Customer-centric product presentations for monoclonal antibodies

Beate Bittner

doi:10.1186/s41120-022-00069-y

Customer-centric product presentations for monoclonal antibodies

Bittner, Beate 2023-01-23 00:00:00 Delivering customer-centric product presentations for biotherapeutics, such as monoclonal antibodies (mAbs), repre- sents a long-standing and paramount area of engagement for pharmaceutical scientists. Activities include improving experience with the dosing procedure, reducing drug administration-related expenditures, and ultimately shifting parenteral treatments outside of a controlled healthcare institutional setting. In times of increasingly cost-constrained markets and reinforced with the coronavirus pandemic, this discipline of “Product Optimization” in healthcare has gained momentum and changed from a nice-to-have into a must. This review summarizes latest trends in the healthcare ecosystem that inform key strategies for developing customer- centric products, including the availability of a wider array of sustainable drug delivery options and treatment man- agement plans that support dosing in a flexible care setting. Three disease area archetypes with varying degree of implementation of customer-centric concepts are introduced to highlight relevant market differences and similarities. Namely, rheumatoid arthritis and inflammatory bowel disease, multiple sclerosis, and oncology have been chosen due to differences in the availability of subcutaneously dosed and ready-to-use self-administration products for mAb medicines and their follow-on biologics. Different launch scenarios are described from a manufacturer’s perspective highlighting the necessity of platform approaches. To unfold the full potential of customer-centric care, value-based healthcare provider reimbursement schemes that incentivize the efficiency of care need to be broadly implemented. Keywords Customer centricity, Parenteral, Oral, Subcutaneous, Flexible care setting, Product optimization (Fernández et al. 2017) and frequently mandates more Introduction burdensome in-clinic dosing (Bohra et al. 2020). Over the past quarter century, biotherapeutics, such In times of continuously growing cost pressure on as monoclonal antibodies (mAbs), have become a pre- healthcare and major implications of the pandemic on vailing novel treatment modality (Lu et al. 2020) and as established medical services (Arsenault et al. 2022), any such significantly contribute to both the costs (Hernan - effort in minimizing the dosing complexity of paren - dez et al. 2018) and the environmental impact (Amasawa teral administration has the potential to reduce expen- et al. 2021) of healthcare. Inherent to their physicochemi- ditures for the drug administration procedure. For cal properties, mAbs must be administered parenter- instance, if permitted by the safety profile of a biologi - ally, a circumstance that can be considered inconvenient cal medicine, an attempt to lessen in-clinic time during an intravenous dosing day is the provision of fast infu- sion regimens. This approach can improve cost-effec - *Correspondence: Beate Bittner tiveness of the treatment, as it allows more people to be beate.bittner@roche.com treated in the clinic within a given time frame (Spadaro F. Hoffmann-La Roche Ltd., Global Product Strategy - Product et al. 2017). To further facilitate intravenous dosing and Optimization, Grenzacher Strasse 124, CH-4070 Basel, Switzerland to aid operators with obtaining central vascular access, © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Bittner AAPS Open (2023) 9:3 Page 2 of 25 new device types, such as a handheld assistive artificial healthcare providers and regulators. This is particularly intelligence-enabled, ultrasound-guided robotic device the case for mAbs that exhibit severe infusion-related for intravenous catheterization, are currently undergo- reactions (IRRs) mainly occurring during the first dosing ing early development (Brattain et al. 2021). cycles (Rombouts et al. 2020). An alternative concept for optimizing hospital To improve adherence to parenteral dosing in a non- resource utilization that has been in the center of inter- controlled setting, the individual demands of people est of many drug delivery researchers in recent years treated with mAbs have to be accounted for by manu- represents reformulating a biological medication for facturers. In addition to interventions that address edu- application via a less-invasive administration route. In cational, behavioral or psychological barriers against 2014, Tetteh et al. (2014) developed a regression-based complying with the dosing regimen (Remington et al. algorithm that included an estimate on how the admin- 2013), providing personalized and thus customer-centric istration route of biotherapeutics, including mAbs, product presentations and administration schemes has may impact on healthcare delivery expenditures. The the potential to enhance adherence to parenteral home analysis suggests that assuming no other change (that administration overall (Ridyard et al. 2016). is, in-clinic dosing, dosing frequency), subcutaneous or The term customer centricity is applied across indus - intramuscular administration of biologics lowers total tries highlighting that in order to achieve sustainable healthcare delivery costs as compared to intravenous product offerings, satisfying the needs of “the customer” infusions. has to be the ultimate focus for any development decision A more significant step in reducing dosing regimen- (Pardo-Jaramillo et al. 2020). For medicinal products, related inconvenience, healthcare institutional spend- “the customer” is classically defined as “the patient,” but ing and in improving affordability and access to mAb increasingly the entire healthcare ecosystem is referred treatments is to shift dosing outside of the clinical set- to using this term. Thus, in addition to people receiving ting (Wolfromm et al. 2017; Bittner et al. 2018; Bittner treatment for a diagnosed medical condition, this eco- and Schmidt 2021). Here, subcutaneous at-home- and system comprises professional healthcare providers and self-administration has become an established dosing institutions, regulators, payers (Pidun et al. 2021), and regimen for mAbs with a favorable safety and tolerabil- ultimately society as a whole. ity profile across different disease areas (Gottlieb et al. In the pharmaceutical industry, efforts to ameliorate 2016, Raffaelli et al. 2019, Van den Bemt et al. 2019, Tim - the product profile of an established medicine are driven mermann et al. 2020, Jappe et al. 2021, Bagel et al. 2022). by the cross-functional discipline of “Product Opti- Especially low-volume subcutaneous injections can mization” (Bittner and Schmidt 2022). “Product Opti- be self-administered by means of a variety of prefilled mization” also referred to as “Formulation and Device syringes or pen device types, thus accounting for per- Lifecycle Management” aims at improving the drug deliv- sonal priorities and capabilities (Anderson and Redondo ery profile and product presentation for a medicine that 2011; Vermeire et al. 2018). While these automated dos- is either already on the market or in late-stage clinical ing aids support convenience with an at-home dosing development and thus at providing a more customer- regimen, adherence and persistence to subcutaneous centric presentation. administration in an unsupervised setting varies between This review is written from a manufacturer’s per - medical products (Tkacz et al. 2014; Nieto et al. 2021). spective and summarizes key trends in the healthcare Besides disease severity or prior experience with sub- ecosystem that define customer-centric drug delivery cutaneous administration, also the dosing schedule can requirements for mAbs across different therapeutic areas, contribute to compliance issues with the prespecified illustrates approaches to obtain insights into emerging application procedures (Tkacz et al. 2014). drug delivery necessities, and compares the latest devel- The situation is complicated specifically for high-dose opments in three distinct disease area archetypes. mAbs requiring comparatively large administration vol- umes and for mAbs dosed in combination therapy. While Drug delivery as treatment enabler user preference assessments demonstrate that even in versus as customer‑centric differentiator the hospital setting, high-dose subcutaneous injections Drug delivery is commonly explained as the “method or with individual dose volumes between 5 and 15 milliliters process of administering a pharmaceutical compound (mL) are preferred over intravenous infusion regimens to achieve a therapeutic effect” (Gupta and Kumar 2012; (Pivot et al. 2014; Rummel et al. 2017; O’Shaughnessy Tiwari et al. 2012). This definition predominantly refers et al. 2021; Usmani et al. 2021), customized dosing to drug delivery technologies that enable the admin- schemes for at-home administration still remain to be istration of pharmaceutical products per se. Such is developed by manufacturers in close cooperation with particularly the case when developing formulation or Bittner AAPS Open (2023) 9:3 Page 3 of 25 device technologies for novel treatment modalities unsupervised parenteral dosing. In this case, provid- with previously unexplored physicochemical and phar- ers, in order to support dosing in a remote setting, macokinetic properties. Frequently, in these instances, require reassurance that high-quality disease monitor- there is neither experience available on how a galeni- ing and adherence to treatment procedures is main- cal formulation can impact bioavailability, safety or tained. Assuming compliance and adequate support efficacy of the medication, nor on what would be the services are guaranteed for parenteral administration most preferred product profile from a customer per - outside of a healthcare institution, the underlying spective. Focus of drug delivery scientists is therefore societal benefits of at-home- and particularly the eco- on progressing a product presentation that achieves the nomic benefits of self-administration (Franken et al. required target exposure via an appropriate administra- 2020) are pivotal elements of value-based healthcare tion route. Especially with new and possibly disease- (Dainty et al. 2018, Teisberg et al. 2020). modifying biological molecules, technologies that go From a regulator’s perspective, mAbs suitable for beyond treatment enablement may either have not yet home administration must possess an appropriate safety been identified or are still in early development (Blanco profile and must be available in a product presentation and Gardinier 2020). Aspects of convenient dosing or that supports unsupervised administration (Bittner and efficient healthcare resource utilization are of second - Schmidt 2022). As data derived from registrational clini- ary priority at this stage. Consequently, any formulation cal trial investigations alone may not exhaustively reveal and device optimization that would delay initial mole- feasibility of a flexible care setting, additional sources cule launch and thus availability of the medication for of information are being considered. In assessing the customers is typically introduced as a lifecycle manage- risk benefit of a medicinal product, regulators progres - ment (Bittner and Schmidt 2022). sively encourage manufacturers to actively implement “Customer-centric” drug delivery, as defined in this real-world data (RWD) and real-world evidence (RWE) article, becomes an important aspect for indications with during development processes and to share “patient- a variety of more mature medications with similar phys- provided information” for evaluation as part of drug icochemical properties available from a given compound and medical device applications (United Stated Food class. Here, treatment enabling technologies have been and Drug Administration 2018). The United States Food established over time (Shams et al. 2021). With emerging and Drug Administration (FDA) defines RWD as “data customer insights on needs for improving the product relating to patient health status and/or the delivery of presentation, drug delivery efforts predominantly focus health care routinely collected from a variety of sources” on differentiating the medication with a more convenient and RWE as “the clinical evidence about the usage and and cost-efficient profile (Roy et al. 2021; Schreiber et al. potential benefits or risks of a medical product derived 2022). from analysis of RWD” (United States Food and Drug In addition to achieving a user-oriented drug delivery Administration 2022b). According to the FDA, RWD profile, manufacturers engage in offering medicines with sources can include registries, collections of electronic overall more sustainable presentations. Activities entail health records, or administrative and medical claims the implementation of measures to reduce drug wastage databases. Besides prescription information, medical via more economic dosing regimens and supply chain diagnoses, bills submitted to payer organizations, costs, concepts (Hendrikx et al. 2017; Tat and Heydari 2021). charges and reimbursement amounts, such databases Over time, and on the basis of progressively established also include insights into procedures and treatments platform technologies, this initially stepwise approach is performed (Rocco et al. 2017; Park and Lee 2021). Glob- emerging into a situation where novel products are avail- ally, clinical trial results are therefore supplemented by able with the best feasible drug delivery profile from ini - RWD and RWE (Hiramatsu et al. 2021). This evidence tial molecule launch onwards. also serves as a source for estimating the impact of drug delivery modalities on healthcare resource utilization Healthcare trends that define customer‑centric (Stearns et al. 2019). mAb product presentations Likewise, the application of robust RWE to supplement Today, people diagnosed with a chronic condition experimental evidence in coverage decisions is being con- are increasingly well informed about particulari- sidered globally (Facey et al. 2020). In a literature review ties of their disease and willing to actively participate on the US healthcare system conducted by Hampson in the design of healthcare processes (Longtin et al. et al. (2018), comparative clinical effectiveness and net - 2010). Resulting customer-centric concepts commonly work meta-analysis for quantitative indirect comparisons include aspects of disease self-management (Holmes were identified as pivotal sources for initial payer cover - et al. 2019) and as such mandate measures that allow age and Heath Technology Assessment decisions. Here, Bittner AAPS Open (2023) 9:3 Page 4 of 25 “patient-reported data” may be used as a complimentary Customer‑centric product presentations data source. For reassessments, that is reconsidering cov- that enable dosing in a flexible care setting erage, formulary placement or payment terms, as well as Reliable application of biotherapeutics in a flexible care in the context of outcomes-based contracting, RWE can setting depends on adequate user training and educa- play a role in further defining the clinical or economic tion and mandates treatment initiation under professional value of an intervention, beyond the evidence gener- supervision (Highlights of Prescribing Information (HPI) ® ® ® ated in the clinical trial setting. Notably, in their review, Humira , Hizentra , Kesimpta : United Stated Food and a number of challenges associated with the use of RWE Drug Administration 2022a). Establishing convenient drug for healthcare payment decisions were identified. These delivery schemes and electronic data capturing tools permit include aspects of reporting bias, incomplete data, lack physicians to make accurate treatment decisions while their of universally accepted methodological standards, lack of patient is dosed outside of a controlled environment (Eun- investigator expertise, or obsolete evidence hierarchies. Young 2017; El-Sappagh et al. 2019; Sebastian et al. 2019). Similar findings were made in a US payer interview con - Especially, if home dosing is facilitated with mechanisms ducted by Timbie et al. (2021). The evaluation identified to collect “patient-provided information,” such data could the evidence from rigorous clinical trials as a prioritized have the potential to reduce payer’s uncertainty around source for assessing efficacy and short-term safety find - adherence and to complement value-based reimbursement ings. Some payers, however, “felt that RWE was particu- models. larly helpful when the long-term durability of devices or Beyond professional support services and electronic rare adverse events were key considerations in coverage data capturing and monitoring tools, drug delivery decisions”. improvements that reduce supply chain complexity, per- Figure 1 highlights key healthcare trends that inform mit simple and intuitive drug administration, and facili- customer-centric drug delivery needs for monoclonal tate medication storage and disposal represent a crucial antibodies. Insights reveal the need for technologies that element of pharmaceutical research and development. enable dosing and data collection in a flexible care set - Figure 2 illustrates drug delivery improvements for ting. Here, contingent upon the medication’s safety and mAbs that reduce dosing complexity and enable dos- tolerability, medication administration may take place ing and data collection in a flexible care setting. Aspects in the clinic, a physician’s office, a community or infu - include (1) improving the product presentation, (2) sion center or in the patient’s home (Bittner and Schmidt reducing the overall burden of parenteral drug adminis- 2021). tration, and (3) complementing combination therapy. In Fig. 1 Key healthcare trends that inform customer-centric drug delivery needs for monoclonal antibodies. Need for technologies that enable dosing and data collection in a flexible care setting (FCS) Bittner AAPS Open (2023) 9:3 Page 5 of 25 Fig. 2 Drug delivery improvements for mAbs that reduce dosing complexity and enable dosing and data collection in a flexible care setting this order, product optimizations are expected to possess medications’ drug delivery profile. For marketed mAbs increasing potential to facilitate remote parenteral care. or for biologics in development in an indication with Attempts in advancing the product presentation entail similar treatment modalities already employed, informa- optimizing storage conditions and shelf-life of the medica- tion on how the product might be improved is typically tion (Kuzman et al. 2021), as well as improving its packag- already available from secondary sources and thus can be ing to account for an easy to store and to handle offering estimated based on existing analogues. Notably, custom- (Zadbuke et al. 2013). Product optimizations that lessen the ers’ desires evolve with the maturity of a market based burden associated with parenteral administration of bio- on emerging sophistication of drug delivery technologies therapeutics comprise fast intravenous infusion regimens (Al and comparisons with other indications with biothera- Zahrani et al. 2009), fixed dosing regimens instead of body peutics with similar drug delivery requirements. The size-adjusted dosing (Egorin 2003), subcutaneous dosing journey of product optimizations is therefore flexible and alternatives to more invasive intravenous infusions (Bittner adaptable to change at all times. et al. 2018), or automated injection devices (Vijayaraghavan An understanding of user and