A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs

Bioanalytical assessments of anti-drug antibodies (ADAs) provide an understanding of the immunogenicity of biological drug molecules. The potential to induce ADAs after treatment with biologics is a safety issue that has become an important consideration in the development of biologics and a critical aspect of regulatory filings. US and European regulatory agencies are recommending that sponsors study immunogenicity using a risk-based approach, encouraging sponsors to formulate and implement their own risk management plans and to conduct discussions with the agencies when necessary. It follows from this that the greater the safety risks of ADAs, the more diligently one should clarify the immunogenicity of the product. Here we propose a general strategy to broadly assign immunogenicity risk levels to biological drug products, and present risk level-based 'fit-for-purpose' bioanalytical schemes for the investigations of treatment-related ADAs in clinical and nonclinical studies.     

China's perspective on similar biotherapeutic products

In order to ensure most Chinese patients, particularly in the population with relatively low incomes, have access to safe, low cost, effective and quality-assured medicines, a number of "stand-alone" biological products, which have good quality, safety and efficacy have been marketed in China. Many countries and regions' regulatory agencies are actively engaging in the development of bio-similar guidance and documents, which is being coordinated by WHO. As a major developing country of new drug development, China is now working hard to promote the process of new similar biotherapeutic products (SBPs) approval and also actively involved in developing and updating technical documents.     

When do tissues and cells become products? – Regulatory oversight of emerging biological therapies

Although therapeutics derived from biological sources have been subjected to regulatory oversight for some time, the products used in transplantation procedures have historically been exempt from this oversight. These products have been viewed as being part of medical practice rather than as the result of mainstream pharmaceutical manufacture. Furthermore, their unique source makes them difficult to assess in traditional regulatory systems based on the␣tenets of pharmaceutical quality control. With the␣increasing use of transplantation therapies to both replace dysfunctional organs and to influence genetic and metabolic processes, public health concerns on these therapies have increased. In addition, it is recognized that therapeutic claims for some of these interventions need to be properly assessed. These considerations have led the established regulatory agencies of the developed world to develop new regulatory paradigms for the products of transplantation practice. While a number of concerns have driven these developments, the minimization of infectious disease risk remains the paramount driver for introducing these regulatory systems. More than the regulation of medicines and medical devices manufactured in traditional pharmaceutical modes, the regulation of cell and tissue products is intimately linked to areas of public health policy and funding. This places regulators in a challenging position as they attempt to reconcile their roles as independent assessors with the needs of the overall public health framework. This is particularly difficult when considering measures which may affect access to life saving therapies. Regulators have recognized the need to assess these therapies through systems which incorporate consideration of risk-benefit ratios and include mechanisms for transparent and accountable release of products when full compliance to traditional concepts of manufacturing practice is not possible.     

Comparison of new Brazilian legislation for the approval of advanced therapy medicinal products with existing systems in the USA,European Union and Japan

Background aimsAdvanced therapy medicinal products (ATMPs) are a class of biological products for human use that are based on genes, cells and tissues. The first ATMP received marketing authorization in Europe in 2009, whereas Brazil granted the first authorization in 2020. The objective of this study was to compare the regulatory models adopted by Brazil, the USA, Japan and the European Union, which comprise the member countries of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, with regard to the marketing authorization of ATMPs.MethodsThe authors performed a review of the scientific literature and official documents of the regulatory agencies in the aforementioned countries.ResultsThe legislation and regulatory guidelines adopted by the regulatory agencies exhibit similarities and differences. It was not possible to assess whether these differences can be translated into divergent final recommendations by regulatory authorities upon a request for marketing authorization.ConclusionsIn the future, it will be appropriate to start a progressive process of harmonization between these agencies in terms of terminology, legal recommendations and characterization requirements. This is particularly important for emerging countries such as Brazil. In this sense, some measures can be taken to achieve alignment between regulators.     

