Biosimilars Flashcards
what is the role of the medicines regulatory authority
- ensure that biosimilars are as effective as the reference biologic before they are licensed
- also demand retesting is done when a manufacturing process changes
- outline the necessary steps required to compare biosimilars with the reference biologic
- or to test if the process change has had an adverse effect on product quality, efficacy or safety
- in both cases, this is a similarity evaluation
what are biosimilars
used to describe a biologic that is considered highly similar to a reference biologic product, not withstanding minor differences in clinically inactive components and for which there is no clinically meaningful differences between the biologic and reference product in terms of the safety, purity and potency of the product
what do changes in manufacturing process lead to
alters the characteristics of a biosimilar which means they must be compared to the originator biologic
what is involved in the similarity evaluation
- as biologics are produced in living cells there will always be batch to batch variation
- even if manufactured under identical conditions, characteristics of biologics can still change (drift)
- legal requirement to carry out preclinical and clinical re-evaluations of the product
give examples of differences between biologics and small molecule drugs
- biologics are often large, complex molecules with primary, secondary, tertiary and quaternary structure
- small molecule drugs are generally small molecules with simple structures - biologics- stability can be impacted by multiple factors and product characteristics can drift over time
- small molecule drugs- product is usually stable under most conditions
describe the biologic and biosimilars clinical trials
- a