provider preferences for 2020). Connected devices and accompanying health apps one over another drug delivery methodology is gained are being implemented to support adherence in an out- either as part of pivotal registrational clinical trials or in patient setting and can be utilized to collect RWE on possible smaller dedicated usability studies (Li and Easton 2018). adverse events and share it back with the treating physician Here, electronic apps with dosing reminders and tools to (Bittner et al. 2019). Drug delivery improvements to comple- collect “patient-reported outcomes” in the home setting ment combination therapy involve the development of fixed- (El Emam et al. 2009) provide early insights into possible dose combinations with two or more mAbs co-formulated challenges and opportunities of a product optimization. in the same dosing vehicle, or dual chamber bags (Allmend- Additionally, treatment satisfaction and quality-of-life inger 2021). Details on underlying concepts and scientific surveys (Kempton et al. 2021), as well as time and motion nonclinical and clinical development approaches have been studies (De Cock et al. 2014; Pivot et al. 2014) that assess summarized previously and are therefore off-scope for this the impact of the drug administration procedure on the article (Bittner and Schmidt 2022). efficiency of dosing in a prespecified setting represent an appreciable source of information. Gaining insights into customer needs for product For marketed medications and relevant reference prod- optimization of biological medicines ucts with a similar drug delivery profile in other indica - To inform investments into customer-centric product tions, insights into the practicality of the drug delivery optimizations for existing medicines, manufacturers reg- profile are frequently derived from direct user or provider ularly collect insights on possible challenges with their feedback to the manufacturer of a medicinal product. Bittner AAPS Open (2023) 9:3 Page 6 of 25 Disease area archetype 1 (rheumatoid arthritis This encompasses anecdotal reports on challenges with and inflammatory bowel disease)—mature markets the drug administration instructions and at times even with a variety of established mAb treatments suggestions on how to improve these. Input is addition- and corresponding follow‑on biologics available ally tracked via established complaint management pro- for self‑administration cesses (Hake et al. 2019) in which customer feedback is Disease area archetype 1 encompasses RA and IBD, collected and reviewed systematically over time. Verifia - representing mature subcutaneous self-administration ble customer co-creation (Adelman et al. 2019; Peng et al. markets with established originator mAbs and other 2022) may be realized via satisfaction surveys or cus- long-standing biological treatments and corresponding tomer workshops designing the most appropriate drug biosimilars either already approved or in development delivery system for a drug and as part of well-defined (De Figueiredo et al. 2021; Findeisen et al. 2021; Radu human factor trials (Lageat et al. 2021). and Bungau 2021). Authorized mAb treatments for both RA and IBD include the tumor necrosis factor-α inhibi- Key developments in providing customer‑centric tors infliximab, adalimumab, golimumab, and certoli - product presentations for mAbs across different zumab pegol. The B-cell-depleting therapy rituximab and disease areas the interleukin-6 receptor antagonists tocilizumab and Disease area archetypes sarilumab are indicated for the treatment of RA (Senolt The availability of product presentations and dosing regi - 2019). The interleukin-12 and interleukin-23 inhibitor mens that support administration of mAbs in a flexible ustekinumab, the α4β7 integrin antagonist vedolizumab, care setting varies considerably across indications. Three and the α4 integrin antagonist natalizumab are author- different disease area archetypes have been selected to ized for the treatment of IBD (Mao et al. 2018; Wyant describe the status and key developments on the journey et al. 2016). to increasing customer centricity of mAb medications. In 1998, the chimeric mAb infliximab was the first Table 1 illustrates the relevant attributes of these differ - tumor necrosis factor-α inhibitor authorized by the FDA ent markets. Disease areas comprise rheumatoid arthri- for the treatment of Crohn’s disease (CD) (Melsheimer tis (RA) and inflammatory bowel disease (IBD), multiple et al. 2019). Branded infliximab was and is still solely sclerosis (MS), and oncology (ONC). Table 1 Key attributes of selected disease area archetypes; considers marketed mAb profiles only Disease mAb safety & tolerability profile mAb drug delivery profile Market maturity (injectables) area archetype 1 mAbs exhibit sufficient tolerability to allow Predominantly SC formulations for self- Several mAbs & other biologics with different RA/IBD unsupervised administration outside of a administration & overlapping indications available controlled healthcare environment Low dosing volumes (below 2 mL) A number of mAbs & other biologics also Ready-to-use PFS & autoinjector/pen used in other indications devices Biosimilars for some mAbs & other biologics available 2 mAb-dependent safety profiles; unsu- Predominantly IV formulations for HCP- Few mAbs with overlapping indications MS pervised and supervised administra- assisted administration Biosimilars for other biologics available tion outside of a controlled healthcare 1 mAb with SC formulations for self- No mAb biosimilar marketed environment administration (dosing volume of 0.4 mL; ready-to-use PFS & autoinjector device) 3 mAb-dependent safety profiles; currently Predominantly IV formulations for HCP- A variety mAbs with different & overlapping ONC no unsupervised administration outside of assisted administration indications available a controlled healthcare environment4 mAbs with high-volume SC formulations Biosimilars for some mAbs available for HCP-assisted administration (volumes of 5 to 15 mL; vial presentations) 1 SC mAb FDC 1 IV mAb FDC FDC fixed-dose combination, HCP healthcare provider, IBD inflammatory bowel disease, IV intravenous, mAb monoclonal antibody, mL milliliters, MS multiple sclerosis, ONC oncology, RA rheumatoid arthritis, SC subcutaneous Following treatment initiation under supervision and training of a HCP Ofatumumab Trastuzumab, rituximab, daratumumab, pertuzumab + trastuzumab Pertuzumab + trastuzumab Nivolumab + relatlimab Bittner AAPS Open (2023) 9:3 Page 7 of 25 available with an intravenous dosing regimen as a pow- seemingly small change was shown to result in a reduc- der for reconstitution (HPI Remicade : United Stated tion of pain at the injection site and ultimately in a sig- Food and Drug Administration 2022a). The first fully nificantly improved adherence and time on treatment human recombinant immunoglobulin G1 mAb in RA, overall (Bergman et al. 2020; Patel and Luu 2020). The adalimumab, was already introduced with a subcutane- finding is all the more important as decreased persis - ous dosing regimen at initial product approval in 2002 tence to anti-tumor necrosis factor therapy had been (Marušić and Klemenčić 2018). The majority of branded reported to be associated with poorer clinical out- injectables in the field are available with either both an comes (Bluett et al. 2015). Additional product optimi- intravenous and a subcutaneous formulation (goli- zations introduced for branded adalimumab comprise mumab, tocilizumab, ustekinumab, vedolizumab; HPIs a reduced injection volume with a higher concentrated ® ® ® ® ® Simponi , Simponi Aria Actemra , Stelara , Entyvio : dosing solution, higher needle gauge, or modifications United Stated Food and Drug Administration 2022a, in the material of the injection devices (St Clair-Jones SMPC Entyvio : European Medicines Agency 2021) et al. 2020). or a subcutaneous formulation only (adalimumab, cer- With the aim to optimize experience with the dosing ® ® tolizumab pegol, sarilumab; HPIs Humira , Cimzia , procedure, to reduce the fear associated with needle use, Kevzara : United Stated Food and Drug Administra- and to aid people with impaired dexterity, in 2016, cer- tion 2022a). The fixed-dose regimens omit the need for tolizumab pegol’s product presentations were comple- body size-normalized dose calculation. Subcutaneous mented with a button-free autoinjector characterized by injection volumes do not exceed 2 mL and dosing fre- a wide, non-slip grip (Bailey et al. 2020). Supported with quencies range from weekly to every 4 weeks. The sub - adequate training, the device could improve user confi - cutaneous administration regimen for ustekinumab dence and satisfaction with subcutaneous self-adminis- consists of an intravenous loading dose followed by every tration. The introduction of a mini cartridge to be applied 8 weeks subcutaneous maintenance doses. Ready-to-use by means of a reusable autoinjector for the biologic prefilled syringes or pen devices provide users with dif - etanercept in 2017 (Collier et al. 2017, Sedo 2018) may in ferent dosing alternatives as per their personal require- the future also serve as a platform for mAbs. The prod - ments. Branded natalizumab, infliximab, and rituximab uct also utilizes an improved dosing solution that had can only be given intravenously with maintenance dosing been shown to lessen injection site pain as compared to frequencies between every 4 weeks and every 6 months the previous formulation (Cohen et al. 2019). Preference ® ® ® (HPIs Tysabri , Remicade , Rituxan : United Stated assessments comparing the novel reusable with the exist- Food and Drug Administration 2022a). These infusion ing disposable automated pen device revealed perceived regimens represent an alternative for people who prefer advantages for both injection aids, thus giving users the intravenous over subcutaneous dosing (Allen et al. 2010) choice between two devices according to personal priori- or value a lower treatment frequency independent of the ties (Collier et al. 2017). administration route (Huynh et al. 2014). In the clinic, To further facilitate compliance with at-home dos- less frequent dosing can be a contributor to a more con- ing, companies are implementing so-called patient sup- venient and cost-efficient treatment management scheme port programs and app-based assistance tools including (Tetteh and Morris 2014), especially if medical exami- customized dosing reminders or injection and symptom nations can be combined with a dosing day. Most nota- trackers (Graigner et al. 2017, Lambrecht et al. 2021). bly, the fact that a variety of injectable medications are Branded certolizumab pegol offers the option to apply the approved both for the treatment of RA and IBD increases first partially reusable electromechanical injection device healthcare provider’s general familiarity with an injec- “of its kind available for use with biologic treatment in tion device type and offers the possibility for leverag - rheumatology and dermatology in Europe” (UCB 2021). ing learnings on challenges with the injections (Chilton Device design was actually guided by intended user feed- and Collett 2008; Domańska et al. 2017; Gely et al. 2019) back through human factor evaluations (Domańska et al. across indications. Table 2 summarizes the mAb presen- 2018). The injector was found to be preferred due to its tations authorized for the treatment of adults diagnosed ease-of-use over other subcutaneous devices in a study with RA or IBD (CD and ulcerative colitis (UC)). with certolizumab pegol-treated people from the Nether- Prominent customer-centric product optimizations in lands, Denmark, and Sweden (Pouls et al. 2020). disease area archetype 1 include changing the composi- Manufacturers of follow-on biologics for mAbs in RA tion of the subcutaneous formulation for adalimumab. and IBD focus efforts on either using established injec - Accounting for "patient-reported pain" immediately fol- tion device platforms or on customizing technologies to lowing injection, the manufacturer changed the chemi- differentiate their products via unique, distinctive drug cal buffer to help stabilize and preserve the mAb. This delivery characteristics. As for the branded counterparts, Bittner AAPS Open (2023) 9:3 Page 8 of 25 Table 2 mAbs authorized for the treatment of RA or IBD (CD and UC) in the US (up until September 2022): administration routes, dosing regimens and product presentations (adult indications) a a Indication mAb Administration route and dosing IV product presentations SC product presentations regimen IV SC b b RA Rituximab 2*1000 mg separated by 2 weeks (one - 100 mg/10 mL, 500 mg/50 mL in - course) every 24 weeks or based on single-dose vials clinical evaluation (not sooner than every 16 weeks) Tocilizumab 4 mg/kg q4w followed by 8 mg/kg Patients < 100 kg: 162 mg q2w, fol- 80 mg/4 mL, 200 mg/10 mL, 162 mg/0.9 mL in single-dose prefilled q4w based on clinical response lowed by increase to q1w based on 400 mg/20 mL in single-dose vials syringe or single-dose prefilled autoin- clinical response jector Patients ≥ 100 kg: 162 mg q1w Sarilumab - 200 mg q2w - 150 mg/1.14 mL or 200 mg/1.14 mL solution in single-dose prefilled syringe or prefilled pen IBD Ustekinumab Induction: 90 mg 8 weeks after the initial IV induc- 130 mg/26 mL solution in single-dose 45 mg/0.5 mL or 90 mg/mL solution in < 55 kg: 260 mg tion dose, then q8w vial single-dose prefilled syringe > 55 kg to 85 kg: 390 mg 45 mg/0.5 mL in single-dose vial > 85 kg: 520 mg Maintenance: 90 mg 8 weeks after the initial dose, then q8w (SC) c c Vedolizumab 300 mg at weeks 0, 2 and 6, then q8w - 300 mg of lyophilized powder in - single-use 20 mL vial d d Natalizumab 300 mg q4w - 300 mg/15 mL solution in single-dose - vial Bittner AAPS Open (2023) 9:3 Page 9 of 25 Table 2 (continued) a a Indication mAb Administration route and dosing IV product presentations SC product presentations regimen IV SC e e RA & IBD Infliximab RA: - 100 mg of lyophilized powder in - 3 mg/kg at weeks 0, 2 and 6, then q8w single-dose vial (may be increased to 10 mg/kg q8w or to dosing frequency of q4w) CD: 5 mg/kg at weeks 0, 2 and 6, then q8w (may be increased to 10 mg/kg q8w if loss of response) UC: 5 mg/kg at weeks 0, 2 and 6, then q8w Adalimumab - RA: - 80 mg/0.8 mL, 40 mg/0.8 mL, and 40 mg q2w (some patients not receiving 40 mg/0.4 mL in single-dose prefilled pen methotrexate may benefit from dose 80 mg/0.8 mL, 40 mg/0.8 mL, increase to 40 mg q1w or 80 mg q2w) 40 mg/0.4 mL, 20 mg/0.4 mL, CD: 20 mg/0.2 mL, 10 mg/0.2 mL, 160 mg on day 1 (given in one day 10 mg/0.1 mL in single-dose prefilled or split over two consecutive days); glass syringe 80 mg on day 15 and 40 mg q2w start- 40 mg/0.8 mL in single-dose glass vial ing on Day 29 for institutional use only UC: 160 mg on day 1 (given in one day or split over two consecutive days); 80 mg on day 15 and 40 mg q2w start- ing on Day 29 Golimumab RA: RA: 50 mg/4 mL solution in single-dose 50 mg/0.5 mL in single-dose prefilled 2 mg/kg at weeks 0 and 4, then q8w 50 mg q1m vial syringe or single-dose prefilled autoinjector UC: 100 mg/1.0 mL in single-dose prefilled 200 mg at week 0, 100 mg at week 2 syringe or single-dose prefilled autoin- and then 100 mg q4w jector Certolizumab pegol - RA: - 200 mg lyophilized powder in single- 400 mg initially and at weeks 2 and 4, dose vial followed by 200 mg q2w; for main- 200 mg/mL solution in single-dose tenance dosing, 400 mg q4w can be prefilled syringe considered CD: 400 mg initially and at weeks 2 and 4. If response occurs, 400 mg q4w CD Crohn’s disease, IV intravenous, mg milligram, mL milliliter, qXd every X day, qXm every X month, qXw every X week, RA rheumatoid arthritis, SC subcutaneous, UC ulcerative colitis This table lists FDA-approved products; deviations with EMA-approved product presentations or other indications are indicated as a footnote A SC formulation for rituximab is approved in oncology indications A SC formulation for vedolizumab is approved in IBD in the EU A SC formulation for natalizumab is approved in MS in the EU e ® Biosimilar infliximab (Remsima ) is approved for subcutaneous administration in the EU Bittner AAPS Open (2023) 9:3 Page 10 of 25 Disease area archetype 2—market with a small number user and healthcare provider satisfaction and usabil- of mAbs established for in‑clinic or self‑administration ity studies are part of the autoinjector development and and no corresponding biosimilars available commercialization strategy (Thakur et al. 2016; Tischer MS, the second disease area archetype, is characterized and Mehl 2018; Fleischmann et al. 2022). This iterative by established non-mAb biological disease-modifying co-creation with customers is particularly important in treatments available for subcutaneous self-administra- disease areas in which people report problems with man- tion. The majority of mAbs is offered with an intrave - ual dexterity, pain linked to joint swelling in the hands, nous infusion regimen, but the first subcutaneous mAb and general challenges with the self-injection procedure for self-administration has recently reached the market. (Keininger and Coteur 2011). To date, no biosimilar mAb is available in the US (United Celltrion’s infliximab biosimilar received European States Food and Drug Administration 2022c). Medicines Agency (EMA) approval for a subcutaneous More precisely, subcutaneous self-administration with dosing alternative in 2019 and FDA review is anticipated interferon beta (IFNβ) indicated to treat relapsing forms to be completed as a next milestone (Rose 2021; Verma of MS is an established standard in the field (Kieseier et al. 2021), while branded infliximab is only available 2011; Filipi and Jack 2020). Back in 1993, the first IFNβ with an intravenous infusion regimen. This subcutaneous was approved in the US and since then several others self-administered infliximab product presentation paired have become available (Bayas and Gold 2003). Due to with telemedicine support and increasingly available their fixed dosing regimens and low injection volumes, RWD is suggested to lessen the time spent for travel and IFNβ products are available in ready-to-use prefilled hospital attendance during dosing days and as such to syringes and autoinjectors including devices with elec- reduce the pressure on healthcare systems (Ahmed et al. tronic adherence aids (Limmroth et al. 2017). IFNβ drug 2021; Perry and Jang 2020; Schreiber et al. 2022). administration regimens range from every second day In aspiring to relieve the burden of parenteral dosing, to every second week for the pegylated version that was the feasibility of oral dosing of mAbs is being examined authorized by the FDA in 2014 (Dashputre et al. 2017). In (Philippart et al. 2016; New 2020Abramson et al. 2022). a German real-world study from 2021, this less frequent Different to injectable dosage forms, the individual dose dosing alternative showed markedly higher scores for level that can be administered orally is markedly reduced treatment satisfaction and convenience compared with due to limited fill volumes of ingested oral dosage forms. previous therapies that included other IFNβ treatments Consequently, this approach is particularly interesting for (Menge et al. 2021). mAbs in immunology, as inherent to their comparatively The first mAb, natalizumab, an α4 integrin antago - low-dose levels, a practicable oral dosing frequency may nist, entered the MS market in in 2004 with a fixed be achievable. dose infused intravenously every 4 weeks over 1 h, and Different oral delivery technologies have recently by now is available for the treatment of clinically iso- advanced