Recent advances in synthetic drug manufacturing have introduced a new dynamic to the European regulatory system, with chemically synthesized polypeptide products using biological originator products as their reference medicine. Whereas biosimilars are subject to a dedicated regulatory framework in the EU, synthetically produced follow-on products are not eligible for assessment through this pathway, requiring approval via the traditional generic pathway under Article 10 (1), or via the hybrid pathway under Article 10 (3). This review presents an overview of recent developments in the field of synthetic peptides referencing biological originators in the EU. The use of different regulatory procedures can have potential implications for regulatory assessments, clinical practice and pharmacovigilance. As more complex synthetic products referencing recombinant originator products are expected in the coming years, this study promotes more transparency as well as global alignment about regulatory procedures for chemically synthesised products referencing biological originator products to ensure approval of safe and high-quality generics.

UNASSIGNED: A new oral paracetamol formulation with the same paracetamol quantity (24 mg/mL) as a marketed formulation but with finer active ingredient particle size and lower amounts of maltitol (5.85 g/dose in the test formulation vs 7.25 g/dose in the reference formulation) and sorbitol (2.4 g/dose vs 2.83 g/dose) was developed.
UNASSIGNED: Establish the bioequivalence of the new pediatric formulation (test treatment) compared with the marketed formulation (reference treatment).
UNASSIGNED: This Phase I, open-label trial assigned healthy adult volunteers to a single 42-mL (1 g para-cetamol) dose of test or reference treatment. Participants received both treatments in a randomized order separated by a 72-hour washout period. The primary endpoints were AUC0-tlast (AUC vs time curve from time 0 to last measurable sampling timepoint), Cmax, and tmax. Safety assessments included adverse event, clinical laboratory, and physical examination data.
UNASSIGNED: Thirty-five participants were randomized and treated. The study population was 42.9% women (57.1% men) with a median age of 30 years; most participants were non-Hispanic White. Mean Cmax values were comparable between test and reference products, with a median tmax of 1.00 hour for both. The test/reference ratios (%) (90% CI) for AUC0-tlast and Cmax were 98.69% (96.46, 100.97) and 100.73% (95.63, 106.10), respectively. There were no adverse events or deaths.
UNASSIGNED: The new paracetamol formulation is bioequivalent to the marketed formulation.

This study compared efficacy, safety, tolerability, pharmacokinetics (PK), and immunogenicity between AVT04 and reference product (RP) ustekinumab (Stelara®) in patients with moderate-to-severe chronic plaque psoriasis (PsO).
This multicenter, double-blind, 52-week study randomized patients in 1:2 ratio to AVT04 or RP. At week 16, responsive patients (≥50% improvement in psoriasis area and severity index (PASI)) previously on AVT04 continued on AVT04, while those on RP were re-randomized 1:1 to switch to AVT04 or stay on RP. The primary endpoint was a percent improvement in PASI from baseline to week 12. Therapeutic equivalence was demonstrated if the confidence interval (CI) for the adjusted difference in means was contained within the equivalence margins; ±10% (90%CI).
Of the 581 patients initially randomized (AVT04:RP, 194:387), 575 completed week 16 and 544 completed end of study visit. The percent PASI improvement for AVT04 vs RP was 87.3% vs 86.8% (CI: -2.14%, 3.01%); study met its primary endpoint. Efficacy, safety and PK profiles were comparable across treatment arms throughout the entire study duration, and the incidence of antibodies to ustekinumab had no clinically meaningful impact.
This study demonstrates the therapeutic equivalence between AVT04 and RP in patients with moderate-to-severe chronic PsO, with similar safety and tolerability.
NCT04930042; EudraCT Number: 2020-004,493-22.

UNASSIGNED: Once-daily tacrolimus reduces non-compliance relative to twice-daily tacrolimus. However, little is known about the safety and efficacy of conversion from twice-daily tacrolimus to generic once-daily tacrolimus in liver transplantation (LT). Herein, we investigated the efficacy and safety of a switch from twice-daily tacrolimus to generic once-daily tacrolimus in patients with stable liver graft function.
UNASSIGNED: This prospective, multicenter, open-label, single-arm study was conducted in 17 medical centers for 1 year from July 2019 to July 2020 (NCT04069065). Primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) for 24 weeks after conversion. Secondary endpoints were graft failure, patient death, and adverse events (AEs).
UNASSIGNED: Of 151 screened LT patients, 144 patients were enrolled. BPAR, graft failure, and patient death did not occur in this patient population. There were no statistical differences in blood tests, liver function tests, or biochemical tests between visits in any of the patients. Median tacrolimus trough level decreased abruptly from 4.7 ng/mL to 3.2 ng/mL after generic once-daily tacrolimus conversion, but median tacrolimus dose increased due to low tacrolimus trough level. Ninety-two adverse events occurred in 54 patients. Liver enzyme levels increased in seven patients (4.9%) after the switch to generic once-daily tacrolimus, but the liver function tests of these patients normalized thereafter. There were three cases of severe AEs not related to investigational drug.
UNASSIGNED: Present study suggests that conversion from twice-daily tacrolimus to generic once-daily tacrolimus is effective and safe in stable LT patients.