Sex,gender, and pharmaceutical politics: From drug development to marketing

Background: Biological sex differences and sociocultural gender norms affect the provision of health care products and services, but there has been little explicit analysis of the impact of sex differences and gender norms on the regulation of pharmaceutical development and marketing.Objectives: This article provides an overview of the regulation of pharmaceuticals and examines the ways that regulatory agencies account for sex and gender in their review of scientific data and marketing materials.Methods: The primary focus is on the US context, but information is also included about regulatory models in Europe, Canada, and Japan for comparative purposes. Specific examples show how sex differences and gender norms influence scientific and policy decisions about pharmaceuticals.Results: The United States and Canada were found to be the only countries that have explicit requirements to include women in clinical trials and to perform sex-based subgroup analysis on study results. The potential influence of politics on regulatory decisions may have led to an uneven application of standards, as seen through the examples of mifepristone (for abortion) and sildenafil citrate (for erectile dysfunction). Three detailed case studies illustrate the importance of considering sex and gender in pharmaceutical development and marketing: Phase I clinical trials; human papillomavirus quadrivalent vaccine; and tegaserod, a drug for irritable bowel syndrome.Conclusions: Sex and gender play important roles in pharmaceutical regulation, from the design of clinical trials and the approval of new drugs to advertising and postmarketing surveillance. However, regulatory agencies pay insufficient attention to both biological sex differences and sociocultural gender norms. This disregard perpetuates inequalities by ignoring drug safety problems that predominate in women and by allowing misleading drug marketing that reinforces gender stereotypes. Recommendations have been made to improve the regulation of pharmaceuticals in regard to sex and gender.     

Nonclinical and quality assessment of cell therapy products: Report on the 4th Asia Partnership Conference of Regenerative Medicine,April 15, 2021

The 4th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 15, 2021, to promote regulatory harmonization of regenerative medicine products throughout Asia. Recognizing domestic regulatory guidelines within each country and region, and their underpinning rationales, is an important initial step toward a convergence of regulations. The 4th APACRM consisted of an open dialog with regulatory agencies regarding nonclinical and quality settings for cell therapy products (CTPs) through industry presentations and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region, and specific regulatory schematics in Japan, were also introduced. The objective of this paper is to summarize the proceedings of the 4th APACRM for public dissemination and to foster further discussion in the future.     

An iterative method to protect the type I error rate in bioequivalence studies under two‐stage adaptive 2×2 crossover designs

Bioequivalence studies are the pivotal clinical trials submitted to regulatory agencies to support the marketing applications of generic drug products. Average bioequivalence (ABE) is used to determine whether the mean values for the pharmacokinetic measures determined after administration of the test and reference products are comparable. Two‐stage 2×2 crossover adaptive designs (TSDs) are becoming increasingly popular because they allow making assumptions on the clinically meaningful treatment effect and a reliable guess for the unknown within‐subject variability. At an interim look, if ABE is not declared with an initial sample size, they allow to increase it depending on the estimated variability and to enroll additional subjects at a second stage, or to stop for futility in case of poor likelihood of bioequivalence. This is crucial because both parameters must clearly be prespecified in protocols, and the strategy agreed with regulatory agencies in advance with emphasis on controlling the overall type I error. We present an iterative method to adjust the significance levels at each stage which preserves the overall type I error for a wide set of scenarios which should include the true unknown variability value. Simulations showed adjusted significance levels higher than 0.0300 in most cases with type I error always below 5%, and with a power of at least 80%. TSDs work particularly well for coefficients of variation below 0.3 which are especially useful due to the balance between the power and the percentage of studies proceeding to stage 2. Our approach might support discussions with regulatory agencies.     

Comparison of regulatory pathways for the approval of advanced therapies in the European Union and the United States