to clinical investigational stage. The first lated syndrome (CIS), relapsing–remitting MS (RRMS), approach aims at precise delivery of biotherapeutics and active secondary progressive MS (SPMS) (Rudick to gastrointestinal tissue thus avoiding high systemic et al. 2013, HPI Tysabri : United Stated Food and Drug exposure and potentially associated side effects. Here, Administration 2022a). While people with prior use of biosimilar infliximab is being assessed for the feasibil - subcutaneous interferon regimens commonly value the ity of an oral version in the treatment of IBD. The aim option for self-administration, especially when facilitated is to target release in the colon and to protect the mAb with automated injection devices (Lugaresi et al. 2012), from digestion in the stomach and upper gastrointesti- the improved efficacy of natalizumab over IFNβ therapy nal tract through local stabilization against proteases (Rudick and Panzara 2008; Lanzillo et al. 2012) is consid- (Intract Pharma 2022). A second advanced oral delivery ered to outweigh the convenience disadvantage of more approach utilizes an orally ingestible robotic pill that invasive intravenous dosing. auto-injects the biotherapeutic into the wall of the small In 2014, the FDA approved alemtuzumab, an anti-clus- intestine (Dhalla et al. 2022). The authors report that in ter of differentiation 52 (CD52) mAb, for the treatment an initial clinical trial with octreotide in healthy partici- of RRMS (Ruck et al. 2015). The medicine is available pants, administration of the pill was safe, well-tolerated, with a fixed-dose intravenous regimen for two treatment and yielded in an oral bioavailability of 65%. Assuming courses. During the first treatment course, alemtuzumab the scientific concept is confirmed in larger clinical tri - is administered over 4 h on five consecutive days and als and treatment can be realized at commercializable on three consecutive days during the second treatment dose levels and dosing regimens, this approach has the course 12 months later. Additional treatment courses potential to provide new clinical strategies in the future may be considered with drug administrations of three (Zhang et al. 2021). Bittner AAPS Open (2023) 9:3 Page 11 of 25 consecutive days (HPI Lemtrada : United Stated Food Stated Food and Drug Administration 2022a), ofatu- and Drug Administration 2022a). This comparatively mumab was launched both in a prefilled syringe and in convenient infrequent dosing regimen is to some extent an automated pen injector. In its final appraisal docu - counterbalanced by the need for regularly monitoring the ment on “Ofatumumab for treating relapsing multiple increased risk of autoimmunity (Garnock-Jones 2014). sclerosis,” the UK’s NICE notes that they heard from While alemtuzumab when delivered via the subcutane- “patient experts” “that a treatment that could be self- ous route may reduce infusion-related adverse events as administered monthly is less disruptive to people’s lives compared to intravenous dosing (Perumal 2012), a sub- than treatments administered by intravenous infusions in cutaneous formulation is not available for use in MS. hospital, so would be valued by people with multiple scle- The anti-CD20 mAb ocrelizumab was first authorized rosis” (National Institute for Health and Care Excellence in the US in 2017 (Frampton 2017) and by now is applied 2021). Launching a mAb in two different presentations for the treatment of relapsing forms of MS (RMS), includ- accounts for distinct preferences (Kivitz et al. 2018; Ver- ing CIS, RRMS, PPMS, and for the treatment of SPMS meire et al. 2018) already at first introduction of the novel (Stahnke et al. 2018, Weinstock-Guttman et al. 2022, medicine. Additionally, a manufacturer-initiated study HPI Ocrevus : United Stated Food and Drug Adminis- revealed user and nurse preference for the autoinjector tration 2022a). The mAb was introduced with an intra - over their current injectables mainly due to the “ease to venous fixed-dose regimen. Here, the initial treatment perform self-injection with the pen” and “patient able to cycle comprises two separate infusions on days 1 and use independently” (Ross et al. 2021). 15, respectively, followed by twice yearly maintenance In 2021, a subcutaneous version of natalizumab with doses. The United Kingdom’s (UK) National Institute for an overall shorter infusion time as compared to the Health and Care Excellence (NICE) noted in their final intravenous regimen received marketing authorization appraisal document on “Ocrelizumab for treating relaps- in the EU (Summary of Product Characteristics (SMPC) ing–remitting multiple sclerosis” that based on insights Tysabri : European Medicines Agency 2021, López et al. from “patient experts” “patients would value a treatment 2021). The product is available in prefilled syringes, two with less frequent dosing or monitoring,” acknowledging of which need to be administered at each dosing day that the intervention is less interruptive for people’s lives with a monthly dosing regimen; home treatment is not compared to other treatments (National Institute for recommended. In the same year, the manufacturer did Health and Care Excellence 2018). receive a complete response letter (CRL) from the FDA To optimize satisfaction and quality of life with intra- to their supplemental Biologic License Application for venous mAb treatments and to improve healthcare insti- the subcutaneous dosing alternative (BioSpace 2021); tutional resource utilization in MS, efforts are made to the underlying reasons for the CRL are unknown to support home-based and outpatient infusion manage- the author of this review. Also, a subcutaneous dosing ment (Vijayan et al. 2017; Schultz et al. 2021; Barrera alternative in development for ocrelizumab has reached et al. 2022; Räuber et al. 2022). It was found that people Phase 3 clinical development stage (clinicaltrials.gov are generally open to receiving the intravenous treat- 2022). Table 3 summarizes the mAb presentations ment at home and that supporting health services need authorized for the treatment of adult people diagnosed to ensure safety and be efficient, responsive, and flex - with MS. ible. Thus, health services should also allow for admin - istering the medication at individually preferred times Disease area archetype 3—market with variety during the day (Rath et al. 2021). Supporting measures of established mAb treatments for healthcare provider include designing appropriate home health care services administration and a number of corresponding biosimilars for natalizumab or shortening ocrelizumab’s intravenous available infusion time from 3.5 to 2 h (Schultz et al. 2019; Har- The ONC area represents the third selected disease area tung et al. 2020). archetype. Here, mAbs for the treatment of malignancies In 2020, a second anti-CD20 mAb, ofatumumab, was have been on the market for decades, but due to at times authorized by the FDA for the treatment of CIS, RRMS, severe IRRs and frequently high individual mAb dose lev- and active SPMS (HPI Kesimpta : United Stated Food els, products are not yet available for self-administration. and Drug Administration 2022a). Notably, the mAb was Until recently, due to the lack of technologies that facili- directly introduced with a subcutaneous formulation for tate high-dose subcutaneous administration, mAb prod- self-administration, a fixed dose, and a dosing volume of ucts were offered as intravenous infusions only. Today, a 0.4 mL. Using an existing autoinjector platform that was number of subcutaneous dosing alternatives have been previously applied to other products of the same manu- established. The first biosimilar mAbs have been author - ® ® ® facturer (HPIs Cosyntex , Elrezi , Hyrimoz : United ized, currently with intravenous dosing regimens only. Bittner AAPS Open (2023) 9:3 Page 12 of 25 Table 3 mAbs authorized for the treatment of MS in the US (up until September 2022): administration routes, dosing regimens and product presentations (adult indications) a a a mAb Administration route and dosing regimen IV product presentations SC product presentations IV SC b b Natalizumab 300 mg q4w - 300 mg/15 mL in single-dose vial - Alemtuzumab Initial treatment (2 courses): - 12 mg/1.2 mL in single-dose vial - First course of 12 mg/day on 5 consecu- tive days; second course of 12 mg/day on 3 consecutive days 12 months after first treatment course Subsequent treatment courses: 12 mg/day on 3 consecutive days as needed, at least 12 months after the previous course Ocrelizumab Start dose: - 300 mg/10 mL in single-dose vial 2*300 mg separated by two weeks Subsequent doses: 600 mg q6m Ofatumumab - Initial dosing: - 20 mg/0.4 mL solution in single-dose 20 mg adminis- prefilled pen or single-dose prefilled tered at syringe weeks 0, 1, and 2 Subsequent dosing: 20 mg q1m starting at week 4 IV intravenous, mg milligram, mL milliliter, qXd every X day, qXm every X month, qXw every X week, SC subcutaneous This table lists FDA-approved products; deviations with EMA-approved product presentations are indicated as a footnote A SC formulation for natalizumab in MS is approved in the EU More specifically, since the approval of rituximab for health services is a pivotal step to reduce time and trave- the treatment of B-cell malignancies back in 1997 (Pier- ling expenditures associated with in-clinic dosing. Nota- pont et al. 2018), numerous other mAbs have become bly, efforts are mandated to ensure that costs underlying available and represent an important modality in the provider work supporting at-home dosing and monitor- treatment of cancer (Zahavi and Weiner 2020). The large ing efforts remain within an affordable range (Franken majority of these mAbs are authorized for intravenous et al. 2020). administration and need to be administered by a health- Initially, mAbs in ONC were made available with a care professional (Kafatos et al. 2020). Depending on the body weight- or body surface area-adjusted dosing regi- nature and severity of IRRs, in some instances patients men (Hendrikx et al. 2017); an approach that was based have to be monitored closely to provide medical treat- on the way cytotoxic agents with a narrow therapeutic ® ® ment when required (HPIs Rituxan , Erbitux : United window are being administered (Egorin 2003). With the Stated Food and Drug Administration 2022a, Graham increasing understanding of the pharmacokinetic-phar- 2009). Understandably, these significant drug administra - macodynamic and -safety correlation (Paci et al. 2020), tion efforts add to the already high expenditures for mAb attempts are made to either develop mAbs with a fixed treatments overall (Chadda et al. 2013). dosing regimen from the very beginning (Garg et al. As described for intravenous treatments in MS, also 2014) or to change from body size-based dosing to fixed in cancer care, rapid infusion regimens (Atay et al. 2012, dosing as a lifecycle management activity following initial Gozzetti et al. 2020) or less frequent dosing regimens launch (Freshwater et al. 2017; Bei et al. 2020). (Lala et al. 2020) represent an attempt to reduce the The subsequent step towards more customer-friendly expenditures associated with drug administrations as drug delivery of mAbs in ONC represented the develop- well as the time people treated with mAbs have to spend ment of subcutaneous dosing options for mAbs (Bittner in the clinic. Here, the pandemic has intensified the and Schmidt 2012). Immanent to the at times high indi- elaboration of clinical strategies for optimizing infusion vidual dose levels, compared to mAbs in immunology for center care (Hanna et al. 2021). The organization of home example (refer to disease area archetype 1), developing Bittner AAPS Open (2023) 9:3 Page 13 of 25 subcutaneous injection regimens was initially compli- with HER2-positive early and metastatic breast cancer. cated due to a number of technical challenges. With the The medication is available with a subcutaneous dosing introduction of methodologies to achieve high-concen- regimen and has been approved by the FDA in 2020 (Gao tration solutions (Mahler et al. 2009; Jiskoot et al. 2022) et al. 2021). It had been shown that patients strongly and the co-administration of the dispersion enhancer preferred this fixed-dose combination over sequential hyaluronidase (Frost 2007), the first moves were made to intravenous infusion of the individual mAbs in separate reduce the overall dosing volume and to facilitate spread- formulations (O’Shaughnessy et al. 2021). Remarkably, ing of an injected fluid in the interstitial space. when approving Phesgo, in its press release, the FDA spe- Approved high-volume subcutaneous treatments that cifically highlights that “…Phesgo offers an out-patient apply these technologies can maintain the infrequent option for patients…” (United States Food and Drug dosing regimen of the initially marketed intravenous Administration 2020), an aspect that is considered very presentations. Up until September 2022, the subcutane- relevant especially in times of the coronavirus pandemic. ous administration alternatives for rituximab in B-cell The first fixed-dose combination of two immunother - malignancies (11.7 and 13.4 mL; FDA approval in 2017), apy mAbs, the programmed death receptor-1 inhibitor trastuzumab in HER2-positive early and metastatic nivolumab and the lymphocyte activation gene-3 block- breast cancer (5 mL, FDA approval in 2019), and dara- ing antibody relatlimab, received FDA approval for the tumumab in multiple myeloma (15 mL; FDA approval in treatment of unresectable or metastatic melanoma in 2020) have been authorized in the US (Yelvington 2018, 2022 (HPI OpdualagTM: United Stated Food and Drug Center for Drug Evaluation and Research 2020, Duco Administration 2022a). The formulation is administered 2020, Kading and Beck 2021). These subcutaneous mAb as a fixed-dose intravenous infusion regimen. presentations are all available with fixed-dose regimens Table 4 summarizes the high-dose subcutaneous omitting the need for body size-adjusted dose calcula- single-active mAb formulations and fixed-dose combi - tion. Dosing solutions are offered in vial presentations nations authorized for the treatment oncological indica- and are injected manually by a healthcare provider using tions in the US. a handheld syringe or an infusion set. The initial follow-on biologics for mAbs in ONC indi - To simplify administration of subcutaneous trastu- cations have been approved by the FDA (Galvão 2020). zumab, a ready-to-use on-body delivery system that Not only have manufacturers mimicked the originator is attached to the skin via an adhesive plaster had been medications, in some cases they also optimized the prod- developed (Bittner et al. 2012, Gligorov 2022). A small uct presentation to make it more user-friendly. Improve- study in 102 participants diagnosed with HER2-positive ments include extending the in-use stability to mitigate early breast cancer revealed that subcutaneous at-home the impact of cold-chain rupture and exceptional tem- injections by a healthcare professional did not introduce perature excursions on drug wastage and the quality of new safety signals and respondents agreed that they had the product (Vieillard et al. 2017; Park et al. 2020). Even benefit from at-home administration to a large (22%) or without the implementation of product optimizations, very large extent (78%) (Denys et al. 2020). Time-and- biosimilars are considered a customer-centric alternative motion and preference assessments demonstrated user to their branded counterparts solely based on the poten- preferences of subcutaneous over intravenous dosing in tial to increase access to mAb-based cancer medicines a healthcare institutional setting, regardless of on-body globally via reduced product costs compared to the origi- delivery system or handheld syringe delivery (Pivot er al nator mAb (Patel et al. 2018; Shelbaya et al. 2021). Here, 2014). As trastuzumab is not permitted for home- or self- interestingly, actual realization of a switch from branded administration, the device was not commercialized at to follow-on biologic or a switch from one to another the time of marketing authorization of the subcutaneous biosimilar varies significantly from country to country. trastuzumab formulation in the EU back in 2013. Regional differences, such as prescriber and/or patient The aspect that mAbs are increasingly developed for insecurity concerning efficacy and safety, conservative combination therapy (Henricks et al. 2015; Peterson prescribing patterns, reimbursements and billing poli- et al. 2018), a condition that further adds to the com- cies, supply logistics, and legal considerations have been plexity of parenteral dosing, makes ONC an intriguing suggested as limiting factors to broader adoption of bio- disease area archetype from a drug delivery perspective. similars (Cortes et al. 2020; Azuz et al. 2021). Consequently, manufacturers started co-formulating two mAbs within the same dosing vehicle as a fixed- Discussion dose combination. The first fixed-dose combination of The term “customer centricity,” indicating that fulfilling two mAbs included pertuzumab and trastuzumab and customer demands is as important as creating the prod- is indicated for the treatment of people diagnosed with uct or services themselves (Ceesay 2020), is not new and Bittner AAPS Open (2023) 9:3 Page 14 of 25 Table 4 High-dose subcutaneous single-active mAb formulations and fixed-dose combinations authorized for the treatment oncological indications in the US (up until September 2022): administration routes, dosing regimens and product presentations a a a mAb Administration route and dosing regimen IV product presentations SC product presentations IV SC Trastuzumab Adjuvant HER2 + BC: HER2 + BC: 150 mg lyophilized powder in single- 600 mg trastuzumab and 10,000 units Loading dose: 4 mg/kg 600 mg trastuzumab and 10,000 units dose vial hyaluronidase per 5 mL solution in Maintenance dose: 2 mg/kg q1w for hyaluronidase q3w 420 mg lyophilized powder in single- single-dose vial 12 weeks followed by 6 mg/kg q3w to dose vial complete a total of 52 weeks or Loading dose: 8 mg/kg Maintenance dose: 6 mg/kg q3w for 52 weeks HER2 + mBC: Loading dose: 4 mg/kg Maintenance dose: 2 mg/kg q1w HER2 + GC: Loading dose: 8 mg/kg Maintenance dose: 6 mg/kg q3w Rituximab NHL: The first dose is administered IV 100 mg/10 mL solution in single-dose 1400 mg rituximab and 23,400 units hya- 375 mg/m (indication-dependent NHL: vial luronidase human per 11.7 mL solution schedule) 1400 mg rituximab and 23,400 units 500 mg/50 mL solution in single-dose in single-dose vial CLL: hyaluronidase (indication-dependent vial 1600 mg rituximab and 26,800 units hya- Cycle 1: 375 mg/m schedule) luronidase human per 13.4 mL solution Cycles 2 − 6: 500 mg/m q28d CLL: in single-dose vial 1600 mg rituximab and 26,800 units hyaluronidase (indication-dependent schedule) Daratumumab MM: MM: 100 mg/5 mL solution in single-dose 1800 mg daratumumab and 30,000 units 16 mg/kg; may be split over two 1800 mg daratumumab and 30,000 vial hyaluronidase per 15 mL solution in consecutive days with 8 mg/kg on day units hyaluronidase (indication- 400 mg/20 mL solution in single-dose single-dose vial 1 and day 2 (indication-dependent dependent schedule) vial schedule) Pertuzumab Adjuvant HER2 + BC: - 420 mg/14 mL in single-dose vial - Loading dose: 840 mg Maintenance dose: 420 mg q3w (com- bination with trastuzumab IV or SC) for up to 18 cycles Neo-adjuvant HER2 + BC: Loading dose: 840 mg Maintenance dose: 420 mg q3w (com- bination with trastuzumab IV or SC) for 3 to 6 cycles HER2 + mBC: Loading dose: 