Non-biological Complex Drugs Research Articles

Differences between intravenous iron products: focus on treatment of iron deficiency in chronic heart failure patients.

Iron deficiency is the leading cause of anaemia and is highly prevalent in patients with chronic heart failure (CHF). Iron deficiency, with or without anaemia, can be corrected with intravenous (i.v.) iron therapy. In heart failure patients, iron status screening, diagnosis, and treatment of iron deficiency with ferric carboxymaltose are recommended by the 2016 European Society of Cardiology guidelines, based on results of two randomized controlled trials in CHF patients with iron deficiency. All i.v. iron complexes consist of a polynuclear Fe(III)‐oxyhydroxide/oxide core that is stabilized with a compound‐specific carbohydrate, which strongly influences their physico‐chemical properties (e.g. molecular weight distribution, complex stability, and labile iron content). Thus, the carbohydrate determines the metabolic fate of the complex, affecting its pharmacokinetic/pharmacodynamic profile and interactions with the innate immune system. Accordingly, i.v. iron products belong to the new class of non‐biological complex drugs for which regulatory authorities recognized the need for more detailed characterization by orthogonal methods, particularly when assessing generic/follow‐on products. Evaluation of published clinical and non‐clinical studies with different i.v. iron products in this review suggests that study results obtained with one i.v. iron product should not be assumed to be equivalent to other i.v. iron products that lack comparable study data in CHF. Without head‐to‐head clinical studies proving the therapeutic equivalence of other i.v. iron products with ferric carboxymaltose, in the highly vulnerable population of heart failure patients, extrapolation of results and substitution with a different i.v. iron product is not recommended.

Snapshots of Iron Speciation: Tracking the Fate of Iron Nanoparticle Drugs via a Liquid Chromatography-Inductively Coupled Plasma-Mass Spectrometric Approach.

Nanomedicines are nanoparticle-based therapeutic or diagnostic agents designed for targeted delivery or enhanced stability. Nanotechnology has been successfully employed to develop various drug formulations with improved pharmacokinetic characteristics, and current research efforts are focused on the development of new innovator and generic nanomedicines. Nanomedicines, which are often denoted as complex or nonbiological complex drugs, have inherently different physicochemical and pharmacokinetic properties than conventional small molecule drugs. The tools necessary to fully evaluate nanomedicines in clinical settings are limited, which can hamper their development. One of the most successful families of nanomedicines are iron-carbohydrate nanoparticles, which are administered intravenously (IV) to treat iron-deficiency anemia. In the U.S., the FDA has approved six distinct iron-carbohydrate nanoparticles but only one generic version (sodium ferric gluconate for Ferrlecit). There is significant interest in approving additional generic iron-carbohydrate drugs; however, the lack of a direct method to monitor the fate of the iron nanoparticles in clinical samples has impeded this approval. Herein we report a novel liquid chromatography-inductively coupled plasma-mass spectrometry (LC-ICP-MS) method that allows for the direct quantification of the iron-carbohydrate drugs in clinical samples, while simultaneously measuring the speciation of the iron released from the nanoparticles in biological samples. To our knowledge, this is the first time that iron nanoparticles have been observed in clinical samples, opening the door for direct pharmacokinetic studies of this family of drugs. This method has potential applications not only for iron-nanoparticle drugs but also for any nanomedicine with an inorganic component.

Non-Biological Complex Drugs

Non-Biological Complex Drugs

Izazovi in vitro karakterizacije nebioloških kompleksnih lekova - primer parenteralnih preparata sa liposomskim nosačima lekovitih supstanci

Izazovi in vitro karakterizacije nebioloških kompleksnih lekova - primer parenteralnih preparata sa liposomskim nosačima lekovitih supstanci

Multiple Sclerosis: A Global Concern with Multiple Challenges in an Era of Advanced Therapeutic Complex Molecules and Biological Medicines.

Multiple sclerosis (MS) has become a common neurological disorder involving populations previously considered to be infrequently affected. Genetic dissemination from high- to low-risk groups is a determining influence interacting with environmental and epigenetic factors, mostly unidentified. Disease modifying therapies (DMT) are effective in treating relapsing MS in variable degrees; one agent is approved for primary progressive disease, and several are in development. In the era of high-efficacy medications, complex molecules, and monoclonal antibodies (MAB), including anti-VLA4 (natalizumab), anti-CD52 (alemtuzumab), and anti-CD20 (ocrelizumab), obtaining NEDA (no evidence of disease activity) becomes an elusive accomplishment in areas of the world where access to MS therapies and care are generally limited. Countries’ income and access to public MS care appear to be a shared socioeconomic challenge. This disparity is also notable in the utilization of diagnostic tools to adhere to the proposed elements of the McDonald Criteria. The impact of follow-on medications (“generics”); injectable non-biological complex drugs (NBCD), oral sphingosine-1-phosphate receptor modulators, and biosimilars (interferon 1-a and 1-b), utilized in many areas of the world, is disconcerting considering these products generally lack data documenting their efficacy and safety. Potential strategies addressing these concerns are discussed from an international point of view.

