Scientific and Regulatory Considerations for the Approval of the First Generic Glucagon

Glucagon for Injection (NDA 020928) is a polypeptide hormone identical to human glucagon approved 20 years ago for severe hypoglycemia in patients with diabetes mellitus. On Dec 28, 2020, the U.S. FDA approved the first generic version of glucagon for injection USP, 1 mg/vial packaged in an emergency kit. The generic and the reference listed drug (RLD) version, i.e., the innovator version, of glucagon were each produced through different manufacturing processes. The RLD version of glucagon is produced via recombinant DNA in yeast while the generic version of glucagon is produced by peptide synthesis. The FDA published its current thinking on how to ensure sameness between the generic and innovator peptide products prepared with different manufacturing processes in a Draft Guidance for Industry: Submission of Abbreviated New Drug Applications for Certain Highly Purified Synthetic Peptide Drug Products, which applies to five peptide drug products, including glucagon. In this presentation, we aim to provide an overview of the regulatory recommendations for submitting generic glucagon drug products for approval, as outlined in the aforementioned draft guidance. Although glucagon may be produced using different manufacturing processes, the sameness in glucagon can be adequately demonstrated using analytical methods, which involve demonstrating physicochemical properties, as well as primary and secondary structures, oligomers and aggregation states. Biological assays may also be used as part of the demonstration of active pharmaceutical ingredient sameness. Synthetic glucagon may have different impurity profiles when compared to the RLD recombinant product. As part of the ANDA review, impurities in the synthetic drugs are analyzed and controlled, in addition, the potential immunogenicity of new impurities, which are not in the RLD products, are assessed and compared using non-clinical assays. In this work, we will discuss non-clinical assays for assessing the immunogenicity risk of these impurities, for both adaptive and innate immune responses. In conclusion, the sameness of an approved generic synthetic glucagon to an RLD can be adequately established through various analytical methods and biological assays.

“Biosimilar” generic version of biologic products?

Biosimilars are currently popular after the expiry date of patents for biological reference products have expired or soon will expire. Besides, this ‘copycat’ version of biologic products offers much lower costs as compared to the reference products, thus promoting better patient access to the treatment of certain diseases such as cancer, inflammatory diseases, skin disorders and diabetes. This review aims to determine the differences between biosimilars and generic drugs and highlight some issues related to biosimilar products such as comparability, interchangeability, immunogenicity, extrapolation of indication, current legislation, pharmacovigilance, and naming system. Scientific sources from PubMed, Google Scholar, ScienceDirect, and Elsevier were accessed for preparation of this review article. Biosimilars are not generic drugs as they have larger and complex structure as compared to the generic drugs. Due to that, biosimilars are highly similar but not identical to the reference products. Many regulatory authorities have authorized biosimilars under a distinct regulatory process from that of the generic drugs and subjected them to comprehensive comparability studies with their reference products (analytical, nonclinical in vitro, and in vivo studies and clinical trials). Additional evidence from interchangeability studies, extrapolation of indication studies, immunogenicity profile assessments, and pharmacovigilance studies are also beneficial to assess the efficacy, safety, and quality of the biosimilar before and/or after receiving their regulatory approval. Biosimilars are different from generic drugs due to their complexity in structure and manufacturing process. More comprehensive studies are required to ensure their benefits is outweigh the risks.

Is Biopharma Ready for the Standard Wars?

This symposium contribution sheds new light on Momenta v. Amphastar, a case in which issues relating to standardization and patent disclosure that have previously been observed in the semiconductor, computing, and telecommunications sectors found their way into a dispute between two biosimilar manufacturers. One such manufacturer, Momenta, participated in the development of a standard for testing the purity of generic enoxaparin under the auspices of the United States Pharmacopeial Convention but failed to disclose that it had applied for a patent on the testing method. When Momenta later sued Amphastar for patent infringement by using the method in accordance with the FDA’s approval of its own generic version of enoxaparin, Amphastar raised waiver and equitable estoppel as defenses, then brought antitrust claims against Momenta and its distribution partner Sandoz. Amphastar prevailed at the district court, obtaining a ruling that Momenta’s patent was unenforceable. This case demonstrates that issues surrounding the acquisition and disclosure of patents on standardized technologies have more salience in the biopharma sector than commonly believed. As such, standards organizations operating in this sector should ensure that their policies and procedures are robust enough to delineate clearly the obligations of participants with respect to patents covering standardized technologies, and organizations that participate in biopharma standards-development should heed the valuable lessons offered by more than three decades of litigation and policy making in the technology sector.

