Drug Discovery Today d Volume 26, Number 8 d August 2021 REVIEWS POST-SCREEN (GREY) Extrapolation: Experience gained from original biologics Luisa-Fernanda Rojas-Chavarro, Fernando de Mora ⇑ Department of Pharmacology, Therapeutics and Toxicology, Universidad Autónoma de Barcelona, Spain Biologicals undergo modifications throughout their commercial lifecycle. Major changes can unin- tentionally magnify their inherent physicochemical variability. Although trials comparing the pre- and the post-change versions have been requested occasionally, analytical comparison is the most sensitive approach to anticipating clinical equivalence. Therefore, it may be concluded, by means of ‘extrapolation’, that non-identical versions of a given biologic will behave equally in all indications. Despite the lessons learned with original biologics, there are still controversies around the approval of biosimilars through extrapolation. Here, a comprehensive analysis of scattered information allows for an account of cases of original biologic versions approved in some indications with no patient trials involved. Healthcare professionals can be reassured that inasmuch as extrapolation has proven valid for new versions of original biologics, the same holds for biosimilars. Keywords: Adalimumab; Biologic; Biosimilar; Canakinumab; Darbepoetin; Extrapolation; Manufacturing change; Omalizumab; Trastuzumab Marketing authorization of new versions of biological most biologics have an inherent structural variability that can be medicines inadvertently magnified through those changes.9,10 Moreover, Throughout their commercial lifecycle, biologics may be subject unwanted variations of other attributes (such as the amount of to changes in their manufacturing process and/or composition impurities) might occur as a result of environmental fluctuations.7 that are neither intended to modify the active substance nor to When a change has the potential to alter the identity, strength, create a new product.1,2 Such changes are meant either to trans- quality, purity, or potency of the product, it is considered a major form the production process (for example, to optimize manufac- change.11 European Medicines Agency (EMA) experts coined the turing efficiency) or to add therapeutic value (for example, to expression ‘new version’ for biomedicines that shift structurally allow a different route of administration).3 In those scenarios, in certain attributes as a result of such modifications.12 no changes in the medicine’s biological activity are expected. In order to ensure that the expected outcome of a major mod- However, besides the intended consequences, modifications ification is not accompanied by an unacceptable threat to the might induce unwanted alterations that can have an uninten- risk-to-benefit balance, authorities often require customized com- tional clinical impact, as documented for a number of original bio- parability studies before granting marketing authorization.13–15 logics.3–8 Indeed, in light of their origin and their protein nature, The nature and extension of the comparability program is Abbreviations: AUC, Area under curve; CHO, Chinese Hamster Ovary; CRF, chronic renal failure; EBC, early breast cancer; EC, European Commission; EMA, European Medicine’s Agency; EPO, erythropoietin; EU, European Union; FDA, US Food & Drug Administration; HCP, health care professionals; HER2, human epidermal growth factor receptor 2; IV, Intravenous; mAB, Monoclonal Antiibody; MAH, marketing authorization holder; MBC, metastatic breast cancer; MCB, Master cell bank; PD, pharmacodynamic; PK, pharmacokinetic; RA, rheumatoid arthritis; rHuEPO, recombinant human EPO; rHuP20, recombinant human hyaluronidase; SC, subcutaneous; TNF-a, Tumor Necrosis Factor-a; tpCR, total pathologic complete response. ⇑ Corresponding author. de Mora, F. (fernando.demora@uab.cat) 1359-6446/Ó 2021 The Author(s). Published by Elsevier Ltd. https://doi.org/10.1016/j.drudis.2021.05.006 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). www.drugdiscoverytoday.com 2003 POST-SCREEN (GREY) Drug Discovery Today d Volume 26, Number 8 d August 2021 established on a case-by-case basis, considering the extent of the change or upgrade technology, move to a new manufacturing modification, the product’s features and its intended clinical use. site, or optimize production efficiency.14 Some changes may be Specifically, when a major change is implemented, it is often nec- considered ‘major’ in light of their potential unintended collat- essary to carry out a comprehensive physicochemical and func- eral impact on the product’s pharmacological behavior. Despite tional comparability exercise, which may occasionally be that risk, regulatory agencies may authorize the use of the mod- supported by non-clinical and/or clinical data.13 Even when a ified product on the basis of comparability data (with no clinical modified original biologic exhibits physicochemical or pharma- trials) in all the targeted indications. AranespÒ is a paradigmatic cological changes, approval for some indications or patient pop- example (summarized in Table 2). ulations may be awarded by means of ‘extrapolation’, with no Darbepoetin alfa (darbepoetin) is the active substance of Ara- POST-SCREEN (GREY) specific comparative trials involved. Although approval based nespÒ, an original biotechnology-derived medicine. Darbepoetin on extrapolation is scientifically justified and has been practiced is a heavily glycosylated recombinant human erythropoietin for decades with original biologics, debate among healthcare pro- (EPO) analog that functions