Blockchain Papers

Ingrid Vasiliu-Feltes, Michael Mylrea, PhD, Christina Yan Zhang, Tyler Cohen Wood · 5 authors

The convergence of Digital Twin technologies with precision health, the pharmaceutical industry, and life sciences has garnered substantial recent attention. As we advance toward personalized medicine and precision health, the fusion of Digital Twin and blockchain technologies is poised to enhance healthcare outcomes fundamentally. This conference discussion highlighted pivotal drivers accelerating the adoption of Digital Twin-enabled blockchain solutions, encompassing the shift to a decentralized World Wide Web (Web 3.0), the establishment of a global interconnected health ecosystem, and the distinct advantages offered by converging frontier technologies in optimizing healthcare, pharmaceutical industry, and life sciences. Yet, the effective deployment of blockchain-powered Digital Twins in precision health necessitates robust cyber safety measures, proactive ethical frameworks, data validation, provenance assurance, streamlined supply chain management, and heightened interoperability. These proceedings underscored blockchain-powered Digital Twins' pivotal role in reshaping health data management, security, sharing, ownership, and monetization and in revolutionizing pharmaceutical supply chain management and novel drugs and therapeutics development within the precision health domain.

Hayes Kathleen

Substandard and falsified (SF) pharmaceuticals account for an estimated 10% of the pharmaceutical supply chain in low- and middle-income countries (LMICs), where a lack of regulatory and laboratory resources limits the ability to conduct effective post-market surveillance and allows SF products to penetrate the supply chain. The Distributed Pharmaceutical Analysis Laboratory (DPAL) was established in 2014 to expand testing of pharmaceutical dosage forms sourced from LMICs; DPAL is an alliance of academic institutions throughout the United States and abroad that provides high quality, validated chemical analysis of pharmaceutical dosage forms sourced from partners in LMICs. Results from analysis are reported to relevant regulatory agencies and are used to inform purchasing decisions made by in-country stakeholders. As the DPAL program has expanded to testing more than 1000 pharmaceutical dosage forms annually, challenges have surfaced regarding data management and sample tracking. Here, we describe a pilot project between DPAL and ARTiFACTs that applies blockchain to organize and manage key data generated during the DPAL workflow, including a sample’s progress through the workflow, its physical location, provenance of metadata, and lab reputability. Recording time and date stamps with this data will create a permanent and verifiable chain-of-custody for samples. This secure, distributed ledger will be linked to an easy-to-use dashboard, allowing stakeholders to view results and experimental details for each sample in real time and verify the integrity of DPAL analysis data. Introducing this blockchain-based system as a pilot will allow us to test the technology with real users analyzing real samples. Feedback from users will be recorded and necessary adjustments will be made to the system before the implementation of blockchain across all DPAL sites. Anticipated benefits of implementing blockchain for managing DPAL data include efficient management for routing work, increasing throughput, creating a chain of custody for samples and their data in alignment with the distributed nature of DPAL, and using the analysis results to detect patterns of quality within and across brands of products and develop enhanced sampling techniques and best practices. 

Marcelo Corrales Compagnucci, Niclas Nilsson, Paul Stankovski, Christoffer Olsson · 7 authors

Research and Development (R&D) in the pharmaceutical sector traditionally occurred in closed, siloed institutional settings. This approach was a function of a rights-oriented intellectual property model which framed access and reuse of data (data sharing) as a threat to rightsholders. However, a closed model of explorative collaboration is less suited to today’s more complex scientific ecosystem, where external engagement and dynamic partnering with multiple actors and diverse information sources has become essential. As such, devising alternative approaches is vital in ensuring that opportunities for scientific advances are not lost or innovation stifled. This article introduces a hybrid contractual framework that combines the benefits of the automated functionality of smart contracts and non-fungible tokens (NFTs) embedded in a blockchain with more traditional rights-based licensing schemes. The presented framework is based on the outcome of an experimental pilot platform that enabled participants to store, find and reuse data following FAIR data principles. The platform documents real-world physical assets in the drug discovery of chemical molecules in an immutable digital ledger. More generally, smart contracts and NFTs point us towards an open and global collaborative platform for exploiting and advancing drug research assets. The resulting platform creates mechanisms for resolving issues regarding standardization, interoperability, and disclosure. As such, it overcomes many of the practical hurdles currently obstructing collaboration in pharmaceutical R&D, as well as providing a framework to address the central conflict in drug discovery, namely the demand for greater data sharing and the protection of rightsholder interests.

