Drug approval delays in hematologic malignancies between Europe and the US and between Japan and the US: a clinical perspective.

OBJECTIVE: Since novel therapeutic agents for malignancies are developed rapidly mainly in the US, the interval of approval timing between the US and other countries is an important issue. Among them, drugs for hematologic malignancies tended to have a particularly long delays in Japan, but its characteristics have not been fully understood. This study assessed the approval delays in drugs for hematologic malignancies in Japan compared with that in Europe. METHODS: Using the public database of Europe, Japan and the US, we analyzed the differences in drug approval delays between Europe and the US and between Japan and US according to disease. New molecular entity drugs for hematologic malignancies that were already approved in the US and were approved from April 2010 to March 2022 in Europe or Japan were identified. RESULTS: The results showed the longer drug approval delays in Japan compared with that in Europe (29 vs. 9.4 months, median), presumably due to the lower proportion of participation in global clinical trials (37 vs. 94%). Notably, the participation rate in global clinical trials varied widely by disease in Japan, resulting in a greater difference in drug approval delays by disease. In contrast, when focusing on early phase trials, Japanese participation was uniformly very limited regardless of the disease. CONCLUSIONS: The current study provided data that can be used as a basis for discussion on how to improve drug approval delays in drugs for hematologic malignancies.

Biosimilar Epoetin in the United States: A View from the Southern Network on Adverse Reactions.

Biosimilar drugs, close copies of patented biologicals, are intended to provide access to less expensive, highly similar versions of reference (previously approved) biological agents (Kozlowski et al. in N Engl J Med 365:385-388, 2011). The biological epoetin accounts for $1.8 billion in drug spending annually worldwide (primarily for the treatment of anemia due to chronic kidney disease or anemia due to cancer chemotherapy.).

Recommendations related to the analytical equivalence assessment of gene panel testing.

Advances in cancer genome care over the past few years have included the development of gene panel testing for various biomarkers. This article summarizes issues and provides recommendations related to analytical performance evaluations for new oncology gene panels. The scope of these recommendations includes comprehensive genomic profiling assays related to gene panel testing that uses histological or serum specimens to detect gene mutations. As a research project of the Japan Agency for Medical Research and Development Research on Regulatory Science of Pharmaceuticals and Medical Devices, we convened the working group committee that consisted of more than 30 experts from academia, industry, and government. We have discussed the points that should be considered to allow maximal simplification of assessments using clinical specimens in evaluating accuracy and limit of detection in equivalence and analytical performance for 3 years. We provide recommendations specific to each type of gene mutation as well as to reference standards or specimens used for evaluations. In addition, in order to facilitate the discussion on the analytical performance of gene panel tests by multidisciplinary tumor boards of hospitals, the present recommendations also describe the items that companies are expected to provide information on in their packaging inserts and reports, and the items that are expected to be discussed by multidisciplinary tumor boards. Our working group document will be important for participants in multidisciplinary tumor boards, including medical oncologists and genome scientists, and developers of gene panels not only in Japan but also in other countries.

Tumor mutational burden measurement using comprehensive genomic profiling assay.

BACKGROUND: Tumors with a high number of mutations in the genome, or tumor mutational burden, are presumed to be more likely to respond to immune checkpoint inhibitors. However, the optimal method to calculate tumor mutational burden using comprehensive genomic profiling assays is unknown. METHODS: Todai OncoPanel is a dual panel of a deoxyribonucleic acid panel and a ribonucleic acid panel. Todai OncoPanel deoxyribonucleic acid panel version 6 is an improvement over version 3 with increased number of targeted genes and limited targeting of intronic regions. We calculated tumor mutational burden measured by Todai OncoPanel deoxyribonucleic acid panel versions 3 and 6 using three different calculation methods: all mutations within the targeted region (target tumor mutational burden), all mutations within the coding region (all coding tumor mutational burden) and non-synonymous mutations (non-synonymous coding tumor mutational burden). We then compared them with whole exosome sequencing tumor mutational burden. In addition, 16 lung cancer patients whose samples were analyzed using Todai OncoPanel deoxyribonucleic acid version 3 were treated with anti-PD-1 or PD-L1 antibody monotherapy. RESULTS: When compared with whole exosome sequencing tumor mutational burden as the standard, tumor mutational burden measured by Todai OncoPanel deoxyribonucleic acid version 3 resulted in accuracy of 71% for all three calculation methods. In version 6, accuracy was 96% for target tumor mutational burden and all coding tumor mutational burden and 91% for non-synonymous coding tumor mutational burden. Patients with either partial response or stable disease had higher non-synonymous coding tumor mutational burden (6.7/Mb vs. 1.6/Mb, P = 0.02) and higher PD-L1 expression (40% vs. 3%, P = 0.01) and a trend toward higher target tumor mutational burden (9.2/Mb vs. 2.4/Mb, P = 0.09) compared with patients with progressive disease. CONCLUSIONS: Increase in targeted gene number and limiting intronic regions improved tumor mutational burden measurement by Todai OncoPanel when compared with whole exosome sequencing tumor mutational burden. Target tumor mutational burden may be the method of choice to measure tumor mutational burden.