840 mg Maintenance dose: 420 mg q3w Bittner AAPS Open (2023) 9:3 Page 15 of 25 Table 4 (continued) a a a mAb Administration route and dosing regimen IV product presentations SC product presentations IV SC Pertuzumab + trastuzumab FDC For single-active formulations see Adjuvant HER2 + BC: For single-active formulations see 1200 mg pertuzumab, 600 mg tras- above Loading dose: 1200 mg pertuzumab, above tuzumab, and 30,000 units hyaluroni- 600 mg trastuzumab, and 30,000 units dase/15 mL in single-dose vial hyaluronidase 600 mg pertuzumab, 600 mg trastu- Maintenance dose: 600 mg pertu- zumab, and 20,000 units hyaluroni- zumab, 600 mg trastuzumab, and dase/10 mL in single-dose vial 20,000 units hyaluronidase for up to 18 cycles Neo-adjuvant HER2 + BC: Loading dose: 1200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase Maintenance dose: 600 mg pertu- zumab, 600 mg trastuzumab, and 20,000 units hyaluronidase for 3 to 6 cycles HER2 + mBC: Loading dose: 1200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase Maintenance dose: 600 mg pertu- zumab, 600 mg trastuzumab, and 20,000 units hyaluronidase Nivolumab Various cancer indications: - 40 mg/4 mL, 100 mg/10 mL, - Indication-dependent dose and 120 mg/12 mL, and 240 mg/24 mL schedule solution in single-dose vial Relatlimab - - - - Nivolumab + relatlimab FDC UMM: - 240 mg of nivolumab and 80 mg of - 480 mg nivolumab and 160 mg relatli- relatlimab per 20 mL in single-dose vial mab q4w (adverse event-dependent dose modifications) CLL chronic lymphocytic leukemia, FDC fixed-dose combination, HER2 + BC HER2-overexpressing breast cancer, HER2 + GC HER2-overexpressing gastric cancer, HER2 + mBC metastatic, HER2 + BC HER2-overexpressing breast cancer, IVintravenous, mg milligram, mL milliliter, MM multiple myeloma, NHL non-Hodgkin’s lymphoma, qXd every X day, qXm, every X month, qXw every X week, SC subcutaneous, UMM unresectable or metastatic melanoma This table lists FDA-approved products Relatlimab is only available in the FDC with nivolumab Bittner AAPS Open (2023) 9:3 Page 16 of 25 applied across various industries. It has, however, gained in-office, or healthcare provider-supervised at-home increasing attention in healthcare facing high economic administration. As a subsequent lifecycle management, pressure, especially in light of the coronavirus pandemic. a subcutaneous dosing alternative is becoming available, Here, customer centricity aims at developing convenient either in a prefilled syringe for self-administration or in medicines that are globally affordable for people, provid - a vial presentation for manual or infusion pump-assisted ers, and the healthcare system as whole. For biotherapeu- injection by a caregiver. Product presentations vary from tics, such as mAbs, customer-centric product offerings case to case depending on the dosing volume and over- and treatment management concepts ideally facilitate a all feasibility of a stable liquid solution. Most frequently, flexible care setting and thus allow for drug administra - medications are offered with a fixed dose, unless a body tion and treatment monitoring outside of a controlled size-, safety-, or response-dependent regimen is justi- healthcare institutional environment. Efforts in the field fied (Strik et al. 2018). In a third step, the manufacturer go beyond the described improvements of the drug deliv- introduces automated injection devices. This scenario ery profile and product presentation and are in many was for example realized for tocilizumab in RA. Initially cases driven by pharmaceutical scientists from different approved in 2010 with a vial for intravenous infusion and disciplines. a monthly regimen (HPI Actemra : United Stated Food The realization of product optimizations differs across and Drug Administration 2022a), the subcutaneous dos- the distinctive disease area archetypes and depends on ing alternative was made available sequentially with a customer and market needs as well as on the clinical and prefilled syringe in 2013 (Burmester et al. 2014, Shetty technical feasibility of the intervention. In an indication et al. 2014), followed by an autoinjector device as a life- in which the identification of disease-modifying medi - cycle management in 2018 (Genentech 2013). To keep cines represents a major unmet need, initial drug deliv- the injection volume low and account for readily available ery efforts focus on enabling treatment per se. This is for devices at the time, the subcutaneous dosing frequency example the case for mAbs in ONC where any new and was increased to weekly and every 2 weeks with a dosing promising molecule is developed with the aim to offer it volume of 0.9 mL (Fettner et al. 2019). to people diagnosed with a given malignancy as soon as Scenario 1 also applies for mAbs in the treatment of feasible. Equally, for mAbs with demonstrated efficacy malignancies. While intravenously dosed mAbs are an but unfavorable exposure-related safety findings, prod - established treatment modality, development of subcuta- uct optimizations target a reduction in the incidence neous dosing alternatives started only years after the first and severity of adverse events through lowering post- mAb approval (Salar et al. 2014; Jackisch et al. 2019). This infusion serum levels. This may be achieved for example is due to at times severe and even fatal IRRs and com- by increasing the dosing frequency (Bai et al. 2012), a paratively high individual dose levels that challenged the schedule change that reduces convenience and increases development of convenient subcutaneous dosing regi- healthcare institutional burden associated with shorter mens. With increasing knowledge about the general fea- dosing intervals. sibility of high-volume subcutaneous dosing, advances in As per the definition in this review article, the journey high-concentration formulations and the co-administra- to more customer-centric products starts with the avail- tion of the dispersion enhancer hyaluronidase, by now, ability of an efficacious product with an acceptable risk/ this route of administration has become a key focus area benefit ratio. Across the selected disease archetypes, the of drug delivery scientists across indications (Bookbinder existence of established drug delivery technology plat- et al. 2006; Mathaes et al. 2016). While in ONC, mAb forms plays a pivotal role in enabling customer-centric dosing in the clinic is standard practice, today, efforts in product presentations early on, ideally already at initial disease management support are made to shift treatment launch of the mAb. Combining the learnings from these and monitoring outside of the clinic (Denys et al. 2020). distinct disease area archetypes, Fig. 3 illustrates possible Independent at-home administration for high-dose launch scenarios for intravenous and subcutaneous dos- mAbs has not yet been realized, but represents a think- ing regimens for mAbs. The underlying assumption is able option in the future with the advancement of larger that mAbs with dosing volumes of up to approximately volume on-body delivery systems (Bittner and Schmidt 2 mL are conventionally dosed in prefilled syringes and 2021). automated pen or autoinjector devices, while higher vol- Notably, next to a lack of technical and clinical feasi- ume mAbs are provided in vial presentations and possi- bility, it is also the healthcare provider reimbursement bly in the future in larger automated pen and autoinjector model applied in a given legislation that challenges sub- devices or in automated on-body delivery systems. cutaneous administration in a decentralized setting. In scenario 1, at initial molecule launch, the mAb is Roughly speaking, one can discriminate between fee-for- available with an intravenous dosing regimen for in-clinic, service payment models with separate service-specific Bittner AAPS Open (2023) 9:3 Page 17 of 25 Fig. 3 Possible launch scenarios for intravenous versus subcutaneous dosing regimens for mAbs payments and models where a medical provider receives syringe in 2009 (HPI Simponi : United Stated Food and a predetermined payment for a sequence of related Drug Administration 2022a), followed by the introduc- healthcare services (Einav et al. 2022). From a drug deliv- tion of an autoinjector 4 years later in 2013 (Center for ery perspective, whereas the first model incentivizes the Drug Evaluation and Research 2013). This device was complexity and quantity of care and as such incentivizes favorably evaluated in a prospective study in biologic- more complex intravenous infusions, the latter rewards naïve people with active RA (Schulze-Koops et al. 2013). the quality of care and thus ready-to-use subcutaneous Likewise, adalimumab was first authorized with a pre - regimens with the potential for at-home administration. filled syringe specifically designed for self-administration Here, any efforts that facilitate shifting treatment outside for people with stiffness in their hands due to destructive of the clinic are usually valued. progression of RA as well as with a vial for institutional In launch sequence scenario 2, the mAb enters the use in 2002 (HPI Humira : United Stated Food and Drug market directly with a subcutaneous formulation. Cur- Administration 2022a). Approval of the automated pen rently, the prerequisite for this approach is that doses are device followed sequentially in 2006 (BioSpace 2006). A low enough to apply established formulation and device comparison of the pen device with the established pre- technologies. Products are offered either in a prefilled filled syringe as assessed in a Phase 2 trial in participants syringe or vial configuration. Subsequently, upon avail - diagnosed with RA revealed preference for the auto- ability, automated injection devices are introduced as a mated injector based on its perceived ease of use and lifecycle management. This scenario is depicted in how a resulting convenience (Kivitz et al. 2006). number of mAb products were introduced into the RA The framework underlying scenario 3, where mAbs are and IBD indications. The sequential market introduction directly and solely launched with a subcutaneous dosing of increasingly optimized product presentations did allow regimen presented in ready-to-use automated injectable manufacturers to consider user feedback on the selec- presentations, to date comprises mAbs and their follow- tion of a ready-to-use device. The device portfolio was on biologics with low dosing volumes that are generally subsequently expanded with additional product offer - well tolerated. These favorable features enable the use of ings for people who prefer one over another injection aid. established drug delivery platforms. Currently, this sce- Examples would be branded golimumab or adalimumab. nario is being realized for adalimumab follow-on biolog- Golimumab was first approved in the US with a prefilled ics (Ghil et al. 2019, HPIs Hulio , Hadlima: United Stated Bittner AAPS Open (2023) 9:3 Page 18 of 25 Food and Drug Administration 2022a). Another example as a whole. The actual realization of product optimi- for scenario 3 is the introduction of ofatumumab in MS, zations is in turn influenced by the safety and efficacy where the mAb was directly obtainable with both a pre- profile of a medication, market maturity, and the avail- filled syringe and an automated injection pen. Leveraging ability of enabling technologies. Here, the application an established autoinjector platform, the manufacturer of platform technologies that have the potential to be conducted the pivotal Phase 3 study for ofatumumab utilized for mAbs across different indications offer with a prefilled syringe and bridged to the autoinjector the possibility to launch a novel mAb already with the in a Phase 2 trial that demonstrated bioequivalence of most preferred drug delivery profile or even with a ofatumumab administered by the autoinjector versus the variety of different customized options at initial mar- prefilled syringe (Bar-Or et al. 2022). ket authorization. This will be especially the case for A comparison of activities among biosimilar manufac- disease areas in which mAb-based medicines currently turers qualifying as customer-centric as defined in this are among the investigated targets, such as Alzhei- article did reveal different focus areas across the desig - mer’s disease or rare diseases (Tambuyzer et al. 2020; nated disease area archetypes. Especially in the event Lacorte et al. 2022). of more than one follow-on biologic accessible for the Subcutaneous at-home administration of low-volume same originator, the competition for market shares via mAb formulations has been feasible for decades and a customized product profile is expected to increasingly illustrates the long-standing efforts in the field. As a next gain momentum. With this, the wider range of injection pivotal step to also warrant high-volume subcutaneous devices qualified will contribute to fulfilling the needs of home administration with dosing volumes exceeding a larger user population. Here, the application of estab- 5 mL, on-body delivery systems need to leave the explor- lished technology platforms for a variety of medications atory stage and require implementation into clinical accounts for both, the familiarity of prescribers with the practice. Electronic adherence aids that further engage device as well as learnings from challenges associated people treated with mAbs and their care partners into with their application and how to most appropriately disease management while still guaranteeing a remote overcome these. For mAbs predominantly available for contact with the physician should be implemented in in-clinic mAb administration, the described seemingly parallel. A significant change in dosing paradigm for smaller product changes, such as a change from a lyo- mAbs would be a shift from parenteral to oral adminis- philized powder for reconstitution to a ready-to-admin- tration, with a variety of technologies in early develop- ister liquid formulation or an increased storage time and ment. A key prerequisite here is that drug administration shelf-life can be an advantage for one over another bio- schedules can still be managed based on the mAb’s dose similar. This is due to for instance improved distribution level and the cost of goods sold associated with the and handling logistics, reduced drug wastage or more provision of these at times device-based technologies. economical resource utilization in the clinic (Smale et al. Manufacturers need to partner with specialized biotech- 2021). It is of note in the context of customer-centric bio- nology companies and, like with any innovation, need similar offerings that depending on the country and asso - to afford some upfront investment at risk. This way oral ciated pricing, reimbursement, and demand-side policies delivery platforms may become a reality for mAbs across (Rémuzat et al. 2017), lower overall treatment costs per disease areas. se may provide an access advantage over their origina- A field of increasing relevance is the sustainabil - tor counterpart (Kvien et al. 2022) without the need for ity of novel drug delivery technologies. Manufacturers further optimizing the product profile. In an attempt to will have to do their homework to understand whether facilitate access to treatment, the FDA has designated the for example reusable technologies indeed offer a more first mAb, an adalimumab biosimilar, as interchangeable environmental dosing alternative, or whether pos- with the reference product in 2021 (United States Food sible advantages come with the challenge of reduced and Drug Administration 2021), meaning that the biolog- user-friendliness. ical product “may be substituted for the reference prod- Pharmaceutical scientists are involved in product opti- uct without the involvement of the prescriber” (United mizations across different disciplines, that is, besides States Food and Drug Administration 2017). their role as practicing healthcare provider, in formula- tion and device development, nonclinical and clinical Summary and outlook pharmacokinetics and pharmacology, or in regulatory Advancing customer-centric medicinal products is an affairs and market access. As such, we have the encourag - adaptive process across the lifecycle of a mAb-based ing opportunity and mandate to leverage existing insights medicine that aims to address individual needs of peo- and synergies across different indications and thus avoid ple treated as well as those of the healthcare ecosystem repeating assessments and reinventing development and Bittner AAPS Open (2023) 9:3 Page 19 of 25 Abramson A, Frederiksen MR, Vegge A, Jensen B, Poulsen M, Mouridsen B, Jes- commercialization pathways from the beginning. The persen MO, Kirk RK, Windum J, Hubálek F, Water JJ, Fels J, Gunnarsson work on improving mAb products should involve co- SB, Bohr A, Straarup EM, Ley MWH, Lu X, Wainer J, Collins J, Tamang S, creation not only with customers, but also collaborations Ishida K, Hayward A, Herskind P, Buckley ST, Roxhed N, Langer R, Rahbek U, Traverso G. (2022). 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J Diabetes Sci and Technol 5(6):1563– SMPC Summary of Product Characteristics 1571. https:// doi. org/ 10. 1177/ 19322 96811 00500 633 SPMS Secondary progressive multiple sclerosis Arsenault C, Gage A, Kim MK, Kapoor NR, Akweongo P, Amponsah F, Aryal A, UC Ulcerative colitis Asai D, Awoonor-Williams JK, Ayele W, Bedregal P, Doubova SV, Dulal UK United Kingdom M, Gadeka DD, Gordon-Strachan G, Mariam DH, Hensman D, Joseph JP, US United States Kaewkamjornchai P, Eshetu MK, Gelaw SK, Kubota S, Leerapan B, Mar- gozzini P, Mebratie AD, Mehata S, Moshabela M, Mthethwa L, Nega A, Acknowledgements Oh J, Park S, Passi-Solar A, Pérez-Cuevas R, Phengsavanh A, Reddy T, Rit- We thank Johannes Schmidt from F. Hoffmann-La Roche Ltd. for thorough tiphairoj T, Sapag JC, Thermidor R, Tlou B, Guiñez FV, Bauhoff S, Kruk ME review of the manuscript. (2022) COVID-19 and resilience of healthcare systems in ten countries. Nat Med 28:1314–1324. https:// doi. org/ 10. 1038/ s41591- 022- 01750-1 Authors’ contributions Atay S, Barista I, Gundogdu F, Akgedik K, Arpaci A (2012) Rapid-infusion rituxi- Beate Bittner drafted the scope and content of the article, conducted the mab in lymphoma treatment: 2-year experience in a single institution. literature research and wrote the manuscript. The author(s) read and approved J Oncol Pract 8(3):141–143. https:// doi. org/ 10. 1200/ JOP. 2011. 000319 the final manuscript. Azuz S, Newton M, Bartels D, Klindt Poulsen B (2021) Uptake of biosimilar trastuzumab in Denmark compared with other European countries: a Funding comparative study and discussion of factors influencing implementa- Not applicable. tion and uptake of biosimilars. Eur J Clin Pharmacol 77:1495–1501. https:// doi. org/ 10. 1007/ s00228- 021- 03155-4 Availability of data and materials Bagel J, Tatla D, Hellot S, Knapp B, Murphy C, Peterson L, Sebastian M (2022) Not applicable (review article). Bimekizumab self-Injection devices: two multicenter, randomized, open-label studies on self-administration by patients with psoriasis. J Drugs Dermatol 21(2):162–171. https:// doi. org/ 10. 36849/ jdd. 6274 Declarations Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, Gupta M, Tang M, Allison DE, Lu D, Zhang Y, Joshi A, Dresser MJ (2012) A guide to rational Competing interests dosing of monoclonal antibodies. Clin Pharmacokinet 51(2):119–135. Beate Bittner is employee of F. Hoffmann-La Roche and owns stock in Roche. https:// doi. org/ 10. 2165/ 11596 370- 00000 0000- 00000 Bailey K, Mountian I, Bruggraber R, Sunderland K, Tilt N, Szegvari B (2020) Patient ® ® satisfaction with CIMZIA (certolizumab pegol) AutoClicks in the UK. 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Publisher: Springer Journals