as a regulator of erythropoiesis.16,17 fessionals (HCP) over the risks of this practice started when The European Commission (EC) approved darbepoetin on the biosimilars, products that are similar to an approved ‘original’ ref- basis of safety and efficacy trials for the treatment of anemia erence biologic, (i.e. versions of original biologics), reached the resulting from chronic renal failure (CRF) in adults and children, market. To reassure HCP, cases in which the US Food and Drug and for the treatment of chemotherapy-induced anemia in Administration (FDA) and/or the EMA supported the marketing adults with non-myeloid malignancies.18–20 In 2008, the manu- authorization of modified original biologics with no comparative facturer of AranespÒ implemented a major change in the produc- patient studies in all indications, despite evidence of unintended tion process16,21: a more scalable and efficient high-throughput alterations, are thoroughly reviewed below. system, based on serum-free bioreactor technology, was intro- duced probably to reduce contamination.22 This necessitated the reestablishment of the master cell bank (MCB). As explained Extrapolation of original biologics by the FDA13 and others,23,24 changing the culture medium and The work over many years of the FDA, EMA, and other reference reestablishing the MCB are both major modifications of the pro- regulatory agencies in assessing original biotechnology-derived duction process. medicines has helped to shape stringent regulatory guidance This change produced a structurally distinct version of darbe- for the authorization of major changes. Three real-world cases poetin, which had a reduced sialylation rate, as reported by the of such modifications to original products containing darbepo- MAH and others.9,25 As the number of sialic acid units may have etin, adalimumab, and trastuzumab are analyzed below. The a significant impact on the behavior of any protein,26 sialylation main features of the products under scrutiny are listed in Table 1. may be considered a critical quality attribute.27,28 Indeed, recom- Although details of the changes implemented and their regula- binant human EPO (rHuEPO) isoforms that have quantitative tory assessment are not publicly available, there are some reliable differences in sialic acid contents exhibit different efficacies as relevant data in scattered FDA and EMA documents and in a result of differences in serum half-life.29 In addition, glycopat- research papers, including some from marketing authorization tern modifications can alter the immunogenicity of rHuEPO.30 In holders (MAH). view of the potential clinical impact of the altered glycopattern in the new darbepoetin version, additional studies to compare AranespÒ (darbepoetin) the functions of the pre- and the post-change versions of Arane- Modifications may be applied to a manufacturing process with spÒ, as well as a bioequivalence trial in healthy individuals,16 no primary intent to change the product’s therapeutic perfor- were undertaken. Neither significant functional differences, nor mance or usage, but rather to meet regulatory requirements in differences in the pharmacokinetic (PK) profile were revealed. A certain jurisdictions, scale up production, improve consistency, TABLE 1 FDA, and/or EMA approved indications, and active substance, of the three original biologics extrapolation case-studies. Original biological product Active substance Approved population or indication AranespÒ Darbepoetin alfa – Pediatric and adult patients with symptomatic anemia associated with chronic renal failure – Chemotherapy-induced anemia in adult cancer patients with non-myeloid malignancies HumiraÒ Adalimumab – Adult patients with rheumatoid arthritis – Juvenile polyarticular idiopathic arthritis – Psoriatic arthritis – Ankylosing spondylitis – Adult and pediatric Crohn’s disease – Ulcerative colitis – Adult and pediatric plaque psoriasis – Axial spondylarthritis without radiographic evidence of ankylosing spondylitis – Enthesitis-related arthritis – Hidradenitis suppurativa HerceptinÒ Trastuzumab – HER2-positive metastatic breast cancer – HER2-positive early breast cancer 2004 www.drugdiscoverytoday.com Drug Discovery Today d Volume 26, Number 8 d August 2021 POST-SCREEN (GREY) TABLE 2 Ò Ò Aranesp case-study. The table highlights a major modification associated with the shift in Aranesp manufacturing (to serum-free bioreactor technology), the purpose of this change, and the unintended physicochemical consequence that affects the glycopattern in the post-change version of this original biological product. It also summarizes the comparability exercise carried out to unravel essential sameness (post-modification studies). A single safety and efficacy trial was conducted to confirm comparability in adult patients who had symptomatic anemia associated with chronic renal failure (CRF). Approval was also granted by means of extrapolation to two additional patient populations/indications: pediatric patients with symptomatic anemia associated with chronic renal failure, and chemotherapy-induced anemia in adult cancer patients with non-myeloid malignancies. Reference POST-SCREEN (GREY) (s) Modification implemented Major modification: production process change to serum-free bioreactor technology 18,24,25 Objective: reduce contamination of the active substance, remove a potential source of infectious agents, and decrease costs Unwanted impact of the modification Glycopattern variation: modification of the sialylation rate. The amount of the more highly 11,28 sialylated isoform decreased by an average of 10%, whereas the less sialylated isoforms increased by 3% and 5% Post-modification studies a) Physicochemical comparability studies. 