Background aimsRegulatory agencies in the European Union (EU) and in the United States of America (USA) have adapted and launched regulatory pathways to accelerate patient access to innovative therapies, such as advanced therapy medicinal products (ATMPs). The aim of this study is to analyze similarities and differences between regulatory pathways followed by the approved ATMPs in both regions.MethodsA retrospective analysis of the ATMPs approved by EU and US regulatory agencies was carried out until May 31, 2020. Data were collected on the features and timing of orphan drug designation (ODD), scientific advice (SA), expedited program designation (EP), marketing authorization application (MAA) and marketing authorization (MA) for both regions.ResultsIn the EU, a total of fifteen ATMPs were approved (eight gene therapies, three somatic cell therapies, three tissue-engineered products and one combined ATMP), whereas in the USA, a total of nine were approved (five gene therapies and four cell therapies); seven of these were authorized in both regions. No statistical differences were found in the mean time between having the ODD or EP granted and the start of the pivotal clinical trial or MAA in the EU and USA, although the USA required less time for MAA assessment than the EU (mean difference, 5.44, P = 0.012). The MAA assessment was shorter for those products with a PRIME or breakthrough designation.. No differences were found in the percentage of ATMPs with expedited MAA assessment between the EU and the USA (33.3% versus 55.5%, respectively, P = 0.285) or in the time required for the MAA expedited review (mean difference 4.41, P = 0.105). Approximately half of the products in both regions required an Advisory Committee during the MAA review, and 60% required an oral explanation in the EU. More than half of the approved ATMPs (67% and 55.55% in the EU and the USA, respectively) were granted an ODD, 70% by submitting preliminary clinical data in the EU. The mean number of SA and protocol assistance per product conducted by the European Medicines Agency was 1.71 and 3.75, respectively, and only 13% included parallel advice with health technology assessment bodies. A total of 53.33% of the products conducted the first SA after the pivotal clinical study had started, reporting more protocol amendments. Finally, of the seven ATMPs authorized in both regions, the type of MA differed for only two ATMPs (28.6%), and four out of eight products non-commercialized in the USA had a non-standard MA in the EU.ConclusionsThe current approved ATMPs mainly target orphan diseases. Although EU and US regulatory procedures may differ, the main regulatory milestones reached by the approved ATMPs are similar in both regions, with the exception of the time for MAA evaluation, the number of authorized products in the regions and the type of authorization for some products. More global regulatory convergence might further simplify and expedite current ATMP development in these regions.     

Selected carboxymethylation of ferri-hemoglobin from insect larvae Chironomus thummi thummi]

Specific modification of the monomeric fraction III of ferri-hemoglobin from insect larvae Chironomus thummi thummi (Hb CTT) was studied on histidyl residues His-G19 (pK 4,8), His-E5 (pK 7,3) and Met-H22 at different pH using iodacetamide and spin label 2,2,6,6-tetramethyl-4-bromacethyl-piperidin-1-oxyl, an analogue of bromacetate. The analysis of the products of carboxymethylation (CM) showed that at pH 5,0 two products of modification CM-(His-G19)-Hb CTT, and CM-(Met-H22)-Hb CTT were obtained. In the case of modification at pH 7,2 with a spin label dicarboxymethylatid product CM-(His-G19)-CM (His-E5)-Hb CTT is obtained. In all products the degree of modification was one spin label per mole protein. Based on the data on the primery and tertiary structures Hb CTT and the results of the investigation, different reactivity of His-G19 and His-E5, as well as the cause of the absence of the product of carboxymethylation on His-G2 have been discussed. By analizing the absorption spectra of carboxymethylated derivatives of hemoglobin in the ultraviolet and visible region, as well as from the pH dependence curves of the absorption at Soret band in the interval pH 5,5-11,5 it has been shown that carboxymethylation of His-G19 and His E5 is not accompanied by any substantial disturbance of the structures of aquous-complexes Hb CTT. Modification of Met-H22 leads to strong changes in the absorption spectrum and to the absence of pH dependence of the absorption at Soret band, which indicates a change in the aquous-complexes Hb CTT structure.     

The basis for camptothecin enhancement of DNA breakage by eukaryotic topoisomerase I.

The eukaryotic topoisomerase I (topo I) is the target of the cytotoxic alkaloid camptothecin (CTT). In vitro, CTT enhances the breakage of DNA by topo I when the reaction is stopped with detergent. Although breakage at some sites is enhanced to a great extent while breakage at others is enhanced only minimally, CTT does not significantly change the breakage specificity of topo I in vitro. It has been suggested that CTT acts by slowing the reclosure step of the nicking-closing reaction. To test this hypothesis, we have measured the rate of reclosure for different break sites in the presence of CTT after adding 0.5 M NaCl to a standard low salt reaction. In support of the hypothesis, we find that topo I-mediated DNA breakage is enhanced the greatest at those sites where closure of the break is the slowest. These results suggest a mechanism for the toxicity of CTT in vivo.     