The brand interchangeability of antiepileptic drugs (AEDs) is a topic of debate, especially regarding their therapeutic equivalence. This study evaluates the efficacy and tolerability of generic levetiracetam compared to the brand-name equivalent in a routine clinical setting. We conducted a retrospective study, examining patients with stable seizure frequency who received generic levetiracetam after the brand-name drug. During the six-month substitution period, changes in seizure frequency, hospitalization due to seizure exacerbation, adverse events, composite outcomes related to adjusting the AED dosage, and switching back to original levetiracetam were analyzed. Seventy-five patients were enrolled; the majority (85.3%) had focal onset seizures, and almost half (49.3%) had refractory epilepsy. Six months after the substitution, the mean seizure frequency per month was not significantly different (3.15 ± 14.47 vs. 2.77 ± 11.41; p = 0.970). In patients with controlled seizures before the change, the seizure frequency increased significantly (0.56 ± 1.83 vs. 0.03 ± 0.16; p = 0.012). Adverse events occurred in six patients. We have observed recurrent seizures or adverse events from 14 days after the transition. The original drug return rates due to recurrent seizures and adverse events were 5.3% and 1.3%, respectively. Generic levetiracetam might not show therapeutic equivalence to the original molecule, especially in patients adequately controlled by the brand-name drug.

OBJECTIVE: Vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor to treat type 2 diabetes mellitus, is available as immediate release (IR) tablets administered at 50 mg twice daily (BID). A 100 mg modified release (MR) formulation was developed for once daily (QD) dosing. This study aimed to compare the therapeutic equivalence of vildagliptin 100 mg MR QD (test) and 50 mg IR BID (reference) formulations at steady state under fasting conditions.
METHODS: This was an open-label, randomized, two-period, single- and multiple-dose, two-way crossover, steady state study conducted in healthy adult subjects. Both vildagliptin formulations were administered for six days. Endpoints included pharmacodynamic equivalence, pharmacokinetic parameters, and tolerability of both formulations.
RESULTS: Thirty subjects were enrolled and 26 completed both treatments. Maximum plasma concentration and exposure achieved with test was lower than reference formulation on day 1 and 6. The DPP-4 enzyme inhibition over time (DPP-4-AUEC0-24) was comparable between the formulations. Both formulations were well tolerated.
CONCLUSIONS: This study confirms the therapeutic equivalence of vildagliptin IR and MR formulations for DPP-4 enzyme inhibition over time. The study supports vildagliptin 100 mg MR QD as a useful therapeutic alternative to 50 mg IR BID formulation to possibly improve treatment adherence and patient compliance. Long-term safety of the vildagliptin 100 mg MR QD formulation is not evaluated in this study.

BACKGROUND: Erythropoietin stimulating agent (ESA) has been standard of care in treating renal anaemia for the past 20 years. Many patients have limited access to ESA in view of long-term costs leading to suboptimal ESA dosage. Biosimilar epoetin is a potential cost-effective alternative to originator for optimal renal anaemia management.
OBJECTIVE: To determine efficacy and safety of PDA10 in treating renal anaemia in haemodialysis patients, in comparison to the originator epoetin-α, Eprex®.
METHODS: A phase 3, multicentre, multi-national, double-blind, randomised, active-controlled and parallel group study conducted over 40 weeks in Malaysia and Korea. End stage kidney disease patients undergoing regular haemodialysis who were on erythropoietin treatment were recruited. The study has 3 phases, which included a 12-week titration phase, followed by 28-week double-blind treatment phase and 24-week open-label extension phase.
RESULTS: The PDA10 and Eprex® were shown to be therapeutically equivalent (p < 0.0001) with mean absolute change in haemoglobin from baseline of - 0.176 (± 0.91) g/dl and - 0.118 (± 1.114) g/dl, respectively. Weekly dose change was 10.01 IU/kg/week in PDA10 group and 10.30 IU/kg/week in Eprex® group, which has no significant difference. There were no significant differences in the safety profile between PDA10 and Eprex® groups.
CONCLUSIONS: This study has confirmed the therapeutic equivalence between PDA10 and Eprex® in terms of efficacy, dosage requirement and safety profile in haemodialysis patients with renal anaemia.
BACKGROUND: The study was registered with the National Medical Research Register ( NMRR-13-400-16313 ). This study has been registered retrospectively with Clinical Research Information Service ( CRiS ), Republic of Korea on 25 March 2021.