18,24,34 b) Non-clinical studies: – Single-dose pharmacokinetics study in male beagle dogs – A 4-week toxicity study in beagle dogs (PK and immunological) – In vitro binding study on frozen sections of human tissues. c) Clinical studies: – Comparative pharmacokinetic study in healthy subjects (n = 48) – Comparative clinical efficacy study in adult patients with symptomatic anemia associ- ated with CRF (n = 446). – Open-label, single-arm clinical safety study in patients with anemia associated with CRF (n = 1127) Approval involving a trial in patients – Adult patients with symptomatic anemia associated with CRF 18 Approval through extrapolation (No – Pediatric patients with symptomatic anemia associated with CRF 18 patient trials conducted) – Chemotherapy-induced anemia in adult cancer patients with non-myeloid malignancies comparative and a non-comparative safety trial in adult patients initially approved in the US and in the EU to treat rheumatoid with CRF confirmed that neither the efficacy nor the safety (in- arthritis (RA) in adult patients.33–35 Subsequent approvals in cluding the immunogenicity) of the drug were significantly adults included use in psoriatic arthritis, ankylosing spondylitis, altered as a result of the new production process.16,21,31 In spite Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis of the undesired physicochemical divergence in the active sub- suppurativa, and axial spondylarthritis without radiographic evi- stance, the European authorities estimated that the comparabil- dence of ankylosing spondylitis (the latter only in the EU). In ity assessment in adult CRF patients was sufficient to also claim pediatric patients, adalimumab was approved for the treatment high similarity in pediatric patients with anemia associated with of polyarticular juvenile idiopathic arthritis, Crohn’s disease, CRF and in adult patients with non-myeloid malignancies under- and, only in the EU, plaque psoriasis and active enthesitis- going chemotherapy, based on the totality of the evidence. The related arthritis.36–38 All of those approvals were based on clinical new, non-identical version of AranespÒ was therefore approved trials in each target population. by means of extrapolation. In 2015, the manufacturer of HumiraÒ presented a supple- mental application for a new formulation, intended to reduce HumiraÒ (adalimumab) pain associated with injection, that contained a doubled concen- Some major modifications are aimed primarily at changing the tration of adalimumab (100 mg/ml) and only two of the eight way in which a given product is administered in order to increase original excipients.33,38,39 Notwithstanding the expected bene- adherence (for example, by reducing the frequency of adminis- fits, the modifications were considered major. The FDA warned tration), reduce the incidence of local adverse reactions, facilitate that the new formulation might produce different plasma con- preparation, or extend the marketing authorization to new indi- centrations of adalimumab, which might change the benefit- cations or populations. Such modifications may involve changes to-risk balance.33 Likewise, an increased strength might foster to the excipients, the strength of the product (i.e. the concentra- aggregate formation, as highlighted by HumiraÒ’s MAH itself.40 tion of the active substance), the formulation and/or the delivery Aggregates can alter the delivery of the medicine, modify the device. Even when those modifications unintentionally alter PK profile, change the medicine’s efficacy and/or safety, and other properties, approval does not necessarily require trials in potentiate immunogenicity.41–43 In light of the warnings, a PK all the targeted patient populations. Modification of the original comparison in healthy individuals between the original and biologic HumiraÒ is one such example (summarized in Table 3). the new formulation was considered necessary.33 The area under Adalimumab, the active substance in HumiraÒ, is a mono- the curve (AUC) showed that the new formulation produced a clonal antibody that binds to tumor necrosis factor (TNF)-a and moderate increase overall in exposure to adalimumab.33,40 Phar- effectively mitigates the inflammatory cascade.32 HumiraÒ was macodynamic (PD) differences between the old and new www.drugdiscoverytoday.com 2005 POST-SCREEN (GREY) Drug Discovery Today d Volume 26, Number 8 d August 2021 TABLE 3 Ò Ò Humira case study. The table highlights the major modification of the composition of Humira (formulation and strength), the purpose of this change, and the unintended consequence for the pharmacokinetic profile of the post-change version of this original biological product. It also summarizes the comparability exercise carried out to unravel essential sameness (post-modification studies). A single safety and efficacy trial was conducted in adult patients with rheumatoid arthritis to confirm comparability. Approval was also granted by means of extrapolation to 11 additional patient populations/indications. References Modification implemented Major modification: formulation/concentration change/device needle 36,41,42 Objective: increasing patient comfort through less injection-related pain on the basis of reduced POST-SCREEN (GREY) injection volume and removal of some of the excipients in the currently marketed formulation that may contribute to pain sensation. Unwanted impact of the modification Pharmacokinetic (PK) variation 36,43 Post-modification