Ivan da Silva Sendin, Rodrigo Sanches Miani

Transforming a vaccine concept into a real vaccine product is a complicated process and includes finding suitable antigens and regulatory, technical, and manufacturing obstacles. A relevant issue within this scope is the clinical trial process. Monitoring and ensuring the integrity of trial data using the traditional system is not always feasible. The search for a vaccine against the coronavirus SARS-CoV-2 illustrates this situation. The scientific credibility of findings from several vaccines' clinical trials contributed to distorted perceptions concerning the benefits and risks of the drug. This scenario is ideal for applying technologies such as Blockchain and Smart Contracts in healthcare issues. This paper proposes a protocol based on Smart Contracts, named VaccSC, to enable transparency, accounting, and confidentiality to Phase III of vaccine experiments. The protocol was implemented in Solidity language, and results show that the VaccSC enables double-blindness, randomization, and the auditability of clinical data, even in the presence of dishonest participants.

Marie Recine

The atmosphere at the 5th Annual Immuno-Oncology 360° (IO360°) Conference, which took place on February 6–8 at the Crowne Plaza Times Square in New York City, was truly collaborative. Co-chaired by Axel Hoos, MD, PhD (GSK), James Gulley, MD, PhD (National Cancer Institute [NCI]), and Andrew Baum, MD (Citi), the conference featured almost 100 speakers and 10 plenary sessions, including 4 keynote talks and 7 panel discussions. More than 400 attendees representing the pharma, biotech, academic, regulatory, and private investment communities gathered to discuss the rapid advancement in scientific, clinical, and business developments in IO, with the goal of accelerating the development of new therapeutics for patients. Over 350 partnering meetings took place over the 3-day conference.“360 degrees means we really want to speak to all stakeholders,” stated Dr. Hoos. The meeting is structured for the scientists to bring their most promising next-generation mechanisms that will help address these challenges. However, it is also important to look at therapies that haven't worked, so we don't repeat the same challenges of the past, he noted. “But IO360° is not just the science, it's about the entire ecosystem in which the science exists, and that includes the patients and those that provide the funding to make the science happen.”Michel Sadelain, MD, PhD, of Memorial Sloan Kettering Cancer Center, opened the meeting with a keynote, Chimeric Antigen Receptor (CAR) - T Cell Therapy and the CD19 Paradigm. With two CD19 CAR-T cells (CAR Ts) approved in 2017, Dr. Sadelain identified three new directions being taken to optimize CAR T therapy and develop next-generation CAR Ts. The first is addressing exhaustion (loss of functionality) using genome engineering at a carefully select locus (TRAC) to create more potent CAR Ts and incorporating new designs that modify the activating portion of the CAR and balance rapid expansion and retained memory (1XX CAR). The second is gaining insight into the pathophysiology of cytokine release syndrome, including CAR T–macrophage interactions, to try and reduce toxicity. The third is employing new strategies for circumventing antigen escape, such as use of radiosensitization and combinatorial targeting.The Discovery and Preclinical Science plenary focused on strategies being investigated to modify the tumor microenvironment and address limitations of patient-sourced therapies. According to the plenary chair, Ronald Herbst, PhD, “we are all excited about the potential for immunotherapy for patients with cancer, but many patients don't respond to checkpoint inhibitors.” Part of the problem is explained by the fact that “immune contexture varies within and across tumor types, and so-called ‘hot’ versus ‘cold’ tumors,” he noted. In order to increase the efficacy of immunotherapy, a number of areas are actively being targeted, including antigen presentation, innate mechanisms of activation, the tumor microenvironment, and overcoming immunosuppression.A variety of cells, growth factors, and cytokines in the tumor microenvironment play a pivotal role in whether or not immunotherapy is effective. Various strategies are being employed that attempt to modify the tumor microenvironment to overcome immunosuppressive mechanisms, such as blocking adenosine with an anti-CD73 monoclonal antibody (oleclumab, Medimmune) or an A2A receptor antagonist (CPI-144, Corvus), or inhibiting the IDO (indoleamine 2,3-dioxygenase) pathway (indoximod, NewLink Genetics). Other strategies are being employed to enhance the efficacy of cytokines to augment the expansion and activation of T cells, such