Dolly for dinner? Assessing commercial and regulatory trends in cloned livestock

As cloning technologies become more widely established, will products enter the food chain sooner than regulatory agencies and the public might be prepared for?     

Pharmaceuticals in the environment: scientific evidence of risks and its regulation

During the past two decades scientists, regulatory agencies and the European Commission have acknowledged pharmaceuticals to be an emerging environmental problem. In parallel, a regulatory framework for environmental risk assessment (ERA) of pharmaceutical products has been developed. Since the regulatory guidelines came into force the German Federal Agency (UBA) has been evaluating ERAs for human and veterinary pharmaceutical products before they are marketed. The results show that approximately 10% of pharmaceutical products are of note regarding their potential environmental risk. For human medicinal products, hormones, antibiotics, analgesics, antidepressants and antineoplastics indicated an environmental risk. For veterinary products, hormones, antibiotics and parasiticides were most often discussed as being environmentally relevant. These results are in good correlation with the results within the open scientific literature of prioritization approaches for pharmaceuticals in the environment. UBA results revealed that prospective approaches, such as ERA of pharmaceuticals, play an important role in minimizing problems caused by pharmaceuticals in the environment. However, the regulatory ERA framework could be improved by (i) inclusion of the environment in the risk–benefit analysis for human pharmaceuticals, (ii) improvement of risk management options, (iii) generation of data on existing pharmaceuticals, and (iv) improving the availability of ERA data. In addition, more general and integrative steps of regulation, legislation and research have been developed and are presented in this article. In order to minimize the quantity of pharmaceuticals in the environment these should aim to (i) improve the existing legislation for pharmaceuticals, (ii) prioritize pharmaceuticals in the environment and (iii) improve the availability and collection of pharmaceutical data.     

Ethics and biomedical research

Ethics in biomedical research took off from the 1947 Nuremberg Code to its own right in the wake of the Declaration of Helsinki in 1964. Since then, (inter)national regulations and guidelines providing a framework for clinical studies and protection for study participants have been drafted and implemented, while ethics committees and drug evaluation agencies have sprung up throughout the world. These two developments were crucial in bringing about the protection of rights and safety of the participants and harmonization of the conduct of biomedical research. Ethics committees and drug evaluation agencies deliver ethical and scientific assessments on the quality and safety of the projects submitted to them and issue respectively approvals and authorizations to carry out clinical trials, while ensuring that they comply with regulatory requirements, ethical principles, and scientific guidelines. The advent of biomedical ethics, together with the responsible commitment of clinical investigators and of the pharmaceutical industry, has guaranteed respect for the patient, for whom and with whom research is conducted. Just as importantly, it has also ensured that patients reap the benefit of what is the primary objective of biomedical research: greater life expectancy, well-being, and quality of life.     

Compliance and cost control for cryopreservation of cellular starting materials: An industry perspective

Over the last decade, cancer immunotherapy has progressed from an academically interesting field to one of the most promising forms of new treatments in which not the cancer but the immune system is treated. In particular, genetic modification for purposeful redirection of autologous T cells is providing hope to many treatment-resistant patients. This personalized form of medicine is radically different from more traditional oncologic drugs. With these evolving medical advancements and more cellular therapies becoming available, some regulatory agencies have created new regulatory requirements to manage the production of these types of products. The regulations are specifically suited for the manufacture of gene and cell therapy products, as they use a risk-based approach towards product development and manufacturing, when there is limited characterization available. The correct interpretation of how and when requirements apply is crucial, since theoretical approaches to implementing GMP can easily lead to disproportionate and unwarranted restrictions that may not address the specific risks that regulators were intending to control. This is especially relevant for cell collection and biopreservation preceding the manufacturing process for products manufactured from autologous T cells. Both the fresh and cryopreserved apheresis materials can be filed as minimally manipulated starting materials to the authorities. The preservation of such cellular material can then routinely be managed using the available regulations for tissues and cells, allowing for a more fit-for-purpose approach to the control measures implemented.     