Copyright: Copyright © The Author(s) 2023
eISSN: 2364-9534
DOI: 10.1186/s41120-022-00069-y
Publisher site: See Article on Publisher Site

Abstract

Delivering customer-centric product presentations for biotherapeutics, such as monoclonal antibodies (mAbs), repre- sents a long-standing and paramount area of engagement for pharmaceutical scientists. Activities include improving experience with the dosing procedure, reducing drug administration-related expenditures, and ultimately shifting parenteral treatments outside of a controlled healthcare institutional setting. In times of increasingly cost-constrained markets and reinforced with the coronavirus pandemic, this discipline of “Product Optimization” in healthcare has gained momentum and changed from a nice-to-have into a must. This review summarizes latest trends in the healthcare ecosystem that inform key strategies for developing customer- centric products, including the availability of a wider array of sustainable drug delivery options and treatment man- agement plans that support dosing in a flexible care setting. Three disease area archetypes with varying degree of implementation of customer-centric concepts are introduced to highlight relevant market differences and similarities. Namely, rheumatoid arthritis and inflammatory bowel disease, multiple sclerosis, and oncology have been chosen due to differences in the availability of subcutaneously dosed and ready-to-use self-administration products for mAb medicines and their follow-on biologics. Different launch scenarios are described from a manufacturer’s perspective highlighting the necessity of platform approaches. To unfold the full potential of customer-centric care, value-based healthcare provider reimbursement schemes that incentivize the efficiency of care need to be broadly implemented. Keywords Customer centricity, Parenteral, Oral, Subcutaneous, Flexible care setting, Product optimization (Fernández et al. 2017) and frequently mandates more Introduction burdensome in-clinic dosing (Bohra et al. 2020). Over the past quarter century, biotherapeutics, such In times of continuously growing cost pressure on as monoclonal antibodies (mAbs), have become a pre- healthcare and major implications of the pandemic on vailing novel treatment modality (Lu et al. 2020) and as established medical services (Arsenault et al. 2022), any such significantly contribute to both the costs (Hernan - effort in minimizing the dosing complexity of paren - dez et al. 2018) and the environmental impact (Amasawa teral administration has the potential to reduce expen- et al. 2021) of healthcare. Inherent to their physicochemi- ditures for the drug administration procedure. For cal properties, mAbs must be administered parenter- instance, if permitted by the safety profile of a biologi - ally, a circumstance that can be considered inconvenient cal medicine, an attempt to lessen in-clinic time during an intravenous dosing day is the provision of fast infu- sion regimens. This approach can improve cost-effec - *Correspondence: Beate Bittner tiveness of the treatment, as it allows more people to be beate.bittner@roche.com treated in the clinic within a given time frame (Spadaro F. Hoffmann-La Roche Ltd., Global Product Strategy - Product et al. 2017). To further facilitate intravenous dosing and Optimization, Grenzacher Strasse 124, CH-4070 Basel, Switzerland to aid operators with obtaining central vascular access, © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Bittner AAPS Open (2023) 9:3 Page 2 of 25 new device types, such as a handheld assistive artificial healthcare providers and regulators. This is particularly intelligence-enabled, ultrasound-guided robotic device the case for mAbs that exhibit severe infusion-related for intravenous catheterization, are currently undergo- reactions (IRRs) mainly occurring during the first dosing ing early development (Brattain et al. 2021). cycles (Rombouts et al. 2020). An alternative concept for optimizing hospital To improve adherence to parenteral dosing in a non- resource utilization that has been in the center of inter- controlled setting, the individual demands of people est of many drug delivery researchers in recent years treated with mAbs have to be accounted for by manu- represents reformulating a biological medication for facturers. In addition to interventions that address edu- application via a less-invasive administration route. In cational, behavioral or psychological barriers against 2014, Tetteh et al. (2014) developed a regression-based complying with the dosing regimen (Remington et al. algorithm that included an estimate on how the admin- 2013), providing personalized and thus customer-centric istration route of biotherapeutics, including mAbs, product presentations and administration schemes has may impact on healthcare delivery expenditures. The the potential to enhance adherence to parenteral home analysis suggests that assuming no other change (that administration overall (Ridyard et al. 2016). is, in-clinic dosing, dosing frequency), subcutaneous or The term customer centricity is applied across indus - intramuscular administration of biologics lowers total tries highlighting that in order to achieve sustainable healthcare delivery costs as compared to intravenous product offerings, satisfying the needs of “the customer” infusions. has to be the ultimate focus for any development decision A more significant step in reducing dosing regimen- (Pardo-Jaramillo et al. 2020). For medicinal products, related inconvenience, healthcare institutional spend- “the customer” is classically defined as “the patient,” but ing and in improving affordability and access to mAb increasingly the entire healthcare ecosystem is referred treatments is to shift dosing outside of the clinical set- to using this term. Thus, in addition to people receiving ting (Wolfromm et al. 2017; Bittner et al. 2018; Bittner treatment for a diagnosed medical condition, this eco- and Schmidt 2021). Here, subcutaneous at-home- and system comprises professional healthcare providers and self-administration has become an established dosing institutions, regulators, payers (Pidun et al. 2021), and regimen for mAbs with a favorable safety and tolerabil- ultimately society as a whole. ity profile across different disease areas (Gottlieb et al. In the pharmaceutical industry, efforts to ameliorate 2016, Raffaelli et al. 2019, Van den Bemt et al. 2019, Tim - the product profile of an established medicine are driven mermann et al. 2020, Jappe et al. 2021, Bagel et al. 2022). by the cross-functional discipline of “Product Opti- Especially low-volume subcutaneous injections can mization” (Bittner and Schmidt 2022). “Product Opti- be self-administered by means of a variety of prefilled mization” also referred to as “Formulation and Device syringes or pen device types, thus accounting for per- Lifecycle Management” aims at improving the drug deliv- sonal priorities and capabilities (Anderson and Redondo ery profile and product presentation for a medicine that 2011; Vermeire et al. 2018). While these automated dos- is either already on the market or in late-stage clinical ing aids support convenience with an at-home dosing development and thus at providing a more customer- regimen, adherence and persistence to subcutaneous centric presentation. administration in an unsupervised setting varies between This review is written from a manufacturer’s per - medical products (Tkacz et al. 2014; Nieto et al. 2021). spective and summarizes key trends in the healthcare Besides disease severity or prior experience with sub- ecosystem that define customer-centric drug delivery cutaneous administration, also the dosing schedule can requirements for mAbs across different therapeutic areas, contribute to compliance issues with the prespecified illustrates approaches to obtain insights into emerging application procedures (Tkacz et al. 2014). drug delivery necessities, and compares the latest devel- The situation is complicated specifically for high-dose opments in three distinct disease area archetypes. mAbs requiring comparatively large administration vol- umes and for mAbs dosed in combination therapy. While Drug delivery as treatment enabler user preference assessments demonstrate that even in versus as customer‑centric differentiator the hospital setting, high-dose subcutaneous injections Drug delivery is commonly explained as the “method or with individual dose volumes between 5 and 15 milliliters process of administering a pharmaceutical compound (mL) are preferred over intravenous infusion regimens to achieve a therapeutic effect” (Gupta and Kumar 2012; (Pivot et al. 2014; Rummel et al. 2017; O’Shaughnessy Tiwari et al. 2012). This definition predominantly refers et al. 2021; Usmani et al. 2021), customized dosing to drug delivery technologies that enable the admin- schemes for at-home administration still remain to be istration of pharmaceutical products per se. Such is developed by manufacturers in close cooperation with particularly the case when developing formulation or Bittner AAPS Open (2023) 9:3 Page 3 of 25 device technologies for novel treatment modalities unsupervised parenteral dosing. In this case, provid- with previously unexplored physicochemical and phar- ers, in order to support dosing in a remote setting, macokinetic properties. Frequently, in these instances, require reassurance that high-quality disease monitor- there is neither experience available on how a galeni- ing and adherence to treatment procedures is main- cal formulation can impact bioavailability, safety or tained. Assuming compliance and adequate support efficacy of the medication, nor on what would be the services are guaranteed for parenteral administration most preferred product profile from a customer per - outside of a healthcare institution, the underlying spective. Focus of drug delivery scientists is therefore societal benefits of at-home- and particularly the eco- on progressing a product presentation that achieves the nomic benefits of self-administration (Franken et al. required target exposure via an appropriate administra- 2020) are pivotal elements of value-based healthcare tion route. Especially with new and possibly disease- (Dainty et al. 2018, Teisberg et al. 2020). modifying biological molecules, technologies that go From a regulator’s perspective, mAbs suitable for beyond treatment enablement may either have not yet home administration must possess an appropriate safety been identified or are still in early development (Blanco profile and must be available in a product presentation and Gardinier 2020). Aspects of convenient dosing or that supports unsupervised administration (Bittner and efficient healthcare resource utilization are of second - Schmidt 2022). As data derived from registrational clini- ary priority at this stage. Consequently, any formulation cal trial investigations alone may not exhaustively reveal and device optimization that would delay initial mole- feasibility of a flexible care setting, additional sources cule launch and thus availability of the medication for of information are being considered. In assessing the customers is typically introduced as a lifecycle manage- risk benefit of a medicinal product, regulators progres - ment (Bittner and Schmidt 2022). sively encourage manufacturers to actively implement “Customer-centric” drug delivery, as defined in this real-world data (RWD) and real-world evidence (RWE) article, becomes an important aspect for indications with during development processes and to share “patient- a variety of more mature medications with similar phys- provided information” for evaluation as part of drug icochemical properties available from a given compound and medical device applications (United Stated Food class. Here, treatment enabling technologies have been and Drug Administration 2018). The United States Food established over time (Shams et al. 2021). With emerging and Drug Administration (FDA) defines RWD as “data customer insights on needs for improving the product relating to patient health status and/or the delivery of presentation, drug delivery efforts predominantly focus health care routinely collected from a variety of sources” on differentiating the medication with a more convenient and RWE as “the clinical evidence about the usage and and cost-efficient profile (Roy et al. 2021; Schreiber et al. potential benefits or risks of a medical product derived 2022). from analysis of RWD” (United States Food and Drug In addition to achieving a user-oriented drug delivery Administration 2022b). According to the FDA, RWD profile, manufacturers engage in offering medicines with sources can include registries, collections of electronic overall more sustainable presentations. Activities entail health records, or administrative and medical claims the implementation of measures to reduce drug wastage databases. Besides prescription information, medical via more economic dosing regimens and supply chain diagnoses, bills submitted to payer organizations, costs, concepts (Hendrikx et al. 2017; Tat and Heydari 2021). charges and reimbursement amounts, such databases Over time, and on the basis of progressively established also include insights into procedures and treatments platform technologies, this initially stepwise approach is performed (Rocco et al. 2017; Park and Lee 2021). Glob- emerging into a situation where novel products are avail- ally, clinical trial results are therefore supplemented by able with the best feasible drug delivery profile from ini - RWD and RWE (Hiramatsu et al. 2021). This evidence tial molecule launch onwards. also serves as a source for estimating the impact of drug delivery modalities on healthcare resource utilization Healthcare trends that define customer‑centric (Stearns et al. 2019). mAb product presentations Likewise, the application of robust RWE to supplement Today, people diagnosed with a chronic condition experimental evidence in coverage decisions is being con- are increasingly well informed about particulari- sidered globally (Facey et al. 2020). In a literature review ties of their disease and willing to actively participate on the US healthcare system conducted by Hampson in the design of healthcare processes (Longtin et al. et al. (2018), comparative clinical effectiveness and net - 2010). Resulting customer-centric concepts commonly work meta-analysis for quantitative indirect comparisons include aspects of disease self-management (Holmes were identified as pivotal sources for initial payer cover - et al. 2019) and as such mandate measures that allow age and Heath Technology Assessment decisions. Here, Bittner AAPS Open (2023) 9:3 Page 4 of 25 “patient-reported data” may be used as a complimentary Customer‑centric product presentations data source. For reassessments, that is reconsidering cov- that enable dosing in a flexible care setting erage, formulary placement or payment terms, as well as Reliable application of biotherapeutics in a flexible care in the context of outcomes-based contracting, RWE can setting depends on adequate user training and educa- play a role in further defining the clinical or economic tion and mandates treatment initiation under professional value of an intervention, beyond the evidence gener- supervision (Highlights of Prescribing Information (HPI) ® ® ® ated in the clinical trial setting. Notably, in their review, Humira , Hizentra , Kesimpta : United Stated Food and a number of challenges associated with the use of RWE Drug Administration 2022a). Establishing convenient drug for healthcare payment decisions were identified. These delivery schemes and electronic data capturing tools permit include aspects of reporting bias, incomplete data, lack physicians to make accurate treatment decisions while their of universally accepted methodological standards, lack of patient is dosed outside of a controlled environment (Eun- investigator expertise, or obsolete evidence hierarchies. Young 2017; El-Sappagh et al. 2019; Sebastian et al. 2019). Similar findings were made in a US payer interview con - Especially, if home dosing is facilitated with mechanisms ducted by Timbie et al. (2021). The evaluation identified to collect “patient-provided information,” such data could the evidence from rigorous clinical trials as a prioritized have the potential to reduce payer’s uncertainty around source for assessing efficacy and short-term safety find - adherence and to complement value-based reimbursement ings. Some payers, however, “felt that RWE was particu- models. larly helpful when the long-term durability of devices or Beyond professional support services and electronic rare adverse events were key considerations in coverage data capturing and monitoring tools, drug delivery decisions”. improvements that reduce supply chain complexity, per- Figure 1 highlights key healthcare trends that inform mit simple and intuitive drug administration, and facili- customer-centric drug delivery needs for monoclonal tate medication storage and disposal represent a crucial antibodies. Insights reveal the need for technologies that element of pharmaceutical research and development. enable dosing and data collection in a flexible care set - Figure 2 illustrates drug delivery improvements for ting. Here, contingent upon the medication’s safety and mAbs that reduce dosing complexity and enable dos- tolerability, medication administration may take place ing and data collection in a flexible care setting. Aspects in the clinic, a physician’s office, a community or infu - include (1) improving the product presentation, (2) sion center or in the patient’s home (Bittner and Schmidt reducing the overall burden of parenteral drug adminis- 2021). tration, and (3) complementing combination therapy. In Fig. 1 Key healthcare trends that inform customer-centric drug delivery needs for monoclonal antibodies. Need for technologies that enable dosing and data collection in a flexible care setting (FCS) Bittner AAPS Open (2023) 9:3 Page 5 of 25 Fig. 2 Drug delivery improvements for mAbs that reduce dosing complexity and enable dosing and data collection in a flexible care setting this order, product optimizations are expected to possess medications’ drug delivery profile. For marketed mAbs increasing potential to facilitate remote parenteral care. or for biologics in development in an indication with Attempts in advancing the product presentation entail similar treatment modalities already employed, informa- optimizing storage conditions and shelf-life of the medica- tion on how the product might be improved is typically tion (Kuzman et al. 2021), as well as improving its packag- already available from secondary sources and thus can be ing to account for an easy to store and to handle offering estimated based on existing analogues. Notably, custom- (Zadbuke et al. 2013). Product optimizations that lessen the ers’ desires evolve with the maturity of a market based burden associated with parenteral administration of bio- on emerging sophistication of drug delivery technologies therapeutics comprise fast intravenous infusion regimens (Al and comparisons with other indications with biothera- Zahrani et al. 2009), fixed dosing regimens instead of body peutics with similar drug delivery requirements. The size-adjusted dosing (Egorin 2003), subcutaneous dosing journey of product optimizations is therefore flexible and alternatives to more invasive intravenous infusions (Bittner adaptable to change at