as engineering enhanced versions of growth factors such as interleukin-2 (IL-2; NKTR-214, Nektar, and MDNA109, Medicenna) and IL-10 (pegilodecakin, ARMO). For example, pegilodecakin, a long-acting pegylated form of IL-10, induces hallmarks of CD8+ T cell immunity in cancer patients. According to Aung Naing, MD, and Martin Oft, MD, pegilodecakin demonstrated clinical benefit in studies as a single agent and in combination with both chemotherapy and checkpoint inhibitors across several tumor types. The agent is currently being investigated in a Phase 3 trial in metastatic pancreatic cancer.Off-the-shelf hematopoietic cell products are being developed to address some of the limitations of patient-sourced cell therapies, such as heterogeneity, single-patient manufacturing, need for sufficient cells, extended production time, and cost. For example, engineered CAR natural killer cells, derived from induced pluripotent stem cells, are being developed that incorporate several individual components that together help to enhance persistence and antitumor efficacy (FT596, Fate Therapeutics). Multicombinatorial strategies such as this may be key in reigniting the endogenous immune system and improving efficacy in solid tumor space.Genentech's Priti Hegde, PhD, opened the Translational Science and Emerging Biomarkers plenary, part 1, with a keynote, Biomarker Signaling: Turning Cold Tumors Hot. Individual cancer types can be characterized along the tumor immunity continuum based on immune phenotype (i.e. inflamed or noninflamed) and tumor mutational burden (TMB). How can we generate an immune response signal in noninflamed tumors when most do not achieve the TMB threshold that selects for benefit? Dr. Hedge highlighted two approaches: adaptive immunity, which has the potential to drive memory response, and synthetic immunity, which has the potential to sustain efficacy and drive log kill. An example of an adaptive immunity approach is neoantigen-specific T-cell therapy, in which there are limited but encouraging data demonstrating its ability to promote adaptive immunity in noninflamed tumors. Synthetic immunity approaches include engineered T cells (e.g. NY-ESO SPEAR T cells [GSK/Adaptimmune], BMCA CAR Ts) and bi-specific biologics (e.g. antibodies, BITEs® [Amgen], ImmTAC® [Immunocore]), in which there is a proof of concept that these approaches are feasible in solid tumors and checkpoint inhibitor-refractory hematologic malignancies.One may also need to address the underlying biology to turn cold tumors hot. According to Dr. Hegde, the future of immunotherapy may be highly personalized, and one will need to look at a variety of markers in biopsy specimens using a variety of techniques. This will only be possible if we have: (1) a tissue-conserving, regulatory-grade decentralized platform to be able to run all of these assays in trials and (2) trial designs and statistical analysis plans that enable diagnostic signal-seeking validation and a path for registration.The remainder of the plenary reported on translational data and evolving biomarkers and applications to help support decision-making for IO drug development.Negative results from the Phase 3 study of the therapeutic prostate cancer vaccine PROSTVAC (Bavarian Nordic) show that a combinatorial approach may be needed with vaccines. Similarly, oncolytic viruses may need multiple transgenes and mechanisms to reverse complex immunosuppressive microenvironments. To address this issue, T-Stealth™ oncolytic viruses (BeneVir) can incorporate multiple genes, evade clearance by the innate and adaptive immune systems, and be combined with other drugs and IO agents.With the increasing need for biomarker support, the clinical trial laboratory reality in the IO space is complex. Patrice Hugo, PhD (Q2 Solutions), summarized important features to consider when selecting a lab partner for drug development. Key strategies to successfully introduce innovation in the clinical trial lab space include joint review of pros and cons of technologies, consideration of joint investments, performing Phase 1 specialized testing in niche labs/academic settings with transfer to a central lab, and discussion and planning for regulatory requirements.Advances in positron emission tomography (PET) imaging and radiomics provide a quantitative, noninvasive way to assess the dynamic changes of the immune system. For example, CD8 PET (Imaging Endpoints) may help distinguish between hot and cold tumors and address fundamental questions regarding the role of CD8 cells in the tumor microenvironment.Other unique biomarkers and applications under investigation include MultiOmyx™ (NeoGenomics), a proprietary multi “omic” technology that enables detection and visualization of up to 60 biomarkers on a single