.

COVID-19: vaccination problems.

This minireview addresses problems of financing the vaccine development, regulatory questions, the ethics and efficacy of vaccine prioritization strategies and the coverage of variant viruses by current vaccines. Serious adverse effects observed with adenovirus vectored vaccines and mRNA vaccines in mass vaccination campaigns are reported. The ethical problems of continuing with placebo controlled vaccine trials and alternative clinical trial protocols are discussed as well as concrete vaccination issues such as the splitting of doses, the delaying of the second dose, the immunization with two different vaccine types and the need of vaccinating seropositive subjects. Strategies to increase vaccine acceptance in the population are shortly mentioned.

Opportunities and challenges for applying model-informed drug development approaches to gene therapies.

As part of the US Food and Drug Administration (FDA)'s Prescription Drug User Fee Act (PDUFA) VI commitments, the Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER) are conducting a model-informed drug development (MIDD) pilot program. Sponsor(s) who apply and are selected will be granted meetings that aim to facilitate the application of MIDD approaches throughout the product development lifecycle and the regulatory process. Due to their complex mechanisms of action and limited clinical experience, cell and gene therapies have the potential to benefit from the application of MIDD methods, which may facilitate their safety and efficacy evaluations. Leveraging data that are generated from all stages of drug development into appropriate modeling and simulation techniques that inform decisions remains challenging. Additional discussions regarding the application of quantitative modeling approaches to drug development decisions, such as through the MIDD pilot program, may be crucial for both the sponsor(s) and regulatory review teams. Here, we share some perspectives on the opportunities and challenges for utilizing MIDD approaches for product review, which we hope will encourage investigators to publish their experiences and application of MIDD in gene therapy product development.

Evolving use of real-world evidence in the regulatory process: a focus on immuno-oncology treatment and outcomes.

In recent years, regulatory bodies have increasingly recognized the utility of real-world evidence (RWE) for supplementing and supporting clinical trial data in new drug applications. Nevertheless, the integration of RWE into established regulatory processes is complex and the generation of 'regulatory-grade' real-world data faces operational, methodological, data-related and policy-related challenges. In parallel with this evolving role for RWE, immuno-oncology therapies have emerged as leading cancer treatments and are expected to continue to play a central role in the future. In this article, we review the current literature on the use of RWE for regulatory submissions, with a focus on novel anticancer immunotherapies, and discuss the utility and current limitations of RWE in the context of drug development and regulatory approvals.

Opportunities and Challenges in Drug Development for Pediatric Cancers.

The use of targeted small-molecule therapeutics and immunotherapeutics has been limited to date in pediatric oncology. Recently, the number of pediatric approvals has risen, and regulatory initiatives in the United States and Europe have aimed to increase the study of novel anticancer therapies in children. Challenges of drug development in children include the rarity of individual cancer diagnoses and the high prevalence of difficult-to-drug targets, including transcription factors and epigenetic regulators. Ongoing pediatric adaptation of biomarker-driven trial designs and further exploration of agents targeting non-kinase drivers constitute high-priority objectives for future pediatric oncology drug development. SIGNIFICANCE: Increasing attention to drug development for children with cancer by regulators and pharmaceutical companies holds the promise of accelerating the availability of new therapies for children with cancer, potentially improving survival and decreasing the acute and chronic toxicities of therapy. However, unique approaches are necessary to study novel therapies in children that take into account low patient numbers, the pediatric cancer genomic landscape and tumor microenvironment, and the need for pediatric formulations. It is also critical to evaluate the potential for unique toxicities in growing hosts without affecting the pace of discovery for children with these life-threatening diseases.

Demystifying the estimand framework: a case study using patient-reported outcomes in oncology.

Patient-reported outcome (PRO) measures describe how a patient feels or functions and are increasingly being used in benefit-risk assessments in the development of cancer drugs. However, PRO research objectives are often ill-defined in clinical cancer trials, which can lead to misleading conclusions about patient experiences. The estimand framework is a structured approach to aligning a clinical trial objective with the study design, including endpoints and analysis. The estimand framework uses a multidisciplinary approach and can improve design, analysis, and interpretation of PRO results. On the basis of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use E9(R1) addendum, we provide an overview of the estimand framework intended for a multistakeholder audience. We apply the estimand framework to a hypothetical trial for breast cancer, using physical function to develop specific PRO research objectives. This Policy Review is not an endorsement of a specific study design or outcome; rather, it is meant to show the application of principles of the estimand framework to research study design and add to ongoing discussion. Use of the estimand framework to review medical products and label PROs in oncology can improve communication between stakeholders and ultimately provide a clearer interpretation of patient experience in the development of oncological drugs.

Lurbinectedin: First Approval.

The oncogenic transcription inhibitor lurbinectedin (ZEPZELCA™) is being developed by PharmaMar as a treatment for various cancers. The drug has been granted orphan drug status for the treatment of small cell lung cancer (SCLC) by regulatory authorities in multiple countries worldwide and was approved in the USA in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The US FDA and international regulators, including the Australian Therapeutic Goods Administration, are collaborating on the review of lurbinectedin under the Project Orbis initiative. Clinical investigation in other solid cancers is ongoing. This article summarizes the milestones in the development of lurbinectedin leading to this first approval for the treatment of metastatic SCLC.

Decitabine/Cedazuridine: First Approval.

A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi®), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.

Integration of Patient Reported Outcomes in Drug Development in Genitourinary Cancers.

