Biological drugs are inaccessible to more than 80% of the world population due mainly to their high costs; this is a significant concern of the World Health Organization. Biosimilars are supposed to reduce the cost burden, but their approval process is complex, including expensive and irrelevant studies. While the Stringent Regulatory Authorities (SRAs) have adopted the guidance of the FDA or EMA, such adoptions are neither necessary nor practical for the rest of the world (ROW). We present a science-driven, rational approach to formulate regulatory guidelines that will enable faster biosimilars' entry into the ROW without compromising their safety and efficacy. The key recommendations include removing animal and safety efficacy testing, making analytical assessment more robust, and cGMP compliance assured through third-party audits. The ROW countries are also recommended to initiate a rapporteur system available in the EU, to overcome the biases and assure state-of-the-science evaluation as the common understanding of the critical quality attributes evolves. It is anticipated that stronger regional agencies like those in the MENA region, with the leadership of the Kingdom of Saudi Arabia, will help propel the idea faster across the globe.

Demonstrating biosimilarity entails comprehensive analytical evaluations, clinical pharmacolo-gy profiling, and efficacy testing for at least one medical indication in patients. These require-ments are stipulated by the U.S. Biologics Price Competition and Innovation Act (BPCIA). The costliest element—efficacy testing—can be waived if other compliance benchmarks are satisfied, including comparing functional pharmacodynamic (PD) biomarkers, even when they do not di-rectly correlate with clinical outcomes. Most biological drugs, such as monoclonal antibodies (mAbs), lack identifiable PD biomarkers. The FDA has employed various 'omics' technologies to identify potential PD biomarkers, including proteomics, glycomics, transcriptomics, genomics, epigenomics, and metabolomics. Although these efforts provide a robust scientific basis for estab-lishing biosimilarity, they are neither practical nor necessarily superior to existing functional biomarkers, such as receptor binding and mode-of-action outcomes. As we report for the first time, these functional biomarkers can effectively serve as PD indicators for all FDA-licensed bio-logical drugs. We recommend that the FDA consider officially listing these functional biomarkers to expedite and reduce the cost of biosimilar development, thereby increasing the accessibility of biological drugs. PD surrogates, like the receptor binding and pharmacokinetic profiles, are more robust and offer a rational solution to finding PD markers to compare for establishing biosimi-larity.

Additionally, the League’s four observing states, with an additional population of 1.7 billion, if join the group, will form the world’s largest consortium to enhance the accessibility of biotechnology drugs. This effort will also remove the criticism of regulatory agencies that are well-equipped to regulate these products. This should also be a significant economic incentive to consortium states to develop these products, particularly biosimilars, to capture the most critical market anticipated. This plan will also reduce the cost burden on regulatory agencies. The program is divided into two classifications; for products sold in any of the Stringent Regulatory Authority (SRA) states, the registration is automatic but with several requirements that assure ongoing pharmacovigilance; this also applies to copies of reference products or biosimilars. For non-SRA sourcing, a stepwise plan requiring a rapporteur review, as practiced by the EMA and a third-party cGMP audit, is necessary to ensure data and product integrity. However, to reduce the cost burden, approval of these products is based on current scientific findings as presented in this paper.

The FDA has concluded that a biosimilar candidate capable of demonstrating pharmacodynamic biomarkers in a healthy subject need not be tested for clinical efficacy in patients, regardless of if the biomarker correlates with clinical response. Since monoclonal antibodies (mAbs) do not trig-ger pharmacodynamic response, they can be substituted with robust functional disqualifying them for this waiver that can be overcome by allowing comparison of functional properties that eventually result in clinical response. This suggestion is based on the FDA's preference for more sensitive testing methods. However, clinical efficacy testing in patients is the least sensitive method, as confirmed by statistical modeling, a fact that regulatory agencies need to admit. In this paper, I present a logical and rational argument to establish the biosimilarity of products that do not have pharmacodynamic biomarkers based on their orthogonally proven functional bio-similarity. This understanding will significantly lower the development cost of biosimilars, a goal that the FDA outlined in all its guidance. Keywords: biosimilarity 1; biosimilars 2; pharmacodynamic biomarkers 3; monoclonal antibodies 4; FDA 5; clinical efficacy testing in healthy subjects 6; clinical efficacy testing in patients 7; functional assays 8; receptor binding 9.

While biologic originators’ patents are expiring, biosimilars are emerging to take their place, offering significant cost savings to healthcare systems. Many challenges still need to be addressed in the clinical practice of inflammatory bowel disease (IBD). A global survey was organized to highlight physicians’ current knowledge and beliefs and to gain insight about their practical management and remaining concerns and obstacles associated with starting a biosimilar, switching from an originator to a biosimilar, or switching from one biosimilar to another (multiple switches and reverse switching). Fifteen physicians with expertise in the field of IBD from 13 countries attended a virtual international consensus meeting to develop practical guidance regarding biosimilar adoption worldwide, considering the survey results. Consensus was reached on 10 statements regarding biosimilar effectiveness, safety, indications and rationale, multiple switches, therapeutic drug monitoring of biosimilars, non-medical switching and future perspectives.

The binding activity of various trastuzumab biosimilars versus the branded trastuzumab towards the glycosylated extracellular domain of the HER2 target in the presence of pertuzumab was in-vestigated. We employed size exclusion chromatography with tetra-detection methodology to simultaneously determine absolute molecular weight, concentration, molecular size, and intrinsic viscosity. All trastuzumab molecules in solution exhibit analogous behavior in their binary action towards HER2 regardless of the order of addition of trastuzumab/pertuzumab. This analogous behavior of all trastuzumab molecules, including biosimilars, highlights the robustness and con-sistency of their binding activity towards HER2. Furthermore, the addition of HER2 to a mixture of trastuzumab and pertuzumab leads to increased formation of high-order HER2 complexes, up to concentrations of one order of magnitude higher than in the case of sequential addition. The observed increase suggests a potential synergistic effect between these antibodies, which could enhance their therapeutic efficacy in HER2-positive cancers. These findings underscore the im-portance of understanding the complex interplay between therapeutic antibodies and their target antigens, providing valuable insights for the development of more effective treatment strategies.