Progress in pharmacogenomics and its promise for medicine

Pharmacogenomics addresses the impacts of diverse and multiple genes in populations as determinants of responses of individual patients to drugs. The field has its roots in basic science, and is pivotal in drug development, elucidation of therapeutic efficacy, and constraining the risks of adverse drug reactions. Regulatory agencies are relying increasingly on pharmacogenomics for identification of patients who are particularly likely to benefit from treatment with specific agents and exclusion of those at risk of adverse drug reactions. Practical applications of pharmacogenomics already abound particularly in the use of drugs acting on the central nervous system and on the cardiovascular system. The Society for Experimental Biology and Medicine (SEBM) is proud and pleased to have devoted its 2008 symposium, presented at the annual Experimental Biology meeting in San Diego on April 6, 2008, to advances in pharmacogenomics with emphasis on drug development, regulatory agency considerations, and clinical applications.     

Pharmacogenetic issues in thorough QT trials

Drug-induced QT prolongation (DI-LQT), through its associated arrhythmias, is a leading cause of drugs being withdrawn from the market. As a consequence, the US FDA and other regulatory agencies are mandating that all new drugs go through a so-called 'Thorough QT' (TQT) study to evaluate the potential for 'QT liability', specifically the potential for a drug to cause a discernible increase in the QT interval. Several genetic factors that modulate the risk of DI-LQT have been discovered. These are genes responsible for the congenital long QT syndrome, drug metabolism genes (mainly CYP2D6 and CYP3A4), and genes in other regulatory pathways. Here, we briefly review the links between genetic variants and drug-induced QT risk, and propose approaches to consider for using pharmacogenetics in planning and analyzing TQT studies.     

Pharma-Planta: road testing the developing regulatory guidelines for plant-made pharmaceuticals

Significant advances over the last few years have seen plant-made pharmaceuticals (PMPs) move from the exploratory research phase towards clinical trials, with the first commercial products for human use expected to reach the market by 2009. Europe has yet to witness the commercial application of PMP technology, although at least one product has begun phase II clinical trials with others following close behind. These emerging products are set to challenge the complex and overlapping regulations that currently govern GM plants and ‘conventional’ pharmaceutical production. The areas of responsibility are being mapped out between the different EU regulatory agencies, with specific guidelines currently being drawn up for the regulation of PMPs. This article discusses issues surrounding the development of robust risk-assessment and risk-management practices based on health and environmental impact, while working with EU regulatory authorities to ensure appropriate regulatory oversight.     

Functional multiplicity and structural correlations in the hemoglobin system of larvae of Chironomus thummi thummi (Insecta, Diptera): Hb components CTT I, CTT II beta, CTT III, CTT IV, CTT VI, CTT VIIB, CTT IX and CTT X

Larvae of the dipteran insect Chironomus thummi thummi that burrow in fresh-water muds, contain at least 12 hemoglobin (Hb) components of which the functional properties have not been systematically documented, although their amino acid sequences have been elucidated, showing mutually distinct primary structures. We isolated eight components (the monomeric Hbs CTT I, CTT III and CTT IV and the dimeric Hbs CTT II beta, CTT VI, CTT VIIB, CTT IX and CTT X) and measured in each O2 affinity and cooperativity and their pH dependence, and the effects of temperature, NaCl and ATP. The O2 affinities, Bohr- and temperature effects of the isohemoglobins are discussed in relation to mode of life and the microenvironmental conditions to which the larvae are subjected in nature, and with regard to the molecular mechanisms underlying the Hb-oxygenation reactions.     

The changing landscape of data monitoring committees—Perspectives from regulators,members, and sponsors

Data Monitoring Committees (DMCs) are an integral part of clinical drug development. Their use has evolved along with changing study designs and regulatory expectations, which has associated statistical and ethical implications. Although there is guidance from the different regulatory agencies, there are opportunities to bring more consistency to address practical issues of establishing and operating a DMC. Challenging issues include defining the scope of DMC decisions, the regulatory requirements and expectations, the perceived independence of DMCs, the specific focus primarily on safety, etc. Wider use of adaptive clinical trial designs in recent years introduce additional challenges in terms of trial governance and the complexity of DMC activities. A panel comprised of clinical and statistical experts from across academia, industry, and regulatory agencies shared their experience and thoughts on the importance of these aspects and offered perspectives on the future of the DMCs. This paper documents the thinking from the panel session at the CEN‐ISBS conference held in Vienna, Austria, 2017.