slide; immunosequencing (immunoSEQ, Adaptive Biotechnologies), a clinical diagnostic for monitoring clonal expansion and predicting/evaluating response to therapy that can also be used in combination with cellular immunology and computational biology (Multiplexed Identification of T cell Receptor Antigen [MIRA] assay, Adaptive Biotechnologies) to map T-cell receptors; and CANscript™ (Mitra), a personalized ex vivo histoculture approach that can be used to evaluate drug-induced modulation of the tumor microenvironment and predict clinical performance.The IO Novel Technologies and Innovative Solutions plenary showcased companies that have technologies and solutions that will help stakeholders in the IO field advance developments for cancer therapeutics. Presenters included Advaxis, Bioxcel Therapeutics, IAG, Provecs Medical, Rgenix, and Sensei Bio.Andrew Baum, MD (Citi), opened the Financial and Commercial Implications plenary with a keynote, Evaluation and Forecast of the IO Space. He started off by discussing key questions on health-care investors' minds. According to Dr. Baum, “what investors don't like very much about IO is that the technology cycles are short, so you can go from here to zero very quickly very easily.” He cited ipilimumab and the fact that it was quickly eclipsed by anti-PD (L)-1 agents. Another issue is the “paradox of choice,” as there are so many different modalities. “It's almost overwhelming,” he noted, “especially for someone that doesn't have a deep scientific background to interpret a Phase one trial.” Other questions involve primary and secondary resistance, cell therapy manufacturing constraints, minimizing/managing toxicity, and financial toxicity. However, despite these questions, “the good news is the amount of capital, the enthusiasm, and the scientific advancement all mean that we're going to make huge strides in IO, I have no doubt.”Dr. Baum stressed the importance of learning from historic disappointments and noted that we need better biomarkers, better trials, and patience so that the benefits can be extended to more patients. He ended his presentation with a slide showing Citi's top 10 novel IO targets for 2020, in which IL-2/IL-15 took the top spot.Khalil Barrage (Invus) agreed that the IO revolution has led to unprecedented investor enthusiasm for oncology, unlocking massive commercial opportunities. However, the discovery of checkpoints and their curative potential has led to hype in IO drug discovery, resulting in risky behavior. In addition, the flood of capital has lowered potential returns and there are a lot of IO agents in development with poorly validated rationale. As a result, Invus' approach to investing incorporates strategies such as diversification, selectivity, exploring synergistic opportunities, investing where innovation is happening, paying a premium for validated approaches when warranted, and assessing reimbursement.The plenary concluded with a panel discussion on monetizing science: the preparation of an IPO, straight licensing with the transition to a public company, and decision-making on prioritization within portfolios. Key takeaways included strategies for building out scientific and executive talent, the importance of having a scientific advisory board to test out the research, and being prepared to be a public company.The Trends and Collaborations plenary featured presentations by three major industry media companies in the IO field, which discussed new trends and their effect on the investment landscape.BioCentury analyzes IO trends at recent medical meetings using machine learning, began Simone Fishburn, PhD, VP, and Executive Editor. Despite the huge focus on PD (L)-1, academics and companies are aggressively looking for, and finding new targets, with LAG3 topping the list in company oncology pipelines in 2019. CAR T activity is moving into solid tumors, with new constructs and multiple tumor antigens targeted. Immunometabolism and tumor mutation burden are hot topics. Funding for IO start-ups is outstripping other areas, both inside and outside oncology, drawing traditional and corporate investors.According to John D. Carroll (Endpoints News), these trends are supported by global data published by the Cancer Research Institute, which show that there were 3394 IO agents representing 417 targets in the pipeline in 2018, representing a 67% increase over 2017.How are these trends affecting the investment landscape? According to Jeff Bockman, PhD (Cello Health BioConsulting), IO dominates oncology growth, but not sales. Moreover, although IO deals have shown evidence of slowing, whether due to maturation, saturation, or fatigue, and oncology and IO investments remain robust.The Business Development plenary, hosted by Solebury Trout, included