studies a) Chemistry, manufacturing and control comparability data. 36,42,43 b) Device functional testing (needle) c) Clinical studies 56,62: – SD comparative PK study in healthy subjects (n = 200). – SD comparative PK study in healthy subjects (n = 296). – 24-week, randomized, double-blind, PK, pharmacodynamic, safety and immunogenic- ity comparative study in adult patients with rheumatoid arthritis (n = 100). – 24-week, open-label study in adult patients with rheumatoid arthritis (n = 88). – Two phase 2, randomized, single-blind, crossover studies in adult patients with rheumatoid arthritis (n = 122). Approval involving a trial in patients – Adult patients with rheumatoid arthritis 36,42,43 Approval through extrapolation (No – Juvenile polyarticular idiopathic arthritis 36,40,41 patient trials conducted) – Psoriatic arthritis – Ankylosing spondylitis – Adult and pediatric Crohn’s disease – Ulcerative colitis – Adult and pediatric plaque psoriasis – Axial spondylarthritis without radiographic evidence of ankylosing spondylitis – Enthesitis-related arthritis – Hidradenitis suppurativa HumiraÒ versions were also reported.33 Therefore, a comparative Trastuzumab, the active substance of HerceptinÒ, is a human- efficacy and safety trial, as well as an open label extension study ized monoclonal antibody that binds to human epidermal with the new formulation, were performed in adult patients with growth factor receptor 2 (HER2). This receptor is overexpressed RA. Those studies did not reveal any clinical difference between on certain tumor cells and trastuzumab inhibits their prolifera- the two product formulations in RA.33,44,45 Furthermore, no dif- tion.47 HerceptinÒ powder formulation was approved for intra- ferences in aggregate formation were found.40 The FDA and the venous (IV) infusion to treat HER2-positive metastatic breast EMA33,37 determined that the results of the analytical studies cancer (MBC) as monotherapy or in combination with pacli- and the clinical assessment in RA were sufficient to anticipate taxel.48–50 Subsequent extensions of marketing authorizations equivalence between both versions in indications that had not included adjuvant treatment of HER2-positive early breast cancer been specifically tested, even though the development of the (EBC) as a monotherapy or in combination with cytotoxic original formulation of HumiraÒ had revealed differences in PK agents, treatment of HER2-positive MBC in combination with and safety across indications.46 Hence, the observed PK and PD aromatase inhibitor or docetaxel (only in the EU), treatment of differences upon reformulation did not prevent agencies from HER2-positive metastatic gastric cancer or gastroesophageal junc- approving the new non-identical HumiraÒ version in nine indi- tion adenocarcinoma in combination with chemotherapy, and cations on the basis of extrapolation. neoadjuvant-adjuvant combination treatment of HER2-positive EBC (only in the EU).51–53 Each of these approvals relied on a specific clinical efficacy and safety trials. HerceptinÒ (trastuzumab) In 2012, the MAH of HerceptinÒ applied for approval of a sub- Modifications that are broader than those described above may cutaneous (SC) formulation to be administered as monotherapy be applied to a biologic with the primary aim of producing an or in combination to treat MBC and EBC patients.51 The SC route incremental therapeutic gain. A change in the delivery route, has the advantage of being less invasive and requiring a shorter for instance, accompanied by dosage adjustments, might be par- time for administration. In addition, as claimed by the alleled by unwanted changes. In spite of the magnitude of the MAH,54,55 SC administration causes fewer infusion-related reac- variation, authorization may be awarded for indications for tions, requires less hospital resources, and costs less than IV which there has been no pre-approval comparative testing in administration, and therefore was expected to improve patient patients; that is, through extrapolation. HerceptinÒ is a well- convenience and compliance. However, as per the relevant guid- documented example (summarized in Table 4). ance,56,57 a change in the administration route can alter the 2006 www.drugdiscoverytoday.com Drug Discovery Today d Volume 26, Number 8 d August 2021 POST-SCREEN (GREY) TABLE 4 Ò Ò Herceptin case study. The table highlights the major modification of the manufacturing and composition of Herceptin resulting from the development of the subcutaneous formulation, the purpose of such development, and the unintended pharmacological consequences uncovered in the subcutaneous (SC) variant of this original biological product. It also summarizes the comparability exercise carried out to unravel essential sameness (post-modification studies). A single safety and efficacy trial comparing the intravenous (IV) and the SC formulation was conducted in HER2-positive early breast cancer (EBC) patients to confirm comparability. Approval was also granted by means of extrapolation to HER2-positive metastatic breast cancer (MBC) and combination therapy in EBC. Reference POST-SCREEN (GREY) (s) Modification implemented Major modification: route of administration change (from IV to SC)/formulation/pharmaceutical 54,57 form/concentration change Objective: reduce infusion-related reactions, improve the use of hospital resources, and reduce the costs associated with IV administration. All in all, this route was meant to improve patient convenience and compliance. Unwanted impact of the modification – Pharmacokinetic (PK) variation 54,64–66 – Adverse events variation – Immunogenicity variation Post-modification studies a) Physicochemical comparability studies for active substance and finished medicinal 54,64,65 product. b) Physicochemical assays for recombinant human EPO (rHuPH20). c) Non-clinical studies: – Toxicity profile of rHuPH20 in mice and in cynomolgus monkeys. – Kinetics of rHuPH20 in mice. – Repeated dose PK study of rHuPh20 in cynomolgus monkeys. – PK study of subcutaneously administered trastuzumab with rHuPH20 in mice, Göttin- gen minipigs and cynomolgus monkeys. – SC local tolerance study with trastuzumab formulated with rHuPH20 in rabbits. Approval involving a trial in patients – HER2-positive early breast cancer. 