Preempting the Entry of Near Perfect Substitutes

When firms compete on price and quality-enhancing promotion in a market for differentiated products, entry of a nearly perfect substitute to one of such products, for example, a generic version of a pharmaceutical drug, intensifies price competition but softens quality competition. We show that consumers are likely to gain from entry when quality is relatively unimportant for them, when business stealing generated by promotion is substantial, and when products are poor substitutes. We also show that entry may be more attractive for consumers in less concentrated markets, as a smaller number of firms and asymmetric market shares may be associated with higher quality.

P0638COMPARISON OF CIRCUIT PATENCY AND EXCHANGE RATES BETWEEN THE ORIGINAL PRODUCTS AND THE GENERIC VERSIONS OF NAFAMOSTAT MESILATE IN ACUTE KIDNEY INJURY RECEIVING CONTINOUS RENAL REPLACEMENT THERAPY

Background and Aims The generic versions have the same main component as the original products. But, due to the difference in additives or the level of impurities, it is questionable the the generic versions are completely identical to the original products. Nafamostat mesilate has been widely used as an anticoagulation in continuous renal replacement therapy (CRRT) with hemorrhagic diathesis. In this study, we performed comparison of circuit patency and exchange rates between the original products and the generic versions of Nafamostat mesilate in acute kidney injury patients receiving continuous renal replacement therapy Method We have conducted retrospective studies to compare the original product of nafamostat mesilate (n=732) with the generic version (n=328) on the CRRT running time. Results CRRT fiter life time of the generic version group was shorter than that of original product group although that was not significantly. Conclusion When generic versions of nafamostat mesilate are adopted in a hospital formulary, it must be emphasized that the effect these versions may be not completely identical to that of the original products.

AB1183 TERIPARATIDE SWITCH TO BIOSIMILAR - IS IT COST EFFECTIVE?

Background:Teriparatide is an effective treatment option for osteoporosis however NICE restricts its use to patients with high disease burden. This was based on cost effectiveness evaluation of the originator (Forsteo®) and would be different for recently introduced generic preparation.Objectives:We wished to evaluate the current prescribing behaviour prior to a potential switch to generic version and associated cost savings.Methods:All patients prescribed Teriparatide since the commencement of specialist osteoporosis service in Aug 2014 at our University teaching hospital covering 350,000 population were included. Data was extracted from electronic database with full access to demographics, population characteristics, disease parameters and medication history.Results:113 patients were prescribed Teriparatide over five years. Mean age of participants was 76 yrs (53-96). They had on average three comorbidities (0-8) with most common being hypertension (n=44, 38.9%) and inflammatory arthritis (n=21, 18.5%). Sixteen (14.1%) individuals had concurrent corticosteroids. Median number of fractures prior to therapy were four (0-12). Prior treatments included oral therapy (n= 90,79.6%), IV zoledronate (n=22, 19.4%) and denosumab (n=19, 16.8%). 66 (58.4%) of patients only had one prior bone active medication. Mean duration of prior therapy was 62.4 months (9-192 months). 17 (15.0%) patients had chronic kidney disease with lowest eGFR of 38. 41 (36.2%) had Vit D level between 40-75 nmol/L. Median T score was -3.8 (-2.1 - -6.0) which improved to -3.4 (-2.9 - -3.9) after two years.Conclusion:Our real-world study shows that teriparatide is used predominantly in complex, multi-morbid older individuals with several prior fractures. Despite that teriparatide remains effective for a wide range of individuals including those with inflammatory arthritis and/or concurrent steroid use. Neither moderate CKD nor mild Vit D insufficiency seems to impact its efficacy. This is in line with recent meta-analysis of real life teriparatide use in complex osteoporosis with multimorbidity. Our study should enhance clinicians’ confidence in its prescribing. It’s notable that the use is higher than current estimates based on NICE cost effectiveness analysis for eligibility of teriparatide. Instead of annual predicted use of 4.8/100,000 population, it was prescribed to 6.4/100,000. This could potentially have a cost impact however the introduction of a generic version would mitigate against it. We calculated our savings to be over £125,000 if all patients were switched. These savings at national level would hopefully improve access to a wider patient cohort and perhaps allow earlier use in the treatment paradigm.Disclosure of Interests:Tahreem Akram: None declared, Maham Siddique: None declared, Hafiz A. Javed: None declared, Julie Begum: None declared, Joanne Fourmy: None declared, Muhammad Khurram Nisar Grant/research support from: Muhammad Nisar undertakes clinical trials and received support (including attendance at conferences, speaker fees and honoraria) from Roche, Chugai, MSD, Abbvie, Pfizer, BMS, Celgene, Novartis and UCB, Consultant of: Muhammad Nisar undertakes clinical trials and received support (including attendance at conferences, speaker fees and honoraria) from Roche, Chugai, MSD, Abbvie, Pfizer, BMS, Celgene, Novartis and UCB, Speakers bureau: Muhammad Nisar undertakes clinical trials and received support (including attendance at conferences, speaker fees and honoraria) from Roche, Chugai, MSD, Abbvie, Pfizer, BMS, Celgene, Novartis and UCB