panel discussions on partnering, fundraising, and rational investing. The first panel discussed IO partnering strategies from the viewpoint of pharma and academia. According to Dr. Hoos, who the partnering in this space have but there has much and is only that companies have started their unique which will a partnering the for is tumor and the and the companies on the panel and there to be both and with some moving from and on those that can IO and agents are being by most in the and are to play which was for and discussed in the IO space and a number of For example, the panel stressed the importance of at and and on key and as a private on their ecosystem their investors with in the past, key to their than at with the top at the with key the of and companies introduce than need to so that can panel focused on IO investment investors this an time, with a future for many modalities. However, the massive of data is it to to to from a The investors on the panel on a variety of such as the of and whether the data support a or whether an agent has a or has a niche in the IO important is a in their and their to plenary ended with a with of by Solebury Trout, the discussion focused on in the company, with a an For companies looking for highlighted the fact that as a and stressed the need to and where are are some very so both and in to a with a can try and to more like in As industry are companies can be quickly with limited capital, like companies have in the began with a keynote, to led by and MD, of of According to Dr. we are at an in it has from one to has the and of tumor types, agents and trials are and there is an to use to enable to of trials are the way new therapies are developed for cancer, make better and more personalized The of are testing drugs where most (i.e. the order of therapy to about response in the of building an to evaluate drugs and using imaging and biomarker and being by is a platform trial for of biopsy is used to assess and imaging and adaptive The and the are structured to enable and release of agents the The primary is response which is a highly of and and is in biomarker The from biomarker and is to drug to Dr. we want innovation to we have to The focus of new drug development be a a from of metastatic to is a huge is also a huge goal of is to of patients to with and of therapy based on Dr. ended with one of for drug from finding out which drug be to the with two The first Science and Emerging Biomarkers Part was led by PhD, of and to focus on biology and to help predict to Technologies discussed included to enhance antibody therapeutics mechanisms of to immune the for biomarker discovery a and a receptor in second for IO was led by of and was for clinical trial who to it to an IO clinical discussed included an clinical trial study a complex Phase 1 trial in IO and clinical trial for The ended in a panel discussion on the challenges with IO data and to advance to PhD, at the and (i.e. may not the clinical benefit of IO agents. As a result, trends include the use of immune response machine learning to the of imaging and new techniques. The IO plenary up the with a discussion of novel imaging are unique challenges with the use of response at IO clinical as a of complex According to some of these challenges can be by the and of response and including a of in the can be by the use of and and analysis and PhD are being used in with to more from to as as better between and such as the CD8 PET discussed is also an evolving Similarly, imaging using PET an to assess all of a tumors for with a single PET and assess use of a novel three opened with the of with cancer, cancer 10 as metastatic chemotherapy and therapies, and of an immunotherapy trial at the The the that cancer, and those cells in the an of the cells and the cancer has the of being the first to be of metastatic cancer a of to to from in the concluded with some to patients who be in the same the same to with cancer or out as much as you can about to a cancer to to not just one of therapy but several of out about clinical trials and whether you can in The is out there and you as try and on the was a panel discussion on to IO in a The are to but be and and the of a tumor to be want to if the tumor has by the adaptive immune is it by T cells if do have an immunosuppressive factors are in the tumor However, are an important the is the of the cell types are but also and able to look in the is but it doesn't provide all the can all these be with a new plenary for Cell According to Dr. Gulley, therapy has the to on the of cancer there is activity in hematologic but it's is needed to achieve the same effect in solid tumors, so this is where there is much The is to was in studies but the benefit to a of patients. The new technologies and