Reaching beyond maximum grade: progress and future directions for modernising the assessment and reporting of adverse events in haematological malignancies.

Remarkable improvements in outcomes for many haematological malignancies have been driven primarily by a proliferation of novel therapeutics over the past two decades. Targeted agents, immune and cellular therapies, and combination regimens have adverse event profiles distinct from conventional finite cytotoxic chemotherapies. In 2018, a Commission comprising patient advocates, clinicians, clinical investigators, regulators, biostatisticians, and pharmacists representing a broad range of academic and clinical cancer expertise examined issues of adverse event evaluation in the context of both newer and existing therapies for haematological cancers. The Commission proposed immediate actions and long-term solutions in the current processes in adverse event assessment, patient-reported outcomes in haematological malignancies, toxicities in cellular therapies, long-term toxicity and survivorship in haematological malignancies, issues in regulatory approval from an international perspective, and toxicity reporting in haematological malignancies and the real-world setting. In this follow-up report, the Commission describes progress that has been made in these areas since the initial report.

The First 2 Years of Biosimilar Epoetin for Cancer and Chemotherapy-Induced Anemia in the U.S.: A Review from the Southern Network on Adverse Reactions.

Biosimilars are biologic drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety, and efficacy. Biosimilar epoetin received Food and Drug Administration (FDA) approval in 2018. The manufacturer received an FDA nonapproval letter in 2017, despite receiving a favorable review by FDA's Oncologic Drugs Advisory Committee (ODAC) and an FDA nonapproval letter in 2015 for an earlier formulation. We discuss the 2018 FDA approval, the 2017 FDA ODAC Committee review, and the FDA complete response letters in 2015 and 2017; review concepts of litigation, naming, labeling, substitution, interchangeability, and pharmacovigilance; review European and U.S. oncology experiences with biosimilar epoetin; and review the safety of erythropoiesis-stimulating agents. In 2020, policy statements from AETNA, United Health Care, and Humana indicated that new epoetin oncology starts must be for biosimilar epoetin unless medical need for other epoetins is documented. Empirical studies report that as of 2012, reference epoetin use decreased from 40%-60% of all patients with cancer with chemotherapy-induced anemia to <5% of such patients because of safety concerns. Between 2018 and 2020, biosimilar epoetin use varied, increasing to 81% among one private insurer's patients covered by Medicare whose cancer care is administered with Oncology Analytics and to 41% with the same private insurer's patients with cancer covered by commercial health insurance and administered by the private insurer, to 0% in several Veterans Administration Hospitals, increasing to 100% in one large county hospital in California, and with yet-to-be-reported data from most oncology settings. We conclude that biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the U.S. is variable. Pricing and safety considerations for all erythropoiesis-stimulating agents are primary determinants of biosimilar epoetin oncology uptake. IMPLICATIONS FOR PRACTICE: Few oncologists understand substitution and interchangeability of biosimilars with reference drugs. Epoetin biosimilar is new to the market, and physician and patient understanding is limited. The development of epoetin biosimilar is not familiar to oncologists.

[Pharmaceutical approval process of drugs for hematological malignancies: current situations in Japan].

Regulatory review processes are important for the clinical implementation of novel technologies. This review discussed the Japanese regulatory programs for expedited drug development and marketing authorization, such as priority review, conditional approval, SAKIGAKE designation, and council on the development promotion scheme for unapproved and off-label drugs. Particularly, similarities and differences between regulatory frameworks for oncologic drugs in Japan and the USA are mainly described.