all times. et al. 2018), or automated injection devices (Vijayaraghavan An understanding of user and provider preferences for 2020). Connected devices and accompanying health apps one over another drug delivery methodology is gained are being implemented to support adherence in an out- either as part of pivotal registrational clinical trials or in patient setting and can be utilized to collect RWE on possible smaller dedicated usability studies (Li and Easton 2018). adverse events and share it back with the treating physician Here, electronic apps with dosing reminders and tools to (Bittner et al. 2019). Drug delivery improvements to comple- collect “patient-reported outcomes” in the home setting ment combination therapy involve the development of fixed- (El Emam et al. 2009) provide early insights into possible dose combinations with two or more mAbs co-formulated challenges and opportunities of a product optimization. in the same dosing vehicle, or dual chamber bags (Allmend- Additionally, treatment satisfaction and quality-of-life inger 2021). Details on underlying concepts and scientific surveys (Kempton et al. 2021), as well as time and motion nonclinical and clinical development approaches have been studies (De Cock et al. 2014; Pivot et al. 2014) that assess summarized previously and are therefore off-scope for this the impact of the drug administration procedure on the article (Bittner and Schmidt 2022). efficiency of dosing in a prespecified setting represent an appreciable source of information. Gaining insights into customer needs for product For marketed medications and relevant reference prod- optimization of biological medicines ucts with a similar drug delivery profile in other indica - To inform investments into customer-centric product tions, insights into the practicality of the drug delivery optimizations for existing medicines, manufacturers reg- profile are frequently derived from direct user or provider ularly collect insights on possible challenges with their feedback to the manufacturer of a medicinal product. Bittner AAPS Open (2023) 9:3 Page 6 of 25 Disease area archetype 1 (rheumatoid arthritis This encompasses anecdotal reports on challenges with and inflammatory bowel disease)—mature markets the drug administration instructions and at times even with a variety of established mAb treatments suggestions on how to improve these. Input is addition- and corresponding follow‑on biologics available ally tracked via established complaint management pro- for self‑administration cesses (Hake et al. 2019) in which customer feedback is Disease area archetype 1 encompasses RA and IBD, collected and reviewed systematically over time. Verifia - representing mature subcutaneous self-administration ble customer co-creation (Adelman et al. 2019; Peng et al. markets with established originator mAbs and other 2022) may be realized via satisfaction surveys or cus- long-standing biological treatments and corresponding tomer workshops designing the most appropriate drug biosimilars either already approved or in development delivery system for a drug and as part of well-defined (De Figueiredo et al. 2021; Findeisen et al. 2021; Radu human factor trials (Lageat et al. 2021). and Bungau 2021). Authorized mAb treatments for both RA and IBD include the tumor necrosis factor-α inhibi- Key developments in providing customer‑centric tors infliximab, adalimumab, golimumab, and certoli - product presentations for mAbs across different zumab pegol. The B-cell-depleting therapy rituximab and disease areas the interleukin-6 receptor antagonists tocilizumab and Disease area archetypes sarilumab are indicated for the treatment of RA (Senolt The availability of product presentations and dosing regi - 2019). The interleukin-12 and interleukin-23 inhibitor mens that support administration of mAbs in a flexible ustekinumab, the α4β7 integrin antagonist vedolizumab, care setting varies considerably across indications. Three and the α4 integrin antagonist natalizumab are author- different disease area archetypes have been selected to ized for the treatment of IBD (Mao et al. 2018; Wyant describe the status and key developments on the journey et al. 2016). to increasing customer centricity of mAb medications. In 1998, the chimeric mAb infliximab was the first Table 1 illustrates the relevant attributes of these differ - tumor necrosis factor-α inhibitor authorized by the FDA ent markets. Disease areas comprise rheumatoid arthri- for the treatment of Crohn’s disease (CD) (Melsheimer tis (RA) and inflammatory bowel disease (IBD), multiple et al. 2019). Branded infliximab was and is still solely sclerosis (MS), and oncology (ONC). Table 1 Key attributes of selected disease area archetypes; considers marketed mAb profiles only Disease mAb safety & tolerability profile mAb drug delivery profile Market maturity (injectables) area archetype 1 mAbs exhibit sufficient tolerability to allow Predominantly SC formulations for self- Several mAbs & other biologics with different RA/IBD unsupervised administration outside of a administration & overlapping indications available controlled healthcare environment Low dosing volumes (below 2 mL) A number of mAbs & other biologics also Ready-to-use PFS & autoinjector/pen used in other indications devices Biosimilars for some mAbs & other biologics available 2 mAb-dependent safety profiles; unsu- Predominantly IV formulations for HCP- Few mAbs with overlapping indications MS pervised and supervised administra- assisted administration Biosimilars for other biologics available tion outside of a controlled healthcare 1 mAb with SC formulations for self- No mAb biosimilar marketed environment administration (dosing volume of 0.4 mL; ready-to-use PFS & autoinjector device) 3 mAb-dependent safety profiles; currently Predominantly IV formulations for HCP- A variety mAbs with different & overlapping ONC no unsupervised administration outside of assisted administration indications available a controlled healthcare environment4 mAbs with high-volume SC formulations Biosimilars for some mAbs available for HCP-assisted administration (volumes of 5 to 15 mL; vial presentations) 1 SC mAb FDC 1 IV mAb FDC FDC fixed-dose combination, HCP healthcare provider, IBD inflammatory bowel disease, IV intravenous, mAb monoclonal antibody, mL milliliters, MS multiple sclerosis, ONC oncology, RA rheumatoid arthritis, SC subcutaneous Following treatment initiation under supervision and training of a HCP Ofatumumab Trastuzumab, rituximab, daratumumab, pertuzumab + trastuzumab Pertuzumab + trastuzumab Nivolumab + relatlimab Bittner AAPS Open (2023) 9:3 Page 7 of 25 available with an intravenous dosing regimen as a pow- seemingly small change was shown to result in a reduc- der for reconstitution (HPI Remicade : United Stated tion of pain at the injection site and ultimately in a sig- Food and Drug Administration 2022a). The first fully nificantly improved adherence and time on treatment human recombinant immunoglobulin G1 mAb in RA, overall (Bergman et al. 2020; Patel and Luu 2020). The adalimumab, was already introduced with a subcutane- finding is all the more important as decreased persis - ous dosing regimen at initial product approval in 2002 tence to anti-tumor necrosis factor therapy had been (Marušić and Klemenčić 2018). The majority of branded reported to be associated with poorer clinical out- injectables in the field are available with either both an comes (Bluett et al. 2015). Additional product optimi- intravenous and a subcutaneous formulation (goli- zations introduced for branded adalimumab comprise mumab, tocilizumab, ustekinumab, vedolizumab; HPIs a reduced injection volume with a higher concentrated ® ® ® ® ® Simponi , Simponi Aria Actemra , Stelara , Entyvio : dosing solution, higher needle gauge, or modifications United Stated Food and Drug Administration 2022a, in the material of the injection devices (St Clair-Jones SMPC Entyvio : European Medicines Agency 2021) et al. 2020). or a subcutaneous formulation only (adalimumab, cer- With the aim to optimize experience with the dosing ® ® tolizumab pegol, sarilumab; HPIs Humira , Cimzia , procedure, to reduce the fear associated with needle use, Kevzara : United Stated Food and Drug Administra- and to aid people with impaired dexterity, in 2016, cer- tion 2022a). The fixed-dose regimens omit the need for tolizumab pegol’s product presentations were comple- body size-normalized dose calculation. Subcutaneous mented with a button-free autoinjector characterized by injection volumes do not exceed 2 mL and dosing fre- a wide, non-slip grip (Bailey et al. 2020). Supported with quencies range from weekly to every 4 weeks. The sub - adequate training, the device could improve user confi - cutaneous administration regimen for ustekinumab dence and satisfaction with subcutaneous self-adminis- consists of an intravenous loading dose followed by every tration. The introduction of a mini cartridge to be applied 8 weeks subcutaneous maintenance doses. Ready-to-use by means of a reusable autoinjector for the biologic prefilled syringes or pen devices provide users with dif - etanercept in 2017 (Collier et al. 2017, Sedo 2018) may in ferent dosing alternatives as per their personal require- the future also serve as a platform for mAbs. The prod - ments. Branded natalizumab, infliximab, and rituximab uct also utilizes an improved dosing solution that had can only be given intravenously with maintenance dosing been shown to lessen injection site pain as compared to frequencies between every 4 weeks and every 6 months the previous formulation (Cohen et al. 2019). Preference ® ® ® (HPIs Tysabri , Remicade , Rituxan : United Stated assessments comparing the novel reusable with the exist- Food and Drug Administration 2022a). These infusion ing disposable automated pen device revealed perceived regimens represent an alternative for people who prefer advantages for both injection aids, thus giving users the intravenous over subcutaneous dosing (Allen et al. 2010) choice between two devices according to personal priori- or value a lower treatment frequency independent of the ties (Collier et al. 2017). administration route (Huynh et al. 2014). In the clinic, To further facilitate compliance with at-home dos- less frequent dosing can be a contributor to a more con- ing, companies are implementing so-called patient sup- venient and cost-efficient treatment management scheme port programs and app-based assistance tools including (Tetteh and Morris 2014), especially if medical exami- customized dosing reminders or injection and symptom nations can be combined with a dosing day. Most nota- trackers (Graigner et al. 2017, Lambrecht et al. 2021). bly, the fact that a variety of injectable medications are Branded certolizumab pegol offers the option to apply the approved both for the treatment of RA and IBD increases first partially reusable electromechanical injection device healthcare provider’s general familiarity with an injec- “of its kind available for use with biologic treatment in tion device type and offers the possibility for leverag - rheumatology and dermatology in Europe” (UCB 2021). ing learnings on challenges with the injections (Chilton Device design was actually guided by intended user feed- and Collett 2008; Domańska et al. 2017; Gely et al. 2019) back through human factor evaluations (Domańska et al. across indications. Table 2 summarizes the mAb presen- 2018). The injector was found to be preferred due to its tations authorized for the treatment of adults diagnosed ease-of-use over other subcutaneous devices in a study with RA or IBD (CD and ulcerative colitis (UC)). with certolizumab pegol-treated people from the Nether- Prominent customer-centric product optimizations in lands, Denmark, and Sweden (Pouls et al. 2020). disease area archetype 1 include changing the composi- Manufacturers of follow-on biologics for mAbs in RA tion of the subcutaneous formulation for adalimumab. and IBD focus efforts on either using established injec - Accounting for "patient-reported pain" immediately fol- tion device platforms or on customizing technologies to lowing injection, the manufacturer changed the chemi- differentiate their products via unique, distinctive drug cal buffer to help stabilize and preserve the mAb. This delivery characteristics. As for the branded counterparts, Bittner AAPS Open (2023) 9:3 Page 8 of 25 Table 2 mAbs authorized for the treatment of RA or IBD (CD and UC) in the US (up until September 2022): administration routes, dosing regimens and product presentations (adult indications) a a Indication mAb Administration route and dosing IV product presentations SC product presentations regimen IV SC b b RA Rituximab 2*1000 mg separated by 2 weeks (one - 100 mg/10 mL, 500 mg/50 mL in - course) every 24 weeks or based on single-dose vials clinical evaluation (not sooner than every 16 weeks) Tocilizumab 4 mg/kg q4w followed by 8 mg/kg Patients < 100 kg: 162 mg q2w, fol- 80 mg/4 mL, 200 mg/10 mL, 162 mg/0.9 mL in single-dose prefilled q4w based on clinical response lowed by increase to q1w based on 400 mg/20 mL in single-dose vials syringe or single-dose prefilled autoin- clinical response jector Patients ≥ 100 kg: 162 mg q1w Sarilumab - 200 mg q2w - 150 mg/1.14 mL or 200 mg/1.14 mL solution in single-dose prefilled syringe or prefilled pen IBD Ustekinumab Induction: 90 mg 8 weeks after the initial IV induc- 130 mg/26 mL solution in single-dose 45 mg/0.5 mL or 90 mg/mL solution in < 55 kg: 260 mg tion dose, then q8w vial single-dose prefilled syringe > 55 kg to 85 kg: 390 mg 45 mg/0.5 mL in single-dose vial > 85 kg: 520 mg Maintenance: 90 mg 8 weeks after the initial dose, then q8w (SC) c c Vedolizumab 300 mg at weeks 0, 2 and 6, then q8w - 300 mg of lyophilized powder in - single-use 20 mL vial d d Natalizumab 300 mg q4w - 300 mg/15 mL solution in single-dose - vial Bittner AAPS Open (2023) 9:3 Page 9 of 25 Table 2 (continued) a a Indication mAb Administration route and dosing IV product presentations SC product presentations regimen IV SC e e RA & IBD Infliximab RA: - 100 mg of lyophilized powder in - 3 mg/kg at weeks 0, 2 and 6, then q8w single-dose vial (may be increased to 10 mg/kg q8w or to dosing frequency of q4w) CD: 5 mg/kg at weeks 0, 2 and 6, then q8w (may be increased to 10 mg/kg q8w if loss of response) UC: 5 mg/kg at weeks 0, 2 and 6, then q8w Adalimumab - RA: - 80 mg/0.8 mL, 40 mg/0.8 mL, and 40 mg q2w (some patients not receiving 40 mg/0.4 mL in single-dose prefilled pen methotrexate may benefit from dose 80 mg/0.8 mL, 40 mg/0.8 mL, increase to 40 mg q1w or 80 mg q2w) 40 mg/0.4 mL, 20 mg/0.4 mL, CD: 20 mg/0.2 mL, 10 mg/0.2 mL, 160 mg on day 1 (given in one day 10 mg/0.1 mL in single-dose prefilled or split over two consecutive days); glass syringe 80 mg on day 15 and 40 mg q2w start- 40 mg/0.8 mL in single-dose glass vial ing on Day 29 for institutional use only UC: 160 mg on day 1 (given in one day or split over two consecutive days); 80 mg on day 15 and 40 mg q2w start- ing on Day 29 Golimumab RA: RA: 50 mg/4 mL solution in single-dose 50 mg/0.5 mL in single-dose prefilled 2 mg/kg at weeks 0 and 4, then q8w 50 mg q1m vial syringe or single-dose prefilled autoinjector UC: 100 mg/1.0 mL in single-dose prefilled 200 mg at week 0, 100 mg at week 2 syringe or single-dose prefilled autoin- and then 100 mg q4w jector Certolizumab pegol - RA: - 200 mg lyophilized powder in single- 400 mg initially and at weeks 2 and 4, dose vial followed by 200 mg q2w; for main- 200 mg/mL solution in single-dose tenance dosing, 400 mg q4w can be prefilled syringe considered CD: 400 mg initially and at weeks 2 and 4. If response occurs, 400 mg q4w CD Crohn’s disease, IV intravenous, mg milligram, mL milliliter, qXd every X day, qXm every X month, qXw every X week, RA rheumatoid arthritis, SC subcutaneous, UC ulcerative colitis This table lists FDA-approved products; deviations with EMA-approved product presentations or other indications are indicated as a footnote A SC formulation for rituximab is approved in oncology indications A SC formulation for vedolizumab is approved in IBD in the EU A SC formulation for natalizumab is approved in MS in the EU e ® Biosimilar infliximab (Remsima ) is approved for subcutaneous administration in the EU Bittner AAPS Open (2023) 9:3 Page 10 of 25 Disease area archetype 2—market with a small number user and healthcare provider satisfaction and usabil- of mAbs established for in‑clinic or self‑administration ity studies are part of the autoinjector development and and no corresponding biosimilars available commercialization strategy (Thakur et al. 2016; Tischer MS, the second disease area archetype, is characterized and Mehl 2018; Fleischmann et al. 2022). This iterative by established non-mAb biological disease-modifying co-creation with customers is particularly important in treatments available for subcutaneous self-administra- disease areas in which people report problems with man- tion. The majority of mAbs is offered with an intrave - ual dexterity, pain linked to joint swelling in the hands, nous infusion regimen, but the first subcutaneous mAb and general challenges with the self-injection procedure for self-administration has recently reached the market. (Keininger and Coteur 2011). To date, no biosimilar mAb is available in the US (United Celltrion’s infliximab biosimilar received European States Food and Drug Administration 2022c). Medicines Agency (EMA) approval for a subcutaneous More precisely, subcutaneous self-administration with dosing alternative in 2019 and FDA review is anticipated interferon beta (IFNβ) indicated to treat relapsing forms to be completed as a next milestone (Rose 2021; Verma of MS is an established standard in the field (Kieseier et al. 2021), while branded infliximab is only available 2011; Filipi and Jack 2020). Back in 1993, the first IFNβ with an intravenous infusion regimen. This subcutaneous was approved in the US and since then several others self-administered infliximab product presentation paired have become available (Bayas and Gold 2003). Due to with telemedicine support and increasingly available their fixed dosing regimens and low injection volumes, RWD is suggested to lessen the time spent for travel and IFNβ products are available in ready-to-use prefilled hospital attendance during dosing days and as such to syringes and autoinjectors including devices with elec- reduce the pressure on healthcare systems (Ahmed et al. tronic adherence aids (Limmroth et al. 2017). IFNβ drug 2021; Perry and Jang 2020; Schreiber et al. 2022). administration regimens range from every second day In aspiring to relieve the burden of parenteral dosing, to every second week for the pegylated version that was the feasibility of oral dosing of mAbs is being examined authorized by the FDA in 2014 (Dashputre et al. 2017). In (Philippart et al. 2016; New 2020Abramson et al. 2022). a German real-world study from 2021, this less frequent Different to injectable dosage forms, the individual dose dosing alternative showed markedly higher scores for level that can be administered orally is markedly reduced treatment satisfaction and convenience compared with due to limited fill volumes of ingested oral dosage forms. previous therapies that included other IFNβ treatments Consequently, this approach is particularly interesting for (Menge et al. 2021). mAbs in immunology, as inherent to their comparatively The first mAb, natalizumab, an α4 integrin antago - low-dose levels, a practicable oral dosing frequency may nist, entered the MS market in in 2004 with a fixed be achievable. dose infused intravenously every 4 weeks over 1 h, and Different