targets discussed in this plenary to do just technology to a T cells their However, in the of approved CAR are According to MD of this as a of of and of He cited a where CD19 in a single cell led to by the CD19 which may have important for manufacturing and other cell therapies. For and the can be with a CAR T or it can be with a new of CAR that the SPEAR are an engineered T-cell of cells that are to a that a antigen in many technology an over CAR T therapy in that it to both and results have in a cancer for which there are no therapies the of noted products a number of over CAR Ts. CAR Ts Chimeric Antigen Receptor developed using the platform are being investigated in and multiple The is to multiple to create T cells with such as the ability to or overcome may an over other therapies in solid tumors in that multiple tumor antigens and there is a of or The technology used to develop the that has and of efficacy have in and the for the has from to to and the is a therapies have the potential to enhance CAR T activity in solid tumors. combination strategies consider both and can be used to enhance cell and and factors in the tumor microenvironment, or and plenary ended with a panel discussion on and clinical to IO therapeutics that will to more and therapies. of the strategies discussed were including a to and products and addressing antigen with or combination In order to we need to address like the when moving from in to the clinical as as cell and the used to create the may the cells, manufacturing and we need to cell therapies so that more patients will have conference concluded with the IO Development plenary, which discussed recent IO clinical The plenary began with an of data for the activity has demonstrated in more than cancer types. The agent has across more than including in is moving into the of therapy, and next-generation biomarkers are to help promising were also for a a and combination immunotherapy and the tumor receptor has to more benefit in Dr. Hoos. However, there is a lot of As a result, “we need to new to the benefit PD Cell therapy has really to the of engineered and we are to the benefit from to solid tumors and overcoming the such as T-cell that in the for patients is

Huub Schellekens

European patents on a number of therapeutic biopharmaceutical agents will expire in 2004 and 2005. These agents and others recently past patent expiry include recombinant human growth hormone, alpha and gamma interferons, streptokinase, interleukin (IL)-2, insulin, glucerase, plasminogen activator, granulocyte colony-stimulating factor, and erythropoietin. Patent expiry for these products opens the door for the development and marketing of generic versions of these drugs, also known as biosimilars or follow-on biologics. The successful introduction of biosimilars into the pharmaceutical market will depend on the establishment of regulatory guidelines that have been adapted for approval of these generic biopharmaceutical agents. Recombinant therapeutic proteins differ significantly from classic small drug molecules, such as diazepam and prednisone, in their size, molecular heterogeneity and complexity, and methods of manufacture. In contrast with classic drugs, it is currently impossible to fully predict the biological characteristics of therapeutic proteins using physicochemical methods. For these reasons, guidelines for demonstrating bioequivalence of biosimilars with approved innovative products must be specially tailored to the characteristics of these molecules. The criteria for regulatory approval of biosimilars differ from those used to evaluate follow-on versions of classic drugs. During the revision of European (EU) legislation concerning medicinal products, the controversial regulatory and patent issues for marketing of biosimilars led to revamping of the regulations by the European Parliament in May of 2004 [1,2]. The revised regulations provide a clearer and more expedient route for developing and testing generic products within the period of protected data exclusivity (8 years for the reference product), and guidance regarding when generics may be sold following expiration of the reference product patent. There is much at stake in establishing regulatory guidelines for approval of biosimilars in terms of the total potential market for these products (approximately US $20 billion, or 24 billion Euros, by 2005) [3]. In addition to the standard demonstration of safety and efficacy, development and marketing approval of biosimilars are complicated by several factors, including: the technically complex methods required to manufacture and characterize biopharmaceutical proteins; susceptibility of these proteins to physical and chemical degradation during and after manufacture; and the observed