UNASSIGNED: A new liquid levothyroxine (LT4) dissolved in glycerol and water has recently been developed by a Greek pharmaceutical company (Uni-Pharma, Athens, Greece).
UNASSIGNED: To evaluate the therapeutic equivalence of this new liquid LT4 preparation versus the already existing tablet formulation of the same manufacturer, in order to obtain approval by the Greek National Organization for Medicines.
UNASSIGNED: This was a prospective, randomized, cross-over phase III study. The study included 50 patients (9 men and 41 non-pregnant women, with a mean age of 42.5 ± 12.5 years), with documented overt primary hypothyroidism. All subjects were well controlled on substitution therapy with various LT4 formulations. None of the patients had known LT4 malabsorption. The patients were randomized into 2 groups (A and B). The individuals of group A initially received T4® tablets for 10 ± 2 weeks and subsequently switched to T4® drops (100 μg/mL solution) at the same dose for another 10 ± 2 weeks. In group B, the reverse procedure was followed. Total T3 (T3), free T4 (fT4), and TSH were measured in all participants at enrollment and at the end of each 10 ± 2-week trial period.
UNASSIGNED: Out of the 50 recruited patients, 6 were lost to follow-up and 5 were excluded due to non-compliance with the study protocol. In the 39 patients who completed the study, the serum TSH levels after 10 ± 2 weeks of treatment either with T4® tablets or with T4® drops did not differ (1.759 ± 1.104 vs. 2.076 ± 1.334 mIU/L, mean ± SD).
UNASSIGNED: In hypothyroid patients, the new liquid LT4 preparation (T4® drops) is therapeutically equivalent to the tablet form (T4® tablets).

Non-Biological Complex Drugs (NBCDs) are complex non-biological drugs comprised of large high molecular weight molecules and, often, nanoparticular structures (including liposomes and block-copolymer micelles). In the case of NBCDs, the entire complex is the active pharmaceutical ingredient and its properties cannot be fully characterized by physicochemical analysis. Moreover, the manufacturing process is fundamental in creating the correct originator product. The same is true for generic versions of the product. A recent appraisal of approval procedures for NBCDs \"follow-on products\" approved in Europe shows a diversity of regulatory pathways. In fact, three different abridged application procedures, under European legislation, were used: the generic application procedure of Article 10(1), the hybrid application procedure of Article 10(3), and the biosimilar application procedure of Article 10(4). Three informed consent applications via Article 10(c) from innovator companies of glatiramer acetate and sevelamer carbonate were submitted shortly after the approval of the first follow-on products. Furthermore, a number of \"well-established use\" applications [via Article 10(a)] were approved for iron sucrose and iron dextran complexes. In order to protect patients from the increased risks of NBCD products and NBCD follow-on products, two complementary approaches should be considered: (i) improving the regulatory procedures and their guidance documents within the pre-registration phase, and (ii) not considering interchangeability whenever clinical data is not available. With regards to the latter, the need for adequate safety and efficacy data might also include risk management programmes within post-approval pharmacovigilance actions. This, however, would depend on a risk appraisal that must be considered for individual medicinal products, based on the nature of the submitted relevant set of safety/efficacy data.

Every two years, the World Health Organization (WHO) updates its Model List of Essential Medicines, intended as a guide for countries to adopt or adapt in accordance with local priorities and treatment guidelines, for the development of national essential medicines lists. When more than one therapeutic option is available for a given indication, the WHO Model List often includes a single medicine as representative of a group of equivalent and interchangeable medicines. The representative medicine of that group is listed with an accompanying \'square box\' symbol. The intended purpose of the square box is to highlight pharmacological classes or groups of medicines for which countries, institutions and health professionals can assume homogeneous therapeutic efficacy and safety and select the most appropriate single medicine based on price, local availability, and acceptability. Though this concept of therapeutic equivalence within a therapeutic class has been endorsed by most authoritative textbooks of pharmacology since Goodman & Gilman\'s The Pharmacological Basis of Therapeutics and evidence-based guidelines, marketing forces have often made claims on individual drugs to distinguish them beyond relevant differences shown by reliable evidence: this has generated the concept of \"me-too drugs\" with its double meaning-i.e., market latecomers differing minimally from products preceding them and whose marketing budgets have significant opportunity costs, or medicines which may be useful to substitute for equivalent products in the event of shortages. The square box concept is applied in the context of a comprehensive list: therapeutic equivalence or interchangeability cannot always be easily established. Different interpretations have been applied to different groups of medicines over the 40+ year history of the Model List. This paper presents the concept of the square box, provides key examples and guidance on how square box listings should be practically interpreted in the development and implementation of national essential medicine lists, considers the applicability of a square box listing concept to biologic medicines and proposes that an updated review of the square box concept and listings is warranted.