OFFICIAL USE ONLY [Medium]
Biosimilar Development:
Examined Through the Lens of Filgrastim and Pegfilgrastim
A biosimilar (BioSim) is a generic-like agent produced with a claim of equivalence (highly similar/no meaningful difference) in profile to an already approved reference biologic (1, 4, 11). This claim is read as regarding product efficacy, safety and quality (4).
Filgrastim granulocyte colony-stimulating factors (G-CSF) are an approved medication used to stimulate neutrophils, preventing neutropenia, in a range of conditions — though most particularly in protecting patients undergoing myelosuppressive chemotherapy as part of their cancer treatment (1). BioSims have also been made available (1, 4, 5, 11).
Problems faced by pegfilgrastim BioSims getting to market, not faced by Filgrastim, were regulatory. Due to the larger, more complex molecule created by pegylation (which also facilitated the longer acting status), regulatory agencies wanted evidence of equal action from the single dose (1, 5). This was particularly so with the USA regulator (FDA — Food and Drug Administration), though in the EU the EMA (European Medicines Agency) did not allow a clear path to market either: it was simply not immediately seen as convincing to posit BioSim status as valid for this claimed long acting equivalent (1, 5). One company, Sandoz, after failing to show equivalent plasma levels in their BioSim application to the FDA, also pulled their application to the EMA (5). Multiple other companies, including Gedeon Richter, Apotex, Mylan and Biocon all faced similar problems meeting requirements in this relatively novel commercial space (1, 5, 14, 15).
To understand the problems BioSims of the longer acting biologic pegfilgrastim faced in getting to market, that were not seen by the BioSims for the forerunner filgrastim; first the regulatory landscape for the production of BioSims more generally best be understood.
Biosimilars v Classical Generics
Biologics are different to the generally structured, chemically synthesized classic small molecule medicines. This is predominantly in that they are not so easily characterized, created and approached analytically using traditional laboratory methods (10, 11); rather being large, more complex in nature and using living components (biological processes) in their manufacture. Additionally, and largely as a result of this, biologics face greater errors in manufacture between batches (5). These ‘errors’ in the batch manufacture of biologics, that clasic drugs do not have to contend with, include a sensitivity to post translational alterations due to environmental condition differences; ‘evolution’ changes as processes/technology keep moving through production; and a not dissimilar problem in genetic ‘drift’ — which can lead to biologics having entirely different effect profiles in vivo (particularly a problem for BioSims seeking approval based on the established profile of a reference product) (5, 18).
However, there is an assumption of efficacy if non clinical trials can show a ‘similar enough’ profile to the reference, meaning the clinical side is conducted to confirm the expected outcomes — and then post market followup surveys for unexpected outcomes (1, 5, 13, 18). This is in many ways similar to the streamlined, and still controversial, ‘grandfathering’ system used in biotechnology applications, when making similar claims to an approved reference product (19).
Developing a Biosimilar, Market Share and Interchangability
Law, as it currently stands in the USA, allows FDA to waive both clinical and nonclinical requirements should it judge them not necessary; a powerful tool which has counterparts in most regions (1, 2, 3 4 ,6 ,7 8, 9, 11, 13). This is in order to more swiftly approve ‘generic’ biosimilars. EMA has similar (though not identical) requirements for BioSims to FDA, and TGA (Theraputic Goods Administration — Australia) follows a path most similar to Europe, although debates allowing BioSim ‘switching’ at the pharmacy level, as with generics commonly (3).
Interchangeability is essentially just another way of saying that you have a viable BioSim (different to ‘switching’, which is changing between BioSims and/or their reference; and as this can have unexpected results, is best left to the primary clinician to manage (5). Though legally, this differs by region, with some countries more centrally managed (5).