X-Phi and Impartiality Thought Experiments: Investigating the Veil of Ignorance

This paper discusses “impartiality thought experiments”, i.e., thought experiments that attempt to generate intuitions which are unaffected by personal characteristics such as age, gender or race. We focus on the most prominent impartiality thought experiment, the Veil of Ignorance (VOI), and show that both in its original Rawlsian version and in a more generic version, empirical investigations can be normatively relevant in two ways: First, on the assumption that the VOI is effective and robust, if subjects dominantly favor a certain normative judgment behind the VOI this provides evidence in favor of that judgment; if, on the other hand, they do not dominantly favor a judgment this reduces our justification for it. Second, empirical investigations can also contribute to assessing the effectiveness and robustness of the VOI in the first place, thereby supporting or undermining its applications across the board.

EP22 Teriparatide use in the real world: can we expect cost savings with a switch to generic version?

Background Teriparatide is an effective treatment option for osteoporosis, however NICE restricts its use to patients with a high disease burden. This was based on a cost effectiveness evaluation of the originator (Forsteo®) and would be different for recently introduced generic preparation. We wished to evaluate the current prescribing behaviour prior to a potential switch to the generic version and associated cost savings. Methods All patients prescribed teriparatide since the commencement of specialist osteoporosis service in Aug 2014 at our University teaching hospital covering a population of 350,000 were included. Data were extracted from an electronic database with full access to demographics, population characteristics, disease parameters and medication history. Results 113 patients were prescribed teriparatide over five years. Mean age of participants was 76 yrs (53-96). They had on average three comorbidities (0-8) with most common being hypertension (n = 44, 38.9%) and inflammatory arthritis (n = 21, 18.5%). Sixteen (14.1%) individuals had concurrent corticosteroids. Median number of fractures prior to therapy were four (0-12). Prior treatments included oral therapy (n = 90,79.6%), IV zoledronate (n = 22, 19.4%) and denosumab (n = 19, 16.8%). 66 (58.4%) of patients only had one prior bone active medication. Mean duration of prior therapy was 62.4 months (9-192 months). 17 (15.0%) patients had chronic kidney disease with lowest eGFR of 38. 41 (36.2%) had Vit D level between 40-75 nmol/L. Median T score was -3.8 (-2.1 - -6.0) which improved to -3.4 (-2.9 - -3.9) after two years. Conclusion Our real-world study shows that teriparatide is used predominantly in complex, multi-morbid older individuals with several prior fractures. Despite that teriparatide remains effective for a wide range of individuals including those with inflammatory arthritis and/or concurrent steroid use. Neither moderate CKD nor mild vitamin D insufficiency seems to impact its efficacy. This is in line with recent meta-analysis of real life teriparatide use in complex osteoporosis with multimorbidity. Though NICE stipulates minimum two fractures requirement (unless T score <-4.0), in practice most patients have had more than two fractures perhaps suggesting that clinicians are reserving it for high disease burden or there is a delay in referral and diagnosis. Our study should enhance clinicians’ confidence in its prescribing. It’s notable that the use is higher than current estimates based on NICE cost effectiveness analysis for eligibility of teriparatide. Instead of annual predicted use of 4.8/100,000 population, it was prescribed to 6.4/100,000. This could potentially have a cost impact however the introduction of a generic version would mitigate against it. We calculated our savings to be over £125,000 if all patients were switched. These savings at national level would hopefully improve access to a wider patient cohort and perhaps allow earlier use in the treatment paradigm. Disclosures T. Akram None. M. Siddique None. H.A. Javed None. J. Fourmy None. M.K. Nisar None.