58 Approval through extrapolation (No – HER2-positive metastatic breast cancer 54 patient trials conducted) – HER2-positive early breast cancer (additional combined therapy) benefit-to-risk balance. Indeed, SC administration of biologics exposure comparable to that achieved through IV administra- has been associated with degradation at the injection site, tion,54 and one pivotal comparative study (HannaH) in which increased incidence of local adverse reactions, greater inter- trastuzumab was administered as a neoadjuvant treatment (in individual variability in dosing, and decreased bioavailability, combination with chemotherapy) and as an adjuvant treatment and it is generally considered to be more immunogenic than (monotherapy) in patients with HER2-positive EBC.55 Although the IV formulation.57–59 In addition to the increased concentra- the efficacies of the SC and IV formulations were found to be tion of trastuzumab, SC HerceptinÒ, which was formulated as a comparable, there were differences at other levels. The SC regi- solution for injection rather than as a powder, contained L- men (a fixed dose every three weeks) resulted in increased sys- methionine as a stabilizer and a novel biological excipient, temic exposure to trastuzumab, especially in patients with recombinant human hyaluronidase (rHuP20).47,51,60 The new lower body weight.51,61–63 Furthermore, immunogenicity and formulation required a shift from a body-weight-adjusted IV reg- the incidence of serious adverse events were higher in patients imen to a fixed-dose SC regimen, with no loading dose that received the SC regimen,51,61,62 although it was not possible required.47,51 These are substantial changes that may have an to unequivocally associate these events to the increased expo- impact on the benefit-to-risk balance of any biologic.11 sure. Despite the remaining uncertainty, SC HerceptinÒ was In the USA, the subcutaneous variant was not considered to approved on the basis of the totality of the evidence for all the be the same product and was re-named HylectaÒ, because accord- combination therapies for which IV HerceptinÒ had been ing to the FDA, this product contains two active ingredients, tras- approved. Including adjuvant settings, and patients with MBC. tuzumab and hyaluronidase-oysk.61 In Europe, the brand name Hence, the conclusion of equivalence between the two formula- was preserved. In light of the anticipated risks, the MAH sup- tions of HerceptinÒ was extrapolated to untested indications on ported the application with a comprehensive comparability data the basis of a consistent scientific rationale. package. Analytical, non-clinical, and clinical studies comparing the SC and IV formulations were conducted. In addition, non- Lessons learned from extrapolating original biologics clinical studies with the new excipient rHuP20 were performed Modifications of the manufacturing or composition of original to supplement the existing knowledge, given that the addition biologics have had unintended clinical consequences. A well- of rHuP20 was considered a major in-product innovation.51,62,63 known example is the unique but dramatic shift in the immuno- The clinical comparability program consisted of one PK study in genicity of epoetin alfa as a result of the replacement of a single healthy male volunteers and female patients with HER2-positive excipient.8 Also, the relocation of manufacturing processes for EBC to determine the dose of SC trastuzumab that resulted in an ErbituxÒ (cetuximab) resulted in significant PK changes, as noti- www.drugdiscoverytoday.com 2007 POST-SCREEN (GREY) Drug Discovery Today d Volume 26, Number 8 d August 2021 fied in the US prescribing information,6,7 although it did not glycan profile was observed around the time of the implementa- result in meaningful differences in efficacy or safety.64 The tion of the new production process,9 although available informa- potential for the development of thrombotic microangiopathy tion does not allow an unequivocal connection between these in a cluster of patients treated with RebifÒ (interferon b-1a) after two events. According to EnbrelÒ’s MAH registry of clinical trials, removing albumin from the formulation4,6 was added to the pre- the new version was probably authorized for various indications scribing information,65 although it was not possible to unam- on the basis of analytical studies and just one non-comparative biguously establish a cause–effect relationship. Likewise, a drift clinical trial in adult patients with RA.72–74 in the glycan expression in some HerceptinÒ batches was found The comparative PK assessment of the two formulations/ to affect the antibody-dependent cell-mediated cytotoxicity strengths of HumiraÒ revealed differences that triggered the POST-SCREEN (GREY) (ADCC),3 which in turn impacted the complete response rate.5,66 requirement for a safety and efficacy trial in RA. Subsequent to In light of