Regulatory challenges of nanomedicines and their follow-on versions: A generic or similar approach?

Nanomedicines and follow-on versions (also called nanosimilars in the EU) have been on the market partially for decades although without recognition of their nano properties in the beginning; a substantial number is in clinical development. Nanomedicines are typically synthetic and belong to the non-biological complex drugs. They show a high variability in form, structure, and size. Additionally large molecule biologics show nano-characteristics meaning nano-dimension in size (1-100 nm) or specific properties related to these dimensions. The high complexity of nanomedicines with their heterogeneous structures do not allow a full physicochemical quality characterization, challenging the regulatory evaluation especially for follow-on versions upon comparison with the reference product. The generic paradigm with the sameness approach for quality and bioequivalence in blood plasma is not appropriate for nanomedicines where a similar approach is needed. After experiencing non-equivalence of authorized parenteral colloidal iron follow-on versions, EMA and FDA issued reflection papers and draft guidances for industry to present their current thinking on the evaluation of such complex products. A stepwise approach to evaluate the extent of similarity, from quality, including critical quality attributes (CQA) and assessment of nano properties, to a non-clinical biodistribution assay, required in the the EU but not in the US, and to clinical evaluation makes sense. The cumulated totality of evidence for the authorization of nanomedicine follow-on versions goes case-by-case. Interchangeability, or substitutability, is a challenge. However, a defined or even harmonized approval pathway for these follow-versions is still missing and causes potential differences in approval. To progress, a science-based discussion platform among stakeholders and experts in the field is necessary. An agenda has been agreed [5], namely CQA assessment, publication of scientific and clinical findings, consensus on nomenclature and labelling, and regulatory actions on substandard complex drug products. Consensus created in a public private approach will support progress towards a defined and harmonized regulatory pathway for nanomedicines and their follow-on versions. This will provide drug innovation but also larger access to follow-on versions of nanomedicines, both a benefit for the patient.

Physicochemical, biological, functional and toxicological characterization of the European follow-on glatiramer acetate product as compared with Copaxone.

For more than 20 years, Copaxone (glatiramer acetate, Teva), a non-biological complex drug, has been a safe and effective treatment option for multiple sclerosis. In 2016, a follow-on glatiramer acetate product (FOGA, Synthon) was approved in the EU. Traditional bulk-based methods and high-resolution assays were employed to evaluate the physicochemical, functional, and bio-recognition attributes, as well as the in vivo toxicity profile of the active substances in Copaxone and Synthon EU FOGA lots. These tests included quality control tests applied routinely in release of Copaxone lots, as well as additional characterization assays, gene expression studies and a rat toxicity study. Even though the Synthon FOGA was designed to copy and compete with Copaxone, the active substances were found to be similar in only 7 of the tested 14 (50%) methods (similar is defined as within approved specifications or within the inherent microheterogeneity range of tested Copaxone batches, or not showing statistically significant differences). With additional methods applied, consistent compositional differences in attributes of surface charge distribution, molecular size, and spatial arrangement were observed. These marked differences were concordantly observed with higher biological activity of some of the Synthon EU FOGA lots compared with Copaxone lots, including potency and cytotoxicity activities as well as gene expression of pathways that regulate apoptosis, IL-2, and inflammation signaling. These observations raise concerns for immunogenicity differences, particularly in (repeated) substitution settings. Another orthogonal finding demonstrated increased frequency of injection-site local toxicity observations for the Synthon EU FOGA in an in vivo daily dosing rat study, thus warranting further qualification of the link between compositional and functional differences in immunogenicity, and potential impact on long-term efficacy and safety.