Flexible and Expedited Regulatory Review Processes for Innovative Medicines and Regenerative Medical Products in the US, the EU, and Japan.

Several expedited regulatory review projects for innovative drugs and regenerative medical products have been developed in the US, the EU, and Japan. Each regulatory agency has elaborated an original regulatory framework and adopted regulatory projects developed by the other regulatory agencies. For example, the Food and Drug Administration (FDA) first developed the breakthrough therapy designation, and then the Pharmaceuticals and Medical Devices Agency (PMDA) and European Medicines Agency (EMA) introduced the Sakigake designation and the priority medicines (PRIME) designation, respectively. In addition, the necessity of the product being first development in Japan is the original feature of the Sakigake designation, while actively supporting the development of advanced-therapy medicinal products (AMTPs) by academia or small/medium-sized sponsors is the original feature of the PRIME; these particular features are different from the breakthrough therapy designation in the US. In this review article, flexible and expedited review processes for new drugs, and cell and gene therapies in the US, the EU, and Japan are described. Moreover, all the drugs and regenerative medical products that were granted conditional approval or Sakigake designation in Japan are listed and analyzed herein.

Addressing the dichotomy between individual and societal approaches to personalised medicine in oncology.

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit.

Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada.

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%-40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. IMPLICATIONS FOR PRACTICE: We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing "rebate traps" where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

Current Trends in Clinical Development of Gene and Cellular Therapeutic Products for Cancer in Japan.

PURPOSE: In Japan, gene therapy and cellular therapy are categorized as regenerative medicine products based on the Pharmaceuticals and Medical Devices Law that was implemented in 2014. In this new law, regenerative medicine products were newly defined, and a conditional and term-limited approval system for regenerative medicine products was instituted. In addition, the Ministry of Health, Labour and Welfare instituted the SAKIGAKE (meaning pioneer or forerunner in Japanese) designation system in 2015. This designation is similar to the breakthrough therapy designation in the United States. These new regulatory frameworks have stimulated clinical development of new gene and cellular products in Japan. In fact, oncolytic virus therapy for glioblastoma and NY-ESO-1 (T-cell receptor) T-cell therapy for synovial sarcoma were granted SAKIGAKE designation in 2016 and 2018, respectively. Oncolytic virus therapy and genetically engineered T-cell therapy for cancer are being actively developed and examined in investigator-initiated trials. METHODS: This review analyzes the domestic and international clinical trial registries to comprehensively collect information on clinical trials of gene and cellular therapeutic products for cancer in Japan. IMPLICATIONS: Current trends in clinical development of gene and cellular therapeutic products for cancer in Japan are discussed.

Global Development of Anticancer Therapies for Rare Cancers, Pediatric Cancers, and Molecular Subtypes of Common Cancers.

Advances in genetic sequencing and other diagnostic technologies have enabled the use of precision medicine in clinical cancer care, as well as the development of novel therapies that are targeted to specific molecular drivers of cancer. Developing these new agents and making them accessible to patients requires global clinical studies and regulatory review and approval by different national regulatory agencies. Whereas these global trials present challenges for drug developers who conduct them and regulatory agencies who oversee them, they also raise practical issues about patients with low-frequency cancers who need these therapies. A lack of uniform standards in both regulatory approval for marketing and reimbursement for approved agents across countries may make the newly developed agent either unavailable or inaccessible to patients in certain countries or regions, even if patients from those countries or regions participated in the clinical research that established the safety and efficacy of the agent. In an effort to further understand and address this need, we convened an international workshop in 2017 in North Bethesda, MD. After presentations of the individual regulatory pathways for marketing approval and reimbursement for individual nations, participants discussed expedited pathways and specific challenges for uncommon cancers. As a matter of justice, agents being developed for rare cancers, pediatric cancers, or uncommon molecular subsets of common cancers need a pragmatic, science-based regulatory policy framework to clearly specify the type and quantity of evidence needed to demonstrate efficacy from these trials and evidence to support accessibility.

Beyond maximum grade: modernising the assessment and reporting of adverse events in haematological malignancies.