the clinical risk associated with major changes, regula- the trial outcome, in spite of PK differences, the new HumiraÒ tors often request comparative studies to inform the approval of version was approved in nine indications by means of extrapola- the novel biologic versions.13,15 Although the FDA and EMA tion. Noticeably, in the development of original HumiraÒ, some have learned lessons from monitoring original biologics, they patients were exposed to higher doses without any consequences usually do not provide detailed information about the studies for the overall safety profile, which probably contributed to the presented to support the approval of post-modified versions. post-change approval decision. Interestingly, by contrast, a com- Therefore, a comprehensive integrative bibliographic analysis, parative PK study of ErbituxÒ, another product undergoing a primarily looking at information from regulatory sources but also strength modification, raised no concerns, and marketing autho- examining information and scientific papers from manufactur- rization was granted without the need for an efficacy trial. 75 Sim- ers, has allowed the reciprocal connection of data, leading to ilarly, major modifications were made to two original biologics, the construction of a rigorous account of the regulatory decisions XolairÒ (omalizumab) and IlarisÒ (canakinumab), to ease the and studies behind authorization. One lesson learned is the low preparation or the administration of the product, or to reduce sensitivity, and therefore the limited value, of efficacy and/or the volume injected.76–81 During the post-modification compara- safety trials in identifying minor differences between versions bility studies, unintended variations of potential clinical concern of a given biologic. Indeed, two versions of a given biomolecule were detected (Table 5). However, preclinical and clinical data must behave the same way clinically if they share the critical packages provided reassuring comparability, which formed the quality attributes shown analytically. The three case studies basis for the approval of the modified versions of both drugs described here (AranespÒ, HumiraÒ, and HerceptinÒ) reflect the without the requirement to extend the comparative assessment regulatory thinking, and hence the scientific evidence, behind to all targeted patient populations and indications. approvals based on extrapolation. The development of a new route of administration for a bio- The FDA, EMA, and other regulatory bodies have provided logic is a considerable endeavor, entailing substantial modifica- extensive explanations of the science behind extrapola- tions for which some health authorities would require a new tion.12,67,68 A study in patients to support a claim of comparabil- marketing authorization.82 In the case of HerceptinÒ, those mod- ity may sometimes be requested by regulators. In these cases, the ifications were implemented to shift from IV to SC administra- trial selection and design should be suitable to unravel version- tion. Notwithstanding the expected benefits, the risks to-version, rather than patient- or disease-related, differences.69 associated with this shift justified the need for an extensive com- Further comparative studies in additional indications or popula- parative assessment. To gain approval, the MAH of HerceptinÒ tions may not be needed in light of the totality of the compara- presented a comprehensive, analytical, nonclinical and clinical bility evidence. The requirement for studies to determine the comparability data package. EMA and HerceptinÒ’s MAH51,83 comparability of pre- and post-change versions needs to be estab- agreed that EBC was the most sensitive population for a compar- lished on a case-by-case basis. ative trial, given the relatively high homogeneity of inter-patient In the AranespÒ situation, where the modifications were not responses resulting from the drug-free phase following adjuvant intended to change the product composition, the new version treatment. Despite revealing comparable efficacy, the two formu- of the active substance exhibited unwanted physicochemical dif- lations exhibited differences in their PK and safety profiles, ferences of potential clinical significance. Despite those struc- which were possibly attributable to either physicochemical dif- tural differences, a PK study in healthy volunteers, a ferences or differences in the dosage regimens. Noticeably, the comparative efficacy trial in a single indication, and a non- new excipient, rHuP20, was shown to generate anti- comparative safety trial were sufficient to justify authorization hyaluronidase antibodies in patients with EBC.51,55 In addition, of the non-identical AranespÒ version in unstudied indications. the production of anti-protein antibodies, as per EMA guidance, Interestingly, approval through extrapolation was granted may vary among indications.57 Furthermore, during the clinical despite evidence that the benefit-to-risk balance and/or the PK development of the original IV formulation, the drug displayed profile might differ among patient populations or indica- differences in safety51,84 and PK85 between patients with EBC tions.20,70 The remaining uncertainty was considered insignifi- and with MBC. In spite of those uncertainties, in light of the cant, a decision that has been justified by the performance of totality of the evidence, the remaining residual risk was consid- the product after the new version reached the market. Likewise, ered acceptable for approval of the SC HerceptinÒ in MBC with EnbrelÒ, an original biologic that contains