PURPOSE OF REVIEW: Patient reported outcomes (PROs) are increasingly utilized in cancer drug development, and are of particular importance in genitourinary cancers due to symptom burden, multiple treatment options with similar efficacy, and often prolonged duration of disease. Here we review current data and perspectives related to use of PROs in drug development for genitourinary cancers, including insights on the regulatory process for drug approval. RECENT FINDINGS: The FDA is committed to incorporating PRO data into the regulatory process for development and approval of new cancer drugs, but challenges exist due to lack of standardization of PRO instrument choice and analytic approach, missing data, and difficulty isolating treatment effect from disease-related effects. We review guidance for standardization of PRO methodology that is nonetheless tailored to disease state and anticipated effects of treatment. PRO and efficacy data should be simultaneously analyzed and reported for best clinical practice. Multiple disease-specific PRO instruments exist for genitourinary cancers. While clinicians, researchers, and regulatory bodies alike recognize the importance of PROs in cancer drug development, challenges remain regarding implementation of best practices.

Patent spotlight: small-molecule lysine acetyltransferase inhibitors (KATi).

Lysine (or histone) acetyltransferases plays a key role in genome maintenance and gene regulation and dysregulation of acetylation is a recognized feature of many diseases, including several cancers. Here, the patent landscape surrounding lysine acetyltransferase inhibitors (KATi or HATi), with a focus on small-molecule compounds, is outlined and assessed. Overall, the 36 KATi-specific patents found were categorized into two distinct groups: specific small-molecule inhibitors (compounds and molecules) and patents applying KATi for targeted disease treatment. These patents recognize the emergent potential of KATi to significantly impact on the management of many diseases (including multiple cancer types, neurological disorders and immunological syndromes), improving the range of treatments (and drug classes) available for personalized medicine.

Pharmacist perspectives and considerations for implementation of therapeutic oncology biosimilars in practice.

PURPOSE: An overview of therapeutic oncology biosimilars, the U.S. biosimilars regulatory pathway, and the clinical development of selected biosimilar products is provided, including discussion of considerations in adopting biosimilars into oncology practice. SUMMARY: Biosimilars are biologic agents that are highly similar to and have no clinically meaningful differences from an approved reference product in terms of safety, purity, and potency. There is a large market for cancer biologics, and approval of biosimilars has the potential to increase access to care and reduce costs. An abbreviated regulatory pathway for the development and approval of biosimilars defines a stepwise approach to demonstrating biosimilarity and conducting clinical comparative trials to confirm equivalent pharmacokinetics, efficacy, safety, and immunogenicity to the reference product. Three therapeutic biologics (bevacizumab, trastuzumab, and rituximab) have been used extensively in the treatment of a variety of cancers and are targets for biosimilar product development. Preclinical and clinical experience with 2 recently approved biosimilars to bevacizumab and trastuzumab is reviewed. Challenges faced by pharmacy and therapeutics committees when considering oncology biosimilars for formulary inclusion are discussed. CONCLUSION: Increased adoption of biosimilars could potentially lower treatment costs and improve access to biologics for patients with cancer. Key considerations in formulary review of biosimilars include the quality and quantity of data from comparative clinical trials, economic factors, manufacturer reliability, and challenges associated with incorporating biosimilars into practice.

[Early clinical drug development]. / Les phases précoces du développement clinique d'un médicament.

The first administrations of a molecule to humans, so-called phase I studies of drug development, follow experimental animal studies which allow to have a first assessment of the pharmacological effects and toxicity of the molecule under development. Typically, these studies are performed in "healthy" subjects or in relapsing patients with cancer. Participants' safety is a priority. Trained professionals administer single doses, followed by repeated doses, in authorized medical centres. They allow to study the pharmacokinetic and pharmacodynamic profile of tested molecules in humans and to explore some sources of variability of these parameters. These studies are highly regulated and their methodology is fairly standardized.

LES PHASES PRÉCOCES DU DÉVELOPPEMENT CLINIQUE D'UN MÉDICAMENT. Les premières administrations d'une molécule à des humains, dites études de phase I du développement font suite aux études expérimentales qui permettent d'avoir une première idée du profil de ses effets pharmacologiques et de sa toxicité. Ces études sont typiquement organisées avec des sujets « normaux ¼ ou, en oncologie, chez des patients en rechute. La sécurité des participants est une priorité. Des doses uniques, suivies de doses répétées, sont administrées par des professionnels formés dans des lieux médicalisés autorisés. Elles permettent d'étudier le profil pharmacocinétique et pharmacodynamique de la molécule chez les humains et d'explorer quelques sources de variabilité de ces paramètres. Elles sont très encadrées réglementairement et relativement stéréotypées méthodologiquement.

The Foundation for the National Institutes of Health Biomarkers Consortium: Past Accomplishments and New Strategic Direction.

The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium (BC) is a public-private partnership that aims to facilitate drug development with biomarkers across a range of therapeutic areas. The BC is organized to address specific precompetitive biomarker projects, giving participating stakeholders a role in the design and conduct of projects and making the results freely public. Ultimately, the goals of the BC are to accelerate the development of new medicines, inform regulatory decision making, and improve patient care. Here, we describe how the BC works and briefly highlight its accomplishments. The BC has had many notable successful biomarker projects in the past 12 years, including I-SPY2, which has improved clinical trials and biomarker use for breast cancer, and an evidentiary framework for biomarker qualification. Recently, the BC has undergone a strategic expansion of its scope to include related drug development tools along the lines of the Biomarkers, Endpoints, and other Tools (BEST) resource.