Safety Concerns in Neurological Clinical Trials: A Challenge That the FDA Must Resolve.

Monoclonal antibodies approved by the FDA, lecanemab, donanemab, and aducanumab, are failing to meet the expected efficacy to treat early Alzheimer's disease, and aducanumab has been recalled. : Recently, it was reported that the clinical trials of these antibodies may have violated patient's rights and subjected them to high, likely lethal risk. The challenge with developing antibodies to treat neurological disorders is their poor blood-brain barrier (BBB) penetration if the antibody must enter the brain, resulting in almost negligible brain bioavailability, requiring high dosing that can be toxic.

MicroRNA Nobel Prize: Timely Recognition and High Anticipation of Future Products-A Prospective Analysis.

MicroRNAs (miRNAs) maintain cellular homeostasis by blocking mRNAs by binding with them to fine-tune the expression of genes across numerous biological pathways. The 2024 Nobel Prize in Medicine and Physiology for discovering miRNAs was long overdue. We anticipate a deluge of research work involving miRNAs to repeat the history of prizes awarded for research on other RNAs.

Advancing Therapeutic and Vaccine Proteins: Switching from Recombinant to Ribosomal Delivery-A Humanitarian Cause.

Recombinant therapeutic and vaccine proteins have revolutionized healthcare, but there remain challenges, as many are awaiting development due to their slow development speed and high development cost. Cell-free in vivo ribosomes offer one choice, but they come with similar constraints. The validation of in vivo messenger RNA (mRNA) technology has been accomplished for COVID-19 vaccines.

Advice to the FDA to Improve Its Proposed Guidelines to Rationalize Clinical Trials by Restricting Placebo Control, Preventing Low-Powered Studies, and Disallowing Studies Where Bioavailability Is Not Proven.

Randomized controlled trials (RCTs) are the gold standard for testing the safety and efficacy of new drugs and biologicals. The US Food and Drug Administration (FDA) has proactively improved the trial designs to make them scientifically rational while avoiding unnecessary human exposure. Several new guidelines by the FDA have come in 2024 that address consolidating the RCTs with the Real-World Evidence (RWE) trials, decentralizing the testing platforms, and allowing the point-of-use clinicians to participate.

Placebo Effects: Neurological Mechanisms Inducing Physiological, Organic, and Belief Responses-A Prospective Analysis.

The placebo effect can induce physiological or clinical neurological and organic responses despite the recipient receiving no active ingredients; these responses are based instead on the recipient's perceptions. Placebo effects come from the rostral anterior cingulate cortex, pontine nucleus, and cerebellum of the brain; this information provides a better understanding of placebo effects and can also help us understand the mechanism of the modulation of neurotransmitters from the use of psychedelic substances, activity of selective serotonin reuptake inhibitors, the process of transcranial magnetic stimulation, and deep brain stimulation, as well as aid in developing novel therapies, challenging the validity of controlled clinical trials (RCTs) that the regulatory agencies now appreciate. Education about how placebo effects bring in social, political, and religious beliefs and whether these can be modulated may help reduce global confrontations.

Lectin-Based Fluorescent Comparison of Glycan Profile-FDA Validation to Expedite Approval of Biosimilars.

Glycan profile comparisons are one of the most tedious analytical exercises for establishing compliance with recombinant therapeutic protein batches. Based on its intensive research, the FDA has confirmed that lectin array binding with fluorescent monitoring is the fastest and most reliable method for profile comparisons. Using a database of over 150 biological products expressed in nine diverse mammalian cell systems, the FDA immobilized 74 lectins to study their binding using fluorescently labeled glycoproteins.

Advice to the US FDA to Allow US Pharmacopeia to Create Biological Product Specifications (BPS) to Remove Side-by-Side Analytical Comparisons of Biosimilars with Reference Products.

Pharmacopeia monographs are not intended to establish biosimilarity. However, the US Food and Drug Administration (FDA) has stopped the US Pharmacopeia (USP) from creating monographs for biological drugs due to the need for side-by-side comparisons with the reference products. The USP can create Biological Product Specifications (BPS), not to be labeled as monographs, based on the analytical testing of reference products and validated test methods that will remove the need for side-by-side analytical testing of biosimilars with reference products.

The United States Food and Drug Administration's Platform Technology Designation to Expedite the Development of Drugs.

Drug development costs can be significantly reduced if proven "platform" technologies are allowed to be used without having to validate their use. The most recent US Food and Drug Administration (FDA) guideline brings more clarity, as well as a greater focus on the most complex technologies that can now be used for faster drug development. The FDA has highlights the use of lipid nanoparticles (LNPs) to package and deliver mRNA vaccines, gene therapy, and short (2-20 length) synthetic nucleotides (siRNA).

Innovative Therapeutic Strategies in Alzheimer's Disease: A Synergistic Approach to Neurodegenerative Disorders.

Alzheimer's disease (AD) remains a significant challenge in the field of neurodegenerative disorders, even nearly a century after its discovery, due to the elusive nature of its causes. The development of drugs that target multiple aspects of the disease has emerged as a promising strategy to address the complexities of AD and related conditions. The immune system's role, particularly in AD, has gained considerable interest, with nanobodies representing a new frontier in biomedical research.

Anti-Idiotypic mRNA Vaccine to Treat Autoimmune Disorders.

The 80+ existing autoimmune disorders (ADs) affect billions with little prevention or treatment options, except for temporary symptomatic management, leading to enormous human suffering and a monumental financial burden. The autoantibodies formed in most ADs have been identified, allowing the development of novel anti-idiotypic antibodies to mute the autoantibodies using vaccines. Nucleoside vaccines have been successfully tested as antigen-specific immunotherapies (ASI), with mRNA technology offering multi-epitope targeting to mute multiple autoantibodies.