the active substance no patient trials involved. Recommended post-authorization etanercept was subjected to a change involving a shift to a studies confirmed the anticipated conclusions.51,53,86,87 Interest- serum-free bioreactor71 (Table 5). A significant variation of the ingly, when the same MAH developed an SC variant of the orig- 2008 www.drugdiscoverytoday.com Drug Discovery Today d Volume 26, Number 8 d August 2021 POST-SCREEN (GREY) TABLE 5 Additional cases of the approval through extrapolation of non-identical versions of biological medicines resulting from major changes. The table highlights the patient trials undertaken for the approval of post-manufacturing-change versions of three original biological medicines containing etanercept, omalizumab and canakinumab, all of which had undergone major modifications. It also lists the unintended variations detected as a result of the modification, and the authorized indications for the new modified non- identical version. On average, most of the approved indications were not tested during the comparability assessment of the pre- and post-change products. Approval has been mostly granted through extrapolation. The table also notes the actual unintended impact of the modifications on the quality attributes of the product and on its clinical behavior. The studies required for approval are not extensively made public, so some relevant facts may be missing. In any case, the information provided to the evaluators allowed them POST-SCREEN (GREY) to justify approval through extrapolation on the basis of a solid scientific rationale. FMF, familial Mediterranean fever; HIDS/MKD, hyperimmunoglobulin D syndrome/mevalonate kinase deficiency; TRAPS, tumor necrosis factor receptor-associated periodic 1 2 3 syndrome. From indirect sources. Variations observed in the initial studies, but not in the definitive studies presented. Cause not reliably identified. Original biological Unwanted impact of Approval involving a trial in patients Approval through extrapolation (No product modification patient trials conducted) Enbrel (etanercept) Change to a serum-free – Adult rheumatoid arthritis (no comparability study) – Polyarticular juvenile idiopathic manufacturing process arthritis in children aged 4 to Impact: 17 years – Glycan profile variation1 – Psoriatic arthritis – Ankylosing spondylitis – Plaque psoriasis in adults Xolair (omalizumab) Formulation/pharmaceutical - Adult patients with asthma, and/or allergic or – Severe persistent asthma in chil- form/concentration/device perennial rhinitis with elevated serum dren from 6 years age change immunoglobulin E (IgE) levels – Chronic idiopathic urticaria in Impact: – Patients (12 years) with moderate to severe per- adults and adolescents 12 years of – new Fab fragment identi- sistent allergic asthma age and older fied (initially2) – PK variation (initially2) – PD variation (initially2) Ilaris (canakinumab) Formulation/pharmaceutical – Adult and pediatric TRAPS – Adult and pediatric (2 years) Cry- form change – Adult and pediatric HIDS/MKD opyrin-associated periodic Impact: – Adult and pediatric FMF syndromes – Immunogenicity – Still’s disease (2 years) variation3 – Systemic juvenile idiopatic arthritis (2 years) – Gouty arthritis in adults inal biologic MabtheraÒ/RituxanÒ (rituximab), regulators deter- patient trials, given that such trials have intrinsically limited res- mined that the evidence did not support extrapolation, and olution when compared to modern analytics.13,69,92,94 Indeed, did not grant authorization for use in the three requested indica- because structure and function are integrally related, extrapola- tions.88 Therefore, extrapolation is not always granted, and needs tion is between molecules and not between indications.13 a thorough scientific justification. In the study cases and exam- Although understanding of the science of biosimilarity has ples mentioned in this paper (AranespÒ, HumiraÒ, HerceptinÒ, increased among HCP, the approval of biosimilars by extrapola- EnbrelÒ, IlarisÒ and XolairÒ), the post-modification versions were tion is still subject to an ongoing controversial debate.95,96 As for granted a marketing authorization by means of data extrapola- pre- and post-change versions of original biologics, studies of tion in an average of 68% of the approved indications (Fig. 1). essential molecular overlap and equivalent biological activity Extrapolation is therefore not a new concept but a well- are the most sensitive approach to detect minute (even clinically established scientific principle. meaningless) differences between a biosimilar candidate and the original reference biologic.89,90 Although analytical comparabil- Extrapolation for biosimilars: Building on lessons ity may be fairly reassuring on its own, regulatory bodies require learned from original biologics additional pre-authorization evidence of similarity. The most sensitive clinical studies for comparing two products include A biosimilar is a biological medicine that is essentially the same PK equivalence (bioequivalence) preferably in healthy volun- as an original reference product as assessed by stringent regula- teers, PD data when there is an appropriate surrogate marker, tory standards,13,69,89 to the extent that they may be considered and immunogenicity assessment.97–99 A regulatory filing should interchangeable.90–92 The scientific principles for establishing contain the data necessary to make a regulatory decision, but not biosimilarity are the same as those for demonstrating compara- be overbuilt for reasons beyond science. Accordingly, on the