NON-BIOLOGICAL COMPLEX DRUGS CONCEPT IN GENERIC DRUGS DEVELOPMENT

Expansion of the range of new medicines leads to a significant increase in healthcare spending and, consequently, to the appearance of more affordable generic drugs. A drug can be recognised as generic if there is sufficient evidence of equivalent structural characteristics of the active substance and therapeutic characteristics of the drug. However, for a number of substances which are multicomponent mixtures of sister compounds it is quite difficult to demonstrate absolute similarity of the chemical structure and to determine a substrate for bioavailability evaluation. Therefore, a separate group of non-biological complex drugs has been singled out. The present article summarises the requirements of the leading regulatory agencies for demonstration of equivalence between the reference product and such medicines as glatiramoids, liposome-encapsulated doxorubicin and iron-based nanosized colloidal products. It has been shown that preclinical and clinical studies are still necessary for these types of products, and the amount of testing will depend on the results of comparability assessment.

Updated Regulatory Considerations for Nanomedicines.

Nanomedicine is a branch which deals with medicinal products, devices, nonbiological complex drugs and antibody-nanoparticle conjugates and general health products that are manufactured using nanotechnology. Nano-medicine provides the same efficacies as traditional medicines owing to their improved solubility and bioavailability with reduced dosages. However, there are currently safety concerns due to the difficulties related to nanomaterial characterization; this might be the reason for unawareness of such medicines among the patients. The absence of clear regulatory guidelines further complicates matters, as it makes the path to registering them with regulatory bodies difficult. However, some products have overcome these obstacles and have been registered. While there are many international initiatives to harmonize the regulatory requirements and helps the industry to determine the most important characteristics that influence in vivo product performance. This review focuses on the various types of nanopharmaceuticals, and developments process with strategies tailored to upcoming regulations may satisfy the patients' needs.

Comment on the non-biological complex drugs paper

Comment on the non-biological complex drugs paper

An overview of biosimilars and non-biologic complex drugs in Europe, the United States, and Canada and their relevance to multiple sclerosis

The advent of biological medicines has significantly transformed the landscapes of many disease spaces and improved the lives of millions around the world. However, the structural complexity and sensitivity of such products result in a high price tag, adding to already financially strained healthcare systems. As these and other expensive complex drugs lose market exclusivity, stakeholders eagerly await the arrival of lower cost alternatives, such as biosimilars and subsequent entry non-biological complex drugs (NBCDs). Nevertheless, stakeholders remain uncertain about key issues which have resulted in heterogeneous reimbursement policies and varying levels of biosimilar uptake and subsequent entry NBCD approval processes between different markets. With the imminent introduction of both subsequent entry NBCDs and biosimilars for multiple sclerosis (MS), it is important to get a better understanding of this new class of products and how healthcare systems have been adapting to their use. This article defines biosimilars and subsequent entry NBCDs and provides an overview of how these products have been introduced in Europe, the United States, and Canada from a regulatory, health technology, and reimbursement perspective. In addition, this article briefly explores the potential impact and outlook of biosimilar and NBCD products related to MS.

Cardiovascular, liver, and renal toxicity associated with an intravenous ferric carboxymaltose similar versus the originator compound.

BackgroundFerric carboxymaltose (FCM) is a stable, non-dextran-based intravenous iron complex used to treat iron deficiency of various etiologies. As FCM is a nonbiological complex drug and cannot be fully characterized by physicochemical analyses, it is important to demonstrate in nonclinical models that FCM similars (FCMS) have similar biodistribution.Materials and methodsA total of 30 nonanemic rats were treated weekly with 40 mg iron/kg body weight intravenous FCM, FCMS, or isotonic saline (controls) for 4 weeks. Blood pressure, liver enzymes, and renal function were evaluated. In liver, heart, and kidney tissue, markers for oxidative stress (malondialdehyde to assess lipid peroxidation and antioxidant enzymes) and inflammation (TNFα and IL6) were measured. Iron deposits were localized.ResultsThe FCMS-treated group had significantly lower blood pressure, higher liver enzymes, increased proteinuria, and reduced creatinine clearance versus the FCM and control groups by day 29. Serum iron and transferrin saturation were significantly higher with FCMS versus FCM or controls. Iron deposition was altered in FCMS-treated animals, with decreased ferritin deposits and iron deposition outside the physiological storage compartments. Markers for lipid peroxidation and antioxidant-enzyme activity were significantly increased after FCMS administration versus FCM and controls, as were inflammatory markers.ConclusionResults from this blinded nonclinical study demonstrated significant differences between the originator FCM and this FCMS.

Equivalence and regulatory approaches of nonbiological complex drug products across the United States, the European Union, and Turkey.