Computer-Aided Drug Design and Drug Discovery: A Prospective Analysis.

In the dynamic landscape of drug discovery, Computer-Aided Drug Design (CADD) emerges as a transformative force, bridging the realms of biology and technology. This paper overviews CADDs historical evolution, categorization into structure-based and ligand-based approaches, and its crucial role in rationalizing and expediting drug discovery. As CADD advances, incorporating diverse biological data and ensuring data privacy become paramount.

Glucagon-like peptide agonists: A prospective review.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising therapeutic options for addressing Type-2 diabetes, obesity, and related conditions. Among these, semaglutide, tirzepatide, liraglutide etc., all notable GLP-1RA, have gained attention owing to their favourable pharmacological properties and clinical efficacy.

Non-Invasive Drug Delivery across the Blood-Brain Barrier: A Prospective Analysis.

Non-invasive drug delivery across the blood-brain barrier (BBB) represents a significant advancement in treating neurological diseases. The BBB is a tightly packed layer of endothelial cells that shields the brain from harmful substances in the blood, allowing necessary nutrients to pass through. It is a highly selective barrier, which poses a challenge to delivering therapeutic agents into the brain.

A Critical Analysis of the FDA's Omics-Driven Pharmacodynamic Biomarkers to Establish Biosimilarity.

Demonstrating biosimilarity entails comprehensive analytical assessment, clinical pharmacology profiling, and efficacy testing in patients for at least one medical indication, as required by the U.S. Biologics Price Competition and Innovation Act (BPCIA).

The FDA's New Guideline "Generally Accepted Scientific Knowledge" (GASK): An Opportunity to Expedite the Approval of Biosimilars.

The US FDA's new guideline suggests using "Generally Accepted Science Knowledge" (GASK) to develop nonclinical testing protocols for developing drugs and biologicals to remove unnecessary testing. Interpreting acceptable scientific knowledge as a rational approach has motivated the author to suggest substantial changes to the development of biosimilars, as demonstrated in this paper. The FDA can accept these suggestions without requiring any legislative change to the Act that defines such requirements.

The Coming of Age of AI/ML in Drug Discovery, Development, Clinical Testing, and Manufacturing: The FDA Perspectives.

Artificial intelligence (AI) and machine learning (ML) represent significant advancements in computing, building on technologies that humanity has developed over millions of years-from the abacus to quantum computers. These tools have reached a pivotal moment in their development. In 2021 alone, the U.

Recent Advances in Machine-Learning-Based Chemoinformatics: A Comprehensive Review.

In modern drug discovery, the combination of chemoinformatics and quantitative structure-activity relationship (QSAR) modeling has emerged as a formidable alliance, enabling researchers to harness the vast potential of machine learning (ML) techniques for predictive molecular design and analysis. This review delves into the fundamental aspects of chemoinformatics, elucidating the intricate nature of chemical data and the crucial role of molecular descriptors in unveiling the underlying molecular properties. Molecular descriptors, including 2D fingerprints and topological indices, in conjunction with the structure-activity relationships (SARs), are pivotal in unlocking the pathway to small-molecule drug discovery.

A Proposed Global Medicines Agency (GMA) to Make Biological Drugs Accessible: Starting with the League of Arab States.

Medical anthropology teaches us of historical disparity in the accessibility of medicines in the developing world due to their lack of availability and affordability, more particularly of biological drugs, including therapeutic proteins, gene therapy, CRISPR-Cas9, mRNA therapeutics, CART therapy, and many more. This challenge can be resolved by establishing an independent regulatory agency, proposed as the Global Medicines Agency (GMA), with a charter to allow originators from the Stringent Regulatory Agency (SRA) countries to receive immediate registrations applicable to all member states, expanding the market potential as an incentive. For non-SRA countries, it will be limited to biological drugs that are allowed their copies to be made, only biosimilars.

RNA Therapeutics: A Healthcare Paradigm Shift.

COVID-19 brought about the mRNA vaccine and a paradigm shift to a new mode of treating and preventing diseases. Synthetic RNA products are a low-cost solution based on a novel method of using nucleosides to act as an innate medicine factory with unlimited therapeutic possibilities. In addition to the common perception of vaccines preventing infections, the newer applications of RNA therapies include preventing autoimmune disorders, such as diabetes, Parkinson's disease, Alzheimer's disease, and Down syndrome; now, we can deliver monoclonal antibodies, hormones, cytokines, and other complex proteins, reducing the manufacturing hurdles associated with these products.

Biosimilars Adoption: Recognizing and Removing the RoadBlocks.

Almost two decades since biosimilars arrived, we still await their broader adoption, as anticipated. The roadblocks to this adoption include the high amortized cost of goods due to regulatory burden, hurdles created by the distribution system, perception of safety and efficacy, and lack of focus by stakeholders on removing these roadblocks. In this paper, I analyze the source of these roadblocks and offer practical solutions to remove them.

Proposal of International Council for Harmonization (ICH) Guideline for the Approval of Biosimilars.

Objectives: Since the initial release of biosimilars 18 years ago, regulations for their licensing have changed considerably; however, there is no global consensus on these regulations. Establishing harmonized regulatory guidelines for the approval of biosimilars with support from the ICH, an independent, non-profit association under Swiss law, will significantly enhance the affordability of biological drugs.

Methods: Regulatory guidelines from the Food and Drug Administration (FDA), European Medicines Agency (EMA), Medicines and Healthcare products Regulatory Agency (MHRA), and World Health Organization (WHO) were analyzed for historical changes and elements critical to the safety and efficacy of biosimilars.