bility after a change in the manufacturing process or in the com- basis of experience gained from the monitoring of original bio- position of an already licensed biological.93 On the basis of such logics, it appears that comparative efficacy and safety trials in principles, relying on the totality of the evidence, a conclusion of patients are generally much less sensitive than analytical compa- biosimilarity may be extended to the full range of indications rability in substantiating a claim of high similarity,100 although granted to the original reference medicine with no comparative www.drugdiscoverytoday.com 2009 POST-SCREEN (GREY) Drug Discovery Today d Volume 26, Number 8 d August 2021 45% 67% POST-SCREEN (GREY) 92% Paent trials NO Paent trials 67% 50% 80% Drug Discovery Today FIGURE 1 Percentage of patient populations in which post-change versions of original biologics were approved with no trials involved. Each color in the chart symbolizes one of six original biological medicines that have been the subject of a manufacturing or composition change. For each medicine/color, the solidly colored area represents the number of patient populations in which a trial was conducted for post-change approval, and the dotted area represents the patient populations in which approval of the post-change version did not involve a patient trial (the relative ratio is stated). The sum of both areas per color represents the overall number of patient populations/indications for which the post-change product was approved. In the six reported cases, approval was granted by means of extrapolation in an average of 67% of the patient populations/indications. in some cases such confirmatory studies have been requested by original biologic that has undergone a manufacturing or a com- authorities on the grounds that they can mitigate a residual position change. Hence, extrapolation of a conclusion of equiv- risk.69,91,97,101,102 On those same grounds, in most cases it would alence among non-identical versions of biological products, be scientifically meaningless, and also ethically questionable, to whether post-manufacturing batches or biosimilar candidates, extend patient comparability studies to all indications.103 reflects the ever-increasing experience of biopharmaceutical Recently, biosimilar industry representatives and the UK regula- companies and regulatory bodies in comparing versions of orig- tory authority have bluntly questioned the need for patient trials inal biologics. HCP should trust that a modified version of a at all, unless exceptionally justified.96,104 Notwithstanding this given biologic is only approved if the active substance, as well current debate, biosimilar products bearing infliximab,105 ritux- as the quality, efficacy, and safety of the pre-change version, imab,106 adalimumab,107 trastuzumab,108 bevacizumab,109 are preserved. Noticeably, referring to the original SC HerceptinÒ rFSH110 and others, have been approved in most patient popula- case, EMA experts stated that12 “a formulation difference of this tions through extrapolation. The European model has proven magnitude would not be acceptable for a biosimilar compared successful,111,112 and such practice has contributed to add value with the reference product”. Approval of biosimilars by extrapo- to biosimilars.113 Hence, to patients. lation should therefore not trigger discomfort among HCP, as it In conclusion, approval through extrapolation has been prac- has not caused concerns in the original biologics scenario. ticed by regulators in the original medicines arena for decades. Despite that, a debate over the risks of extrapolation was created Declaration of Competing Interest with the arrival of biosimilars. The approval of non-identical ver- The authors declare the following financial interests/personal sions of original biologics for indications or populations that are relationships which may be considered as potential competing not specifically studied during development has been fully justi- interests: FdeM has worked as speaker or consultant for both com- fied scientifically, and extensively explained. Real world evidence panies that develop and/or market biosimilars (Amgen, Biogen, from post-marketing surveillance has further supported such Boehringer, Celltrion, Kern Pharma, Lilly, Novartis, Pfizer, Sam- practice. Likewise, more than fourteen years of experience with sung Bioepis, Sandoz, and Stada) and companies that develop biosimilars in the European market supports their efficacy and and/or market original biologics (Amgen, Biogen, Boehringer, safety in all approved indications, whether tested during devel- Lilly, Pfizer, Roche). LFRC declares no competing financial inter- opment or authorized on the basis of extrapolation.13,112,113 This ests or other relationships with other people or organizations that supports the affirmation that biosimilars are at least as safe as any could have appeared to influence the work reported in this paper. 2010 www.drugdiscoverytoday.com Drug Discovery Today d Volume 26, Number 8 d August 2021 POST-SCREEN (GREY) References 1 European Medicines Agency. Manufacturing process changes, biologic product scientific-discussion-variation_en.pdf Published 9 October 2007 [accessed 29 comparability and post approval changes, SME Workshop 16 April 2015. www. December, 2019]. ema.europa.eu/en/documents/presentation/presentation-manufacturing- 21 AMGEN. Clinical study report synopsis AMGEN; study ID 20040104. process-changes-biologic-product-comparability-post-approval-changes_en.pdf. 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