immunogenicity of several approved biologics such as recombinant streptokinase [4], interferon-beta [5], GM-CSF [6], hirudin, interleukin (IL)-2 [7] and, more recently, epoetin alfa [8], which can lead to neutralization of these biologic agents and lack of efficacy or sometimes severe, adverse reactions. Immunologic safety will be an increasingly important criterion for evaluating the safety of biosimilars, especially in light of the recently observed increase in cases of antibody (Ab)-mediated pure red cell aplasia (PRCA) [9,10]. These cases have been associated primarily with subcutaneous (SC) administration of epoetin alpha (Eprex®, Ortho Biologics LLC, Manati, Puerto Rico), which was reformulated in 1998. Establishing proper and comprehensive guidelines for biosimilars is further complicated by the absence of clear-cut criteria and methods for determining their potential immunogenicity. Preclinical in vitro or in vivo surrogate markers of immunogenicity are not always available or representative of immune responses in patients [11]. Therefore, the definitions for bioequivalence of biosimilars with approved products will likely differ from definitions used for bioequivalence of classic drugs [12,13]. The pharmaceutical and biotechnology industries have different viewpoints from generic drug manufacturers on what is required for evaluating the safety and efficacy of biosimilars for regulatory approval [14,15]. Innovator companies explain that the complexities of manufacture and process validation, the intrinsic heterogeneity of biopharmaceutic products, and the potential immunogenicity of products manufactured by different processes preclude reliance on in vitro surrogates of activity alone for evaluating substitutability of biosimilars [14]. For these reasons, innovator companies maintain that full-fledged clinical trials are required to demonstrate the substitutability and safety/efficacy of biosimilar products. In contrast, manufacturers of biogeneric products argue that surrogate in vitro or in vivo assays that mimic the absorption kinetics and dose–response of reference drugs may be sufficient to demonstrate bioequivalence of biosimilars. These assays can be performed in the absence of large, controlled clinical studies, which are required for approval of pioneer drugs [10,15]. The situation with demonstrating immunologic safety is more problematic, especially with products with a low incidence of immunogenicity. The European Committee for Human Medicinal Products (CHMP) states that the potential immunogenicity of biosimilar products should be evaluated at the preclinical and clinical stages using validated state-of-art techniques, including animal models, physicochemical methods, and computer algorithms [12,16]. However, the lack of standardization of assays for detecting Abs against therapeutic proteins is a major hurdle because of differences in procedure and calibration, assay sensitivity, and other factors [16]. For example, the potential immunogenicity of erythropoiesis-stimulating agents (ESAs), including epoetin, is confounded by the undefined mechanism of the Ab response to these recombinant proteins, with respect to contributing product characteristics or any predisposing patient factors. There is a need for an appropriate in vivo model to fully evaluate the immunogenicity of new ESAs or biosimilars because of the potential development of an immunopathology such as Ab-mediated PRCA [10]. Such a deleterious consequence of treatment underscores the need to unequivocally demonstrate immunologic safety for ESAs and their biosimilars in addition to the classic parameters of safety, efficacy, and bioequivalence [11]. The ultimate proof of immunologic safety of ESAs and other therapeutic proteins will come from results of clinical studies and post marketing analyses [10]. In conclusion, the development of Ab-mediated PRCA in patients receiving reformulated erythropoietin underscores the problems associated with maintaining safety and efficacy of approved products following changes in manufacture. Alterations in protein structure or stability can result in serious reactions in patients or loss of therapeutic efficacy. For these reasons, rigorous criteria must be established by the medical, manufacturing, and regulatory communities to protect patients from adverse immune responses to therapeutic recombinant proteins, in general, and biosimilars in particular. These same criteria will also help to establish standards of manufacture and process validation that can be used by all biopharmaceutical manufacturers. Ultimately, these criteria will ensure the safety and efficacy of biosimilars while reducing the potential for immune neutralization of therapeutic proteins or severe treatment-related complications.