Tremendous progress in treatment and outcomes has been achieved across the whole range of haematological malignancies in the past two decades. Although cure rates for aggressive malignancies have increased, nowhere has progress been more impactful than in the management of typically incurable forms of haematological cancer. Population-based data have shown that 5-year survival for patients with chronic myelogenous and chronic lymphocytic leukaemia, indolent B-cell lymphomas, and multiple myeloma has improved markedly. This improvement is a result of substantial changes in disease management strategies in these malignancies. Several haematological malignancies are now chronic diseases that are treated with continuously administered therapies that have unique side-effects over time. In this Commission, an international panel of clinicians, clinical investigators, methodologists, regulators, and patient advocates representing a broad range of academic and clinical cancer expertise examine adverse events in haematological malignancies. The issues pertaining to assessment of adverse events examined here are relevant to a range of malignancies and have been, to date, underexplored in the context of haematology. The aim of this Commission is to improve toxicity assessment in clinical trials in haematological malignancies by critically examining the current process of adverse event assessment, highlighting the need to incorporate patient-reported outcomes, addressing issues unique to stem-cell transplantation and survivorship, appraising challenges in regulatory approval, and evaluating toxicity in real-world patients. We have identified a range of priority issues in these areas and defined potential solutions to challenges associated with adverse event assessment in the current treatment landscape of haematological malignancies.

Drug approval based on randomized phase 3 trials for relapsed malignancy: analysis of oncologic drugs granted accelerated approval, publications and clinical trial databases.

Background As relapsed disease is frequently the first target of newly developed therapies, it is vital to address the difficulty in demonstrating the efficacy of new drugs for relapsed malignancy in randomized phase 3 trials. Methods We analyzed the approved indications, target populations, and development status of post-marketing confirmatory trials of all oncology-related drugs that were granted accelerated approval for both hematological and solid malignancies. Furthermore, we searched for randomized phase 3 trials for adult patients with relapsed lymphoid malignancy, other than chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). Results Thirty-one (81.6%) of the 38 hematological indications and 23 (53.5%) of the 43 solid malignancy indications were in the relapsed settings. The target population of post-marketing studies was different from the approved indication in 18 (47.4%) of 38 hematological indications and 11 (25.6%) of 43 solid malignancy indications; all 18 hematological indications involved relapsed settings. Improved time-to-event outcome for relapsed patients was the primary endpoint in 6 (19.3%) of the 31 relapsed hematological indications. In 4 published studies of relapsed lymphoid malignancy, the medication significantly improved outcomes. From 33 trials listed at Clinicaltrials.gov , 2 were positive and 13 were negative. Five out of the 13 negative trials were terminated due to poor accrual. Conclusion Our analysis indicates that drug approval based on phase 3 trials is more challenging for relapsed hematological malignancies than for solid malignancies. Therefore, determining proper evaluation methods for the efficacy and safety of drugs for relapsed malignancy, without randomized trials, is important.

New Japanese Regulatory Frameworks for Clinical Research and Marketing Authorization of Gene Therapy and Cellular Therapy Products.

INTRODUCTION: In Japan, the Pharmaceuticals and Medical Devices Law was passed in 2014. In this new law, regenerative medical products were defined, and a conditional and term-limited approval system only for regenerative medical products was instituted. Therefore, regenerative medical products can be approved based on phase I and/or II trials. Gene therapy and adoptive cellular therapy are categorized as regenerative medical products. This law is intended for registration trials for marketing authorization. The Act on the Safety of Regenerative Medicine was also implemented in 2014. This act is intended for clinical research and medical practice involving processed cells other than registration trials. Under this act, a review of plans on medical treatments or clinical studies by a certified committee and submission of the plans to the Ministry of Health, Labour and Welfare (MHLW) are mandatory. The MHLW instituted the SAKIGAKE (meaning a pioneer or forerunner in Japanese) designation system in 2015. This designation is similar to the breakthrough therapy designation in the US and PRIME in the EU. In addition, the MHLW started the "Project for Enhanced Practical Application of Innovative Drugs, Medical Devices and Regenerative Medical Products" to promote personnel exchange and cooperation in writing of guidelines on the evaluation of innovative medical products between the Pharmaceuticals and Medical Devices Agency and academia. Some new guidelines regarding gene and cellular therapy were published. CONCLUSION: In this review, we comprehensively described these complicated regulations and problems to be solved in order to facilitate global readers' understanding of Japanese regulatory frameworks.

Generic oncology drugs: are they all safe?

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.