oral delivery technologies have recently by now is available for the treatment of clinically iso- advanced to clinical investigational stage. The first lated syndrome (CIS), relapsing–remitting MS (RRMS), approach aims at precise delivery of biotherapeutics and active secondary progressive MS (SPMS) (Rudick to gastrointestinal tissue thus avoiding high systemic et al. 2013, HPI Tysabri : United Stated Food and Drug exposure and potentially associated side effects. Here, Administration 2022a). While people with prior use of biosimilar infliximab is being assessed for the feasibil - subcutaneous interferon regimens commonly value the ity of an oral version in the treatment of IBD. The aim option for self-administration, especially when facilitated is to target release in the colon and to protect the mAb with automated injection devices (Lugaresi et al. 2012), from digestion in the stomach and upper gastrointesti- the improved efficacy of natalizumab over IFNβ therapy nal tract through local stabilization against proteases (Rudick and Panzara 2008; Lanzillo et al. 2012) is consid- (Intract Pharma 2022). A second advanced oral delivery ered to outweigh the convenience disadvantage of more approach utilizes an orally ingestible robotic pill that invasive intravenous dosing. auto-injects the biotherapeutic into the wall of the small In 2014, the FDA approved alemtuzumab, an anti-clus- intestine (Dhalla et al. 2022). The authors report that in ter of differentiation 52 (CD52) mAb, for the treatment an initial clinical trial with octreotide in healthy partici- of RRMS (Ruck et al. 2015). The medicine is available pants, administration of the pill was safe, well-tolerated, with a fixed-dose intravenous regimen for two treatment and yielded in an oral bioavailability of 65%. Assuming courses. During the first treatment course, alemtuzumab the scientific concept is confirmed in larger clinical tri - is administered over 4 h on five consecutive days and als and treatment can be realized at commercializable on three consecutive days during the second treatment dose levels and dosing regimens, this approach has the course 12 months later. Additional treatment courses potential to provide new clinical strategies in the future may be considered with drug administrations of three (Zhang et al. 2021). Bittner AAPS Open (2023) 9:3 Page 11 of 25 consecutive days (HPI Lemtrada : United Stated Food Stated Food and Drug Administration 2022a), ofatu- and Drug Administration 2022a). This comparatively mumab was launched both in a prefilled syringe and in convenient infrequent dosing regimen is to some extent an automated pen injector. In its final appraisal docu - counterbalanced by the need for regularly monitoring the ment on “Ofatumumab for treating relapsing multiple increased risk of autoimmunity (Garnock-Jones 2014). sclerosis,” the UK’s NICE notes that they heard from While alemtuzumab when delivered via the subcutane- “patient experts” “that a treatment that could be self- ous route may reduce infusion-related adverse events as administered monthly is less disruptive to people’s lives compared to intravenous dosing (Perumal 2012), a sub- than treatments administered by intravenous infusions in cutaneous formulation is not available for use in MS. hospital, so would be valued by people with multiple scle- The anti-CD20 mAb ocrelizumab was first authorized rosis” (National Institute for Health and Care Excellence in the US in 2017 (Frampton 2017) and by now is applied 2021). Launching a mAb in two different presentations for the treatment of relapsing forms of MS (RMS), includ- accounts for distinct preferences (Kivitz et al. 2018; Ver- ing CIS, RRMS, PPMS, and for the treatment of SPMS meire et al. 2018) already at first introduction of the novel (Stahnke et al. 2018, Weinstock-Guttman et al. 2022, medicine. Additionally, a manufacturer-initiated study HPI Ocrevus : United Stated Food and Drug Adminis- revealed user and nurse preference for the autoinjector tration 2022a). The mAb was introduced with an intra - over their current injectables mainly due to the “ease to venous fixed-dose regimen. Here, the initial treatment perform self-injection with the pen” and “patient able to cycle comprises two separate infusions on days 1 and use independently” (Ross et al. 2021). 15, respectively, followed by twice yearly maintenance In 2021, a subcutaneous version of natalizumab with doses. The United Kingdom’s (UK) National Institute for an overall shorter infusion time as compared to the Health and Care Excellence (NICE) noted in their final intravenous regimen received marketing authorization appraisal document on “Ocrelizumab for treating relaps- in the EU (Summary of Product Characteristics (SMPC) ing–remitting multiple sclerosis” that based on insights Tysabri : European Medicines Agency 2021, López et al. from “patient experts” “patients would value a treatment 2021). The product is available in prefilled syringes, two with less frequent dosing or monitoring,” acknowledging of which need to be administered at each dosing day that the intervention is less interruptive for people’s lives with a monthly dosing regimen; home treatment is not compared to other treatments (National Institute for recommended. In the same year, the manufacturer did Health and Care Excellence 2018). receive a complete response letter (CRL) from the FDA To optimize satisfaction and quality of life with intra- to their supplemental Biologic License Application for venous mAb treatments and to improve healthcare insti- the subcutaneous dosing alternative (BioSpace 2021); tutional resource utilization in MS, efforts are made to the underlying reasons for the CRL are unknown to support home-based and outpatient infusion manage- the author of this review. Also, a subcutaneous dosing ment (Vijayan et al. 2017; Schultz et al. 2021; Barrera alternative in development for ocrelizumab has reached et al. 2022; Räuber et al. 2022). It was found that people Phase 3 clinical development stage (clinicaltrials.gov are generally open to receiving the intravenous treat- 2022). Table 3 summarizes the mAb presentations ment at home and that supporting health services need authorized for the treatment of adult people diagnosed to ensure safety and be efficient, responsive, and flex - with MS. ible. Thus, health services should also allow for admin - istering the medication at individually preferred times Disease area archetype 3—market with variety during the day (Rath et al. 2021). Supporting measures of established mAb treatments for healthcare provider include designing appropriate home health care services administration and a number of corresponding biosimilars for natalizumab or shortening ocrelizumab’s intravenous available infusion time from 3.5 to 2 h (Schultz et al. 2019; Har- The ONC area represents the third selected disease area tung et al. 2020). archetype. Here, mAbs for the treatment of malignancies In 2020, a second anti-CD20 mAb, ofatumumab, was have been on the market for decades, but due to at times authorized by the FDA for the treatment of CIS, RRMS, severe IRRs and frequently high individual mAb dose lev- and active SPMS (HPI Kesimpta : United Stated Food els, products are not yet available for self-administration. and Drug Administration 2022a). Notably, the mAb was Until recently, due to the lack of technologies that facili- directly introduced with a subcutaneous formulation for tate high-dose subcutaneous administration, mAb prod- self-administration, a fixed dose, and a dosing volume of ucts were offered as intravenous infusions only. Today, a 0.4 mL. Using an existing autoinjector platform that was number of subcutaneous dosing alternatives have been previously applied to other products of the same manu- established. The first biosimilar mAbs have been author - ® ® ® facturer (HPIs Cosyntex , Elrezi , Hyrimoz : United ized, currently with intravenous dosing regimens only. Bittner AAPS Open (2023) 9:3 Page 12 of 25 Table 3 mAbs authorized for the treatment of MS in the US (up until September 2022): administration routes, dosing regimens and product presentations (adult indications) a a a mAb Administration route and dosing regimen IV product presentations SC product presentations IV SC b b Natalizumab 300 mg q4w - 300 mg/15 mL in single-dose vial - Alemtuzumab Initial treatment (2 courses): - 12 mg/1.2 mL in single-dose vial - First course of 12 mg/day on 5 consecu- tive days; second course of 12 mg/day on 3 consecutive days 12 months after first treatment course Subsequent treatment courses: 12 mg/day on 3 consecutive days as needed, at least 12 months after the previous course Ocrelizumab Start dose: - 300 mg/10 mL in single-dose vial 2*300 mg separated by two weeks Subsequent doses: 600 mg q6m Ofatumumab - Initial dosing: - 20 mg/0.4 mL solution in single-dose 20 mg adminis- prefilled pen or single-dose prefilled tered at syringe weeks 0, 1, and 2 Subsequent dosing: 20 mg q1m starting at week 4 IV intravenous, mg milligram, mL milliliter, qXd every X day, qXm every X month, qXw every X week, SC subcutaneous This table lists FDA-approved products; deviations with EMA-approved product presentations are indicated as a footnote A SC formulation for natalizumab in MS is approved in the EU More specifically, since the approval of rituximab for health services is a pivotal step to reduce time and trave- the treatment of B-cell malignancies back in 1997 (Pier- ling expenditures associated with in-clinic dosing. Nota- pont et al. 2018), numerous other mAbs have become bly, efforts are mandated to ensure that costs underlying available and represent an important modality in the provider work supporting at-home dosing and monitor- treatment of cancer (Zahavi and Weiner 2020). The large ing efforts remain within an affordable range (Franken majority of these mAbs are authorized for intravenous et al. 2020). administration and need to be administered by a health- Initially, mAbs in ONC were made available with a care professional (Kafatos et al. 2020). Depending on the body weight- or body surface area-adjusted dosing regi- nature and severity of IRRs, in some instances patients men (Hendrikx et al. 2017); an approach that was based have to be monitored closely to provide medical treat- on the way cytotoxic agents with a narrow therapeutic ® ® ment when required (HPIs Rituxan , Erbitux : United window are being administered (Egorin 2003). With the Stated Food and Drug Administration 2022a, Graham increasing understanding of the pharmacokinetic-phar- 2009). Understandably, these significant drug administra - macodynamic and -safety correlation (Paci et al. 2020), tion efforts add to the already high expenditures for mAb attempts are made to either develop mAbs with a fixed treatments overall (Chadda et al. 2013). dosing regimen from the very beginning (Garg et al. As described for intravenous treatments in MS, also 2014) or to change from body size-based dosing to fixed in cancer care, rapid infusion regimens (Atay et al. 2012, dosing as a lifecycle management activity following initial Gozzetti et al. 2020) or less frequent dosing regimens launch (Freshwater et al. 2017; Bei et al. 2020). (Lala et al. 2020) represent an attempt to reduce the The subsequent step towards more customer-friendly expenditures associated with drug administrations as drug delivery of mAbs in ONC represented the develop- well as the time people treated with mAbs have to spend ment of subcutaneous dosing options for mAbs (Bittner in the clinic. Here, the pandemic has intensified the and Schmidt 2012). Immanent to the at times high indi- elaboration of clinical strategies for optimizing infusion vidual dose levels, compared to mAbs in immunology for center care (Hanna et al. 2021). The organization of home example (refer to disease area archetype 1), developing Bittner AAPS Open (2023) 9:3 Page 13 of 25 subcutaneous injection regimens was initially compli- with HER2-positive early and metastatic breast cancer. cated due to a number of technical challenges. With the The medication is available with a subcutaneous dosing introduction of methodologies to achieve high-concen- regimen and has been approved by the FDA in 2020 (Gao tration solutions (Mahler et al. 2009; Jiskoot et al. 2022) et al. 2021). It had been shown that patients strongly and the co-administration of the dispersion enhancer preferred this fixed-dose combination over sequential hyaluronidase (Frost 2007), the first moves were made to intravenous infusion of the individual mAbs in separate reduce the overall dosing volume and to facilitate spread- formulations (O’Shaughnessy et al. 2021). Remarkably, ing of an injected fluid in the interstitial space. when approving Phesgo, in its press release, the FDA spe- Approved high-volume subcutaneous treatments that cifically highlights that “…Phesgo offers an out-patient apply these technologies can maintain the infrequent option for patients…” (United States Food and Drug dosing regimen of the initially marketed intravenous Administration 2020), an aspect that is considered very presentations. Up until September 2022, the subcutane- relevant especially in times of the coronavirus pandemic. ous administration alternatives for rituximab in B-cell The first fixed-dose combination of two immunother - malignancies (11.7 and 13.4 mL; FDA approval in 2017), apy mAbs, the programmed death receptor-1 inhibitor trastuzumab in HER2-positive early and metastatic nivolumab and the lymphocyte activation gene-3 block- breast cancer (5 mL, FDA approval in 2019), and dara- ing antibody relatlimab, received FDA approval for the tumumab in multiple myeloma (15 mL; FDA approval in treatment of unresectable or metastatic melanoma in 2020) have been authorized in the US (Yelvington 2018, 2022 (HPI OpdualagTM: United Stated Food and Drug Center for Drug Evaluation and Research 2020, Duco Administration 2022a). The formulation is administered 2020, Kading and Beck 2021). These subcutaneous mAb as a fixed-dose intravenous infusion regimen. presentations are all available with fixed-dose regimens Table 4 summarizes the high-dose subcutaneous omitting the need for body size-adjusted dose calcula- single-active mAb formulations and fixed-dose combi - tion. Dosing solutions are offered in vial presentations nations authorized for the treatment oncological indica- and are injected manually by a healthcare provider using tions in the US. a handheld syringe or an infusion set. The initial follow-on biologics for mAbs in ONC indi - To simplify administration of subcutaneous trastu- cations have been approved by the FDA (Galvão 2020). zumab, a ready-to-use on-body delivery system that Not only have manufacturers mimicked the originator is attached to the skin via an adhesive plaster had been medications, in some cases they also optimized the prod- developed (Bittner et al. 2012, Gligorov 2022). A small uct presentation to make it more user-friendly. Improve- study in 102 participants diagnosed with HER2-positive ments include extending the in-use stability to mitigate early breast cancer revealed that subcutaneous at-home the impact of cold-chain rupture and exceptional tem- injections by a healthcare professional did not introduce perature excursions on drug wastage and the quality of new safety signals and respondents agreed that they had the product (Vieillard et al. 2017; Park et al. 2020). Even benefit from at-home administration to a large (22%) or without the implementation of product optimizations, very large extent (78%) (Denys et al. 2020). Time-and- biosimilars are considered a customer-centric alternative motion and preference assessments demonstrated user to their branded counterparts solely based on the poten- preferences of subcutaneous over intravenous dosing in tial to increase access to mAb-based cancer medicines a healthcare institutional setting, regardless of on-body globally via reduced product costs compared to the origi- delivery system or handheld syringe delivery (Pivot er al nator mAb (Patel et al. 2018; Shelbaya et al. 2021). Here, 2014). As trastuzumab is not permitted for home- or self- interestingly, actual realization of a switch from branded administration, the device was not commercialized at to follow-on biologic or a switch from one to another the time of marketing authorization of the subcutaneous biosimilar varies significantly from country to country. trastuzumab formulation in the EU back in 2013. Regional differences, such as prescriber and/or patient The aspect that mAbs are increasingly developed for insecurity concerning efficacy and safety, conservative combination therapy (Henricks et al. 2015; Peterson prescribing patterns, reimbursements and billing poli- et al. 2018), a condition that further adds to the com- cies, supply logistics, and legal considerations have been plexity of parenteral dosing, makes ONC an intriguing suggested as limiting factors to broader adoption of bio- disease area archetype from a drug delivery perspective. similars (Cortes et al. 2020; Azuz et al. 2021). Consequently, manufacturers started co-formulating two mAbs within the same dosing vehicle as a fixed- Discussion dose combination. The first fixed-dose combination of The term “customer centricity,” indicating that fulfilling two mAbs included pertuzumab and trastuzumab and customer demands is as important as creating the prod- is indicated for the treatment of people diagnosed with uct or services themselves (Ceesay 2020), is not new and Bittner AAPS Open (2023) 9:3 Page 14 of 25 Table 4 High-dose subcutaneous single-active mAb formulations and fixed-dose combinations authorized for the treatment oncological indications in the US (up until September 2022): administration routes, dosing regimens and product presentations a a a mAb Administration route and dosing regimen IV product presentations SC product presentations IV SC Trastuzumab Adjuvant HER2 + BC: HER2 + BC: 150 mg lyophilized powder in single- 600 mg trastuzumab and 10,000 units Loading dose: 4 mg/kg 600 mg trastuzumab and 10,000 units dose vial hyaluronidase per 5 mL solution in Maintenance dose: 2 mg/kg q1w for hyaluronidase q3w 420 mg lyophilized powder in single- single-dose vial 12 weeks followed by 6 mg/kg q3w to dose vial complete a total of 52 weeks or Loading dose: 8 mg/kg Maintenance dose: 6 mg/kg q3w for 52 weeks HER2 + mBC: Loading dose: 4 mg/kg Maintenance dose: 2 mg/kg q1w HER2 + GC: Loading dose: 8 mg/kg Maintenance dose: 6 mg/kg q3w Rituximab NHL: The first dose is administered IV 100 mg/10 mL solution in single-dose 1400 mg rituximab and 23,400 units hya- 375 mg/m (indication-dependent NHL: vial luronidase human per 11.7 mL solution schedule) 1400 mg rituximab and 23,400 units 500 mg/50 mL solution in single-dose in single-dose vial CLL: hyaluronidase (indication-dependent vial 1600 mg rituximab and 26,800 units hya- Cycle 1: 375 mg/m schedule) luronidase human per 13.4 mL solution Cycles 2 − 6: 500 mg/m q28d CLL: in single-dose vial 1600 mg rituximab and 26,800 units hyaluronidase (indication-dependent schedule) Daratumumab MM: MM: 100 mg/5 mL solution in single-dose 1800 mg daratumumab and 30,000 units 16 mg/kg; may be split over two 1800 mg daratumumab and 30,000 vial hyaluronidase per 15 mL solution in consecutive days with 8 mg/kg on day units hyaluronidase (indication- 400 mg/20 mL solution in single-dose single-dose vial 1 and day 2 (indication-dependent dependent schedule) vial schedule) Pertuzumab Adjuvant HER2 + BC: - 420 mg/14 mL in single-dose vial - Loading dose: 840 mg Maintenance dose: 420 mg q3w (com- bination with trastuzumab IV or SC) for up to 18 cycles Neo-adjuvant HER2 + BC: Loading dose: 840 mg Maintenance