Regulatory agencies around the world may have different standards and approaches to evaluate and approve drug products and biological products. We describe the U.S. Food and Drug Administration's (FDA) Generic Drug User Fee Act program, as well as their approach to complex products. We discuss regulatory approaches for the development of nonbiological complex drug follow-ons and approval pathways in the United States. We compare FDA policies with other regulatory agencies (i.e., the European Medicines Agency and the Turkish Medicines and Medical Devices Agency). In particular, we describe the policies/pathways across these three agencies to assess equivalence of glatiramer acetate, enoxaparin sodium, and sodium ferric gluconate complex products. We also examine the Turkish market for these selected nonbiological complex drugs.

Compositional differences between Copaxone and Glatopa are reflected in altered immunomodulation ex vivo in a mouse model.

Copaxone (glatiramer acetate, GA), a structurally and compositionally complex polypeptide nonbiological drug, is an effective treatment for multiple sclerosis, with a well-established favorable safety profile. The short antigenic polypeptide sequences comprising therapeutically active epitopes in GA cannot be deciphered with state-of-the-art methods; and GA has no measurable pharmacokinetic profile and no validated pharmacodynamic markers. The study reported herein describes the use of orthogonal standard and high-resolution physicochemical and biological tests to characterize GA and a U.S. Food and Drug Administration-approved generic version of GA, Glatopa (USA-FoGA). While similarities were observed with low-resolution or destructive tests, differences between GA and USA-FoGA were measured with high-resolution methods applied to an intact mixture, including variations in surface charge and a unique, high-molecular-weight, hydrophobic polypeptide population observed only in some USA-FoGA lots. Consistent with published reports that modifications in physicochemical attributes alter immune-related processes, genome-wide expression profiles of ex vivo activated splenocytes from mice immunized with either GA or USA-FoGA showed that 7-11% of modulated genes were differentially expressed and enriched for immune-related pathways. Thus, differences between USA-FoGA and GA may include variations in antigenic epitopes that differentially activate immune responses. We propose that the assays reported herein should be considered during the regulatory assessment process for nonbiological complex drugs such as GA.

How to select a nanosimilar

Nanomedicines in the class of nonbiological complex drugs (NBCDs) are becoming increasingly available. Up to 23 nanomedicines have been approved, and approximately 50 are in clinical development. Meanwhile, the first nanosimilars have entered the market through the generic approval pathway, but clinical differences have been observed. Many healthcare professionals may be unaware of this issue and must be informed of these clinically relevant variances. This article provides a tool for rational decision making for the inclusion of nanomedicines into the hospital formulary, including defined criteria for evaluation of substitutability or interchangeability. The tool was generated by conducting a roundtable with an international panel of experts and follows the same thought process that was developed and published earlier for the selection of biologicals/biosimilars. In addition to the existing criteria for biosimilars, a set of seven criteria was identified that specifically apply to nanosimilars. These include (1) particle size and size distribution, (2) particle surface characteristics, (3) fraction of uncaptured bioactive moiety, (4) stability on storage, (5) bioactive moiety uptake and (6) distribution, and (7) stability for ready-to-use preparation. Pharmacists should utilize their pharmaceutical expertise to use the appropriate criteria to evaluate the comparability of the drug to decide on interchangeability or substitutability.

Equivalence of complex drug products: advances in and challenges for current regulatory frameworks

Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified.

Ocular emulsions and dry eye: a case study of a non-biological complex drug product delivered to a complex organ to treat a complex disease

Ocular emulsions and dry eye: a case study of a non-biological complex drug product delivered to a complex organ to treat a complex disease

Medication practice in hospitals: are nanosimilars evaluated and substituted correctly?

IntroductionThis study investigates the drug selection and dispensing behaviour of hospital pharmacists of intravenous iron products including iron sucrose and iron sucrose similar, with special emphasis on substitution and interchangeability...

The role of thromboxane A2 in complement activation-related pseudoallergy

AbstractComplement activation-related pseudoallergy (CARPA) is a hypersensitivity reaction occurring upon intravenous administration of numerous liposomal therapeutics, other nonbiological complex drugs and biologicals. It has a complex molecular and cellular mechanism that involves the production, actions and interactions of numerous vasoactive mediators in blood, including thromboxane A

Воспроизведенные лекарственные средства и особенности их регулирования

The article discusses the factors that influence the efficacy and safety of generic drugs, including regular generics, biosimilars, and generic nonbiological complex drugs. It emphasizes the importance of adequate regulatory requirements to provide a comparable therapeutic efficacy and a comparable cost-effectiveness ratio for generics versus brand-name drugs.