What Pegfilgrastim BioSims Had To Demonstrate to Regulators
Biosimilars, when compared to the reference product, are to show: That the reference product is licensed and sourced in their jurisdiction; that strength/route/form mirror the reference; the reference itself is to have had a complete dossier to reach market, and not be under ‘special provisions’ of some kind; one reference is to be used for all of product development, ie no switching between approved products or altering endpoints; manufacture sites must meet cGMP guidelines; formulation differences may not have ‘clinically relevant’ impacts; ‘stepwise’ development is to show at each step — from production to non clinical to clinical (where appropriate) — the results match the index reference; the MOA is to encode the same primary amino acid sequence; there should be a head to head demonstration of similarity; pharmaco kinetic/dynamic similarities should be demonstrated before phase 3; an immunogenicity assessment is required in a phase 1 (5, 6, 7, 9); evidence of interchangeability and switching between reference and BioSim safely ‘without consulting prescriber*’’ (*though this has some variability in application by states even within regions — it is best to know if it is required in a target market); and indications for the BioSim have to have first been approved for reference use in those cases (although not all applications need be applied for: they can not be novel to the reference product). (1, 2, 3 4 ,6 ,7 8, 9, 11).
There is a ‘totality of evidence’ standard, that does not allow even relatively minor differences to qualify as a BioSim, if other markers along the stepwise development also show subtle differences (17, 13). Though, another interpretation of this could be that, in order to rush products to market, very little clinical evidence is used and it is applied only as a kind of validation of the bench results, rather than patient efficacy in its own right (13). The moral implications of this are situation sensitive, with genuine arguments on both sides. There is also some leeway for BioSims to be approved for fewer applications than the index reference; fewer routs of administration; and to utilize a different delivery device; and container closure (17, 13).
Although the terms ‘spontaneous’ (SRS) or ‘active’ (AS) post market surveillance are used, in truth, once a product is launched there are only variations of passive, post hoc, arguably low quality surveillance that go on [13]. One is dependent on patients, or interested parties, making a case/lodging complaints, and the other is a retrospective chart analysis (and other databases) post hoc review. This can be used to both alert one to adverse events, or equally to obscure responsibility, depending on how clear the signal and how great/frequent the harm.
However, there are pricing and reimbursement incentives for physicians in the EU system, in order to facilitate prescribing (13). This is helpful, as the more product that is moved off the shelf, the more patient data may be accidentally and indirectly gleaned via the haphazard post market monitoring system currently in place in most regions.
There are other concerns regarding the price of these interventions. A product has to survive the development and regulatory process long enough to get to market. Although, a product that no one can purchase (or not enough people can purchase) may inhibit innovation. However, concerns over “profit making” versus “profiteering” are ever present in the biologics space (21, 22).
Some solutions offered to cover costs, in addition to launching across multiple markets, include: government subsidies, taken from regional tax payers (though usually without giving government a say on sales price points or acknowledging where a product has benefited by infrastructure and public university research along the way); ‘duel branding’ an astoundingly common, and somehow legal, practice whereby anti-trust principles are flagrantly violated as ‘competitors’ openly own multiple versions of a product, that they package differently, and sell at different price points against themselves (2, 19, 21, 22); as well as ‘access solutions’ on the patient side, for example ‘home loan style’ schemes to access treatments, that the patient can pay off as long as they live* (*only should they become unwell in a family with a good credit rating, of course. And, failing this, perhaps descendants could pay off company profit margins by working for scrip in a multi-generational factory, as is done in parts of Africa and with variations in the west already being seen?) (2, 19).
Although the particulars of grief profiteering encountered in researching Filgrastim are beyond the scope of this piece, it is worthy of note that currently we do seem to see the worst of all possible worlds: unenforced regulations — but a lot of them; a favoring of particular companies who have captured boards and committees, irrespective of the science behind a product being evaluated; and a revolving door between industry and regulators as bad as any other government sector (21, 22). This sees both good interventions unable to reach market, and lesser products crowding out the marketplace, and for a higher profit margin than is medically justified.
Conclusion — Towards A More Unified System
A more unified, transparent, global system with clear guidelines of what is required by regulators at each step, would be of great benefit. In addition, proper active patient follow up, to include head to head trials with current treatment product leaders for given conditions longer term, would all improve the chances of biosimilars, like those for pegfilgrastim, making it to market in all regions more swiftly. While, at the same time, optimizing patient care and scientific advancement by defending against profiteering and committee capture by established corporations.
JC
Jai Cilento is the medical ethicology consultant and Ed@Lg for the Chronicle in Letters and Science Network. | @Jai_Cilento /@JCVerified | JChronLettSci.Network
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Original: Extended piece from Sydney University, OCT 2020.