dose: 420 mg q3w (com- bination with trastuzumab IV or SC) for 3 to 6 cycles HER2 + mBC: Loading dose: 840 mg Maintenance dose: 420 mg q3w Bittner AAPS Open (2023) 9:3 Page 15 of 25 Table 4 (continued) a a a mAb Administration route and dosing regimen IV product presentations SC product presentations IV SC Pertuzumab + trastuzumab FDC For single-active formulations see Adjuvant HER2 + BC: For single-active formulations see 1200 mg pertuzumab, 600 mg tras- above Loading dose: 1200 mg pertuzumab, above tuzumab, and 30,000 units hyaluroni- 600 mg trastuzumab, and 30,000 units dase/15 mL in single-dose vial hyaluronidase 600 mg pertuzumab, 600 mg trastu- Maintenance dose: 600 mg pertu- zumab, and 20,000 units hyaluroni- zumab, 600 mg trastuzumab, and dase/10 mL in single-dose vial 20,000 units hyaluronidase for up to 18 cycles Neo-adjuvant HER2 + BC: Loading dose: 1200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase Maintenance dose: 600 mg pertu- zumab, 600 mg trastuzumab, and 20,000 units hyaluronidase for 3 to 6 cycles HER2 + mBC: Loading dose: 1200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase Maintenance dose: 600 mg pertu- zumab, 600 mg trastuzumab, and 20,000 units hyaluronidase Nivolumab Various cancer indications: - 40 mg/4 mL, 100 mg/10 mL, - Indication-dependent dose and 120 mg/12 mL, and 240 mg/24 mL schedule solution in single-dose vial Relatlimab - - - - Nivolumab + relatlimab FDC UMM: - 240 mg of nivolumab and 80 mg of - 480 mg nivolumab and 160 mg relatli- relatlimab per 20 mL in single-dose vial mab q4w (adverse event-dependent dose modifications) CLL chronic lymphocytic leukemia, FDC fixed-dose combination, HER2 + BC HER2-overexpressing breast cancer, HER2 + GC HER2-overexpressing gastric cancer, HER2 + mBC metastatic, HER2 + BC HER2-overexpressing breast cancer, IVintravenous, mg milligram, mL milliliter, MM multiple myeloma, NHL non-Hodgkin’s lymphoma, qXd every X day, qXm, every X month, qXw every X week, SC subcutaneous, UMM unresectable or metastatic melanoma This table lists FDA-approved products Relatlimab is only available in the FDC with nivolumab Bittner AAPS Open (2023) 9:3 Page 16 of 25 applied across various industries. It has, however, gained in-office, or healthcare provider-supervised at-home increasing attention in healthcare facing high economic administration. As a subsequent lifecycle management, pressure, especially in light of the coronavirus pandemic. a subcutaneous dosing alternative is becoming available, Here, customer centricity aims at developing convenient either in a prefilled syringe for self-administration or in medicines that are globally affordable for people, provid - a vial presentation for manual or infusion pump-assisted ers, and the healthcare system as whole. For biotherapeu- injection by a caregiver. Product presentations vary from tics, such as mAbs, customer-centric product offerings case to case depending on the dosing volume and over- and treatment management concepts ideally facilitate a all feasibility of a stable liquid solution. Most frequently, flexible care setting and thus allow for drug administra - medications are offered with a fixed dose, unless a body tion and treatment monitoring outside of a controlled size-, safety-, or response-dependent regimen is justi- healthcare institutional environment. Efforts in the field fied (Strik et al. 2018). In a third step, the manufacturer go beyond the described improvements of the drug deliv- introduces automated injection devices. This scenario ery profile and product presentation and are in many was for example realized for tocilizumab in RA. Initially cases driven by pharmaceutical scientists from different approved in 2010 with a vial for intravenous infusion and disciplines. a monthly regimen (HPI Actemra : United Stated Food The realization of product optimizations differs across and Drug Administration 2022a), the subcutaneous dos- the distinctive disease area archetypes and depends on ing alternative was made available sequentially with a customer and market needs as well as on the clinical and prefilled syringe in 2013 (Burmester et al. 2014, Shetty technical feasibility of the intervention. In an indication et al. 2014), followed by an autoinjector device as a life- in which the identification of disease-modifying medi - cycle management in 2018 (Genentech 2013). To keep cines represents a major unmet need, initial drug deliv- the injection volume low and account for readily available ery efforts focus on enabling treatment per se. This is for devices at the time, the subcutaneous dosing frequency example the case for mAbs in ONC where any new and was increased to weekly and every 2 weeks with a dosing promising molecule is developed with the aim to offer it volume of 0.9 mL (Fettner et al. 2019). to people diagnosed with a given malignancy as soon as Scenario 1 also applies for mAbs in the treatment of feasible. Equally, for mAbs with demonstrated efficacy malignancies. While intravenously dosed mAbs are an but unfavorable exposure-related safety findings, prod - established treatment modality, development of subcuta- uct optimizations target a reduction in the incidence neous dosing alternatives started only years after the first and severity of adverse events through lowering post- mAb approval (Salar et al. 2014; Jackisch et al. 2019). This infusion serum levels. This may be achieved for example is due to at times severe and even fatal IRRs and com- by increasing the dosing frequency (Bai et al. 2012), a paratively high individual dose levels that challenged the schedule change that reduces convenience and increases development of convenient subcutaneous dosing regi- healthcare institutional burden associated with shorter mens. With increasing knowledge about the general fea- dosing intervals. sibility of high-volume subcutaneous dosing, advances in As per the definition in this review article, the journey high-concentration formulations and the co-administra- to more customer-centric products starts with the avail- tion of the dispersion enhancer hyaluronidase, by now, ability of an efficacious product with an acceptable risk/ this route of administration has become a key focus area benefit ratio. Across the selected disease archetypes, the of drug delivery scientists across indications (Bookbinder existence of established drug delivery technology plat- et al. 2006; Mathaes et al. 2016). While in ONC, mAb forms plays a pivotal role in enabling customer-centric dosing in the clinic is standard practice, today, efforts in product presentations early on, ideally already at initial disease management support are made to shift treatment launch of the mAb. Combining the learnings from these and monitoring outside of the clinic (Denys et al. 2020). distinct disease area archetypes, Fig. 3 illustrates possible Independent at-home administration for high-dose launch scenarios for intravenous and subcutaneous dos- mAbs has not yet been realized, but represents a think- ing regimens for mAbs. The underlying assumption is able option in the future with the advancement of larger that mAbs with dosing volumes of up to approximately volume on-body delivery systems (Bittner and Schmidt 2 mL are conventionally dosed in prefilled syringes and 2021). automated pen or autoinjector devices, while higher vol- Notably, next to a lack of technical and clinical feasi- ume mAbs are provided in vial presentations and possi- bility, it is also the healthcare provider reimbursement bly in the future in larger automated pen and autoinjector model applied in a given legislation that challenges sub- devices or in automated on-body delivery systems. cutaneous administration in a decentralized setting. In scenario 1, at initial molecule launch, the mAb is Roughly speaking, one can discriminate between fee-for- available with an intravenous dosing regimen for in-clinic, service payment models with separate service-specific Bittner AAPS Open (2023) 9:3 Page 17 of 25 Fig. 3 Possible launch scenarios for intravenous versus subcutaneous dosing regimens for mAbs payments and models where a medical provider receives syringe in 2009 (HPI Simponi : United Stated Food and a predetermined payment for a sequence of related Drug Administration 2022a), followed by the introduc- healthcare services (Einav et al. 2022). From a drug deliv- tion of an autoinjector 4 years later in 2013 (Center for ery perspective, whereas the first model incentivizes the Drug Evaluation and Research 2013). This device was complexity and quantity of care and as such incentivizes favorably evaluated in a prospective study in biologic- more complex intravenous infusions, the latter rewards naïve people with active RA (Schulze-Koops et al. 2013). the quality of care and thus ready-to-use subcutaneous Likewise, adalimumab was first authorized with a pre - regimens with the potential for at-home administration. filled syringe specifically designed for self-administration Here, any efforts that facilitate shifting treatment outside for people with stiffness in their hands due to destructive of the clinic are usually valued. progression of RA as well as with a vial for institutional In launch sequence scenario 2, the mAb enters the use in 2002 (HPI Humira : United Stated Food and Drug market directly with a subcutaneous formulation. Cur- Administration 2022a). Approval of the automated pen rently, the prerequisite for this approach is that doses are device followed sequentially in 2006 (BioSpace 2006). A low enough to apply established formulation and device comparison of the pen device with the established pre- technologies. Products are offered either in a prefilled filled syringe as assessed in a Phase 2 trial in participants syringe or vial configuration. Subsequently, upon avail - diagnosed with RA revealed preference for the auto- ability, automated injection devices are introduced as a mated injector based on its perceived ease of use and lifecycle management. This scenario is depicted in how a resulting convenience (Kivitz et al. 2006). number of mAb products were introduced into the RA The framework underlying scenario 3, where mAbs are and IBD indications. The sequential market introduction directly and solely launched with a subcutaneous dosing of increasingly optimized product presentations did allow regimen presented in ready-to-use automated injectable manufacturers to consider user feedback on the selec- presentations, to date comprises mAbs and their follow- tion of a ready-to-use device. The device portfolio was on biologics with low dosing volumes that are generally subsequently expanded with additional product offer - well tolerated. These favorable features enable the use of ings for people who prefer one over another injection aid. established drug delivery platforms. Currently, this sce- Examples would be branded golimumab or adalimumab. nario is being realized for adalimumab follow-on biolog- Golimumab was first approved in the US with a prefilled ics (Ghil et al. 2019, HPIs Hulio , Hadlima: United Stated Bittner AAPS Open (2023) 9:3 Page 18 of 25 Food and Drug Administration 2022a). Another example as a whole. The actual realization of product optimi- for scenario 3 is the introduction of ofatumumab in MS, zations is in turn influenced by the safety and efficacy where the mAb was directly obtainable with both a pre- profile of a medication, market maturity, and the avail- filled syringe and an automated injection pen. Leveraging ability of enabling technologies. Here, the application an established autoinjector platform, the manufacturer of platform technologies that have the potential to be conducted the pivotal Phase 3 study for ofatumumab utilized for mAbs across different indications offer with a prefilled syringe and bridged to the autoinjector the possibility to launch a novel mAb already with the in a Phase 2 trial that demonstrated bioequivalence of most preferred drug delivery profile or even with a ofatumumab administered by the autoinjector versus the variety of different customized options at initial mar- prefilled syringe (Bar-Or et al. 2022). ket authorization. This will be especially the case for A comparison of activities among biosimilar manufac- disease areas in which mAb-based medicines currently turers qualifying as customer-centric as defined in this are among the investigated targets, such as Alzhei- article did reveal different focus areas across the desig - mer’s disease or rare diseases (Tambuyzer et al. 2020; nated disease area archetypes. Especially in the event Lacorte et al. 2022). of more than one follow-on biologic accessible for the Subcutaneous at-home administration of low-volume same originator, the competition for market shares via mAb formulations has been feasible for decades and a customized product profile is expected to increasingly illustrates the long-standing efforts in the field. As a next gain momentum. With this, the wider range of injection pivotal step to also warrant high-volume subcutaneous devices qualified will contribute to fulfilling the needs of home administration with dosing volumes exceeding a larger user population. Here, the application of estab- 5 mL, on-body delivery systems need to leave the explor- lished technology platforms for a variety of medications atory stage and require implementation into clinical accounts for both, the familiarity of prescribers with the practice. Electronic adherence aids that further engage device as well as learnings from challenges associated people treated with mAbs and their care partners into with their application and how to most appropriately disease management while still guaranteeing a remote overcome these. For mAbs predominantly available for contact with the physician should be implemented in in-clinic mAb administration, the described seemingly parallel. A significant change in dosing paradigm for smaller product changes, such as a change from a lyo- mAbs would be a shift from parenteral to oral adminis- philized powder for reconstitution to a ready-to-admin- tration, with a variety of technologies in early develop- ister liquid formulation or an increased storage time and ment. A key prerequisite here is that drug administration shelf-life can be an advantage for one over another bio- schedules can still be managed based on the mAb’s dose similar. This is due to for instance improved distribution level and the cost of goods sold associated with the and handling logistics, reduced drug wastage or more provision of these at times device-based technologies. economical resource utilization in the clinic (Smale et al. Manufacturers need to partner with specialized biotech- 2021). It is of note in the context of customer-centric bio- nology companies and, like with any innovation, need similar offerings that depending on the country and asso - to afford some upfront investment at risk. This way oral ciated pricing, reimbursement, and demand-side policies delivery platforms may become a reality for mAbs across (Rémuzat et al. 2017), lower overall treatment costs per disease areas. se may provide an access advantage over their origina- A field of increasing relevance is the sustainabil - tor counterpart (Kvien et al. 2022) without the need for ity of novel drug delivery technologies. Manufacturers further optimizing the product profile. In an attempt to will have to do their homework to understand whether facilitate access to treatment, the FDA has designated the for example reusable technologies indeed offer a more first mAb, an adalimumab biosimilar, as interchangeable environmental dosing alternative, or whether pos- with the reference product in 2021 (United States Food sible advantages come with the challenge of reduced and Drug Administration 2021), meaning that the biolog- user-friendliness. ical product “may be substituted for the reference prod- Pharmaceutical scientists are involved in product opti- uct without the involvement of the prescriber” (United mizations across different disciplines, that is, besides States Food and Drug Administration 2017). their role as practicing healthcare provider, in formula- tion and device development, nonclinical and clinical Summary and outlook pharmacokinetics and pharmacology, or in regulatory Advancing customer-centric medicinal products is an affairs and market access. As such, we have the encourag - adaptive process across the lifecycle of a mAb-based ing opportunity and mandate to leverage existing insights medicine that aims to address individual needs of peo- and synergies across different indications and thus avoid ple treated as well as those of the healthcare ecosystem repeating assessments and reinventing development and Bittner AAPS Open (2023) 9:3 Page 19 of 25 Abramson A, Frederiksen MR, Vegge A, Jensen B, Poulsen M, Mouridsen B, Jes- commercialization pathways from the beginning. The persen MO, Kirk RK, Windum J, Hubálek F, Water JJ, Fels J, Gunnarsson work on improving mAb products should involve co- SB, Bohr A, Straarup EM, Ley MWH, Lu X, Wainer J, Collins J, Tamang S, creation not only with customers, but also collaborations Ishida K, Hayward A, Herskind P, Buckley ST, Roxhed N, Langer R, Rahbek U, Traverso G. (2022). Oral delivery of systemic monoclonal antibodies, between academia, manufacturers, and biotechnology peptides and small molecules using gastric auto-injectors. Nat Biotech- companies. nol. 40(1):103-109. https:// doi. org/ 10. 1038/ s41587- 021- 01024-0 Adelman DT, Van Genechten D, Megret CM, Truong Thanh XT, Hand P, Mar- tin WA (2019) Co-creation of a lanreotide autogel/depot syringe for Abbreviations the treatment of acromegaly and neuroendocrine tumours through CD Crohn’s disease collaborative human factor studies. Adv Ther 36(12):3409–3423. CD52 Cluster of differentiation 52 https:// doi. org/ 10. 1007/ s12325- 019- 01112-3 CIS Clinically isolated syndrome Ahmed M, Bankov G, Casey D, Perry ME (2021) CT-P13 subcutaneous CRL Complete response letter infliximab in gastroenterology and rheumatology. 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Nat Med 28:1314–1324. https:// doi. org/ 10. 1038/ s41591- 022- 01750-1 Authors’ contributions Atay S, Barista I, Gundogdu F, Akgedik K, Arpaci A (2012) Rapid-infusion rituxi- Beate Bittner drafted the scope and content of the article, conducted the mab in lymphoma treatment: 2-year experience in a single institution. literature research and wrote the manuscript. The author(s) read and approved J Oncol Pract 8(3):141–143. https:// doi. org/ 10. 1200/ JOP. 2011. 000319 the final manuscript. Azuz S, Newton M, Bartels D, Klindt Poulsen B (2021) Uptake of biosimilar trastuzumab in Denmark compared with other European countries: a Funding comparative study and discussion of factors influencing implementa- Not applicable. tion and uptake of biosimilars. Eur J Clin Pharmacol 77:1495–1501. https:// doi. org/ 10. 1007/ s00228- 021- 03155-4 Availability of data and materials Bagel J, Tatla D, Hellot S, Knapp B, Murphy C, Peterson L, Sebastian M (2022) Not applicable (review article). 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Journal

AAPS Open – Springer Journals

Published: Jan 23, 2023

Keywords: Customer centricity; Parenteral; Oral; Subcutaneous; Flexible care setting; Product optimization

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Customer-centric product presentations for monoclonal antibodies

Customer-centric product presentations for monoclonal antibodies

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Customer-centric product presentations for monoclonal antibodies

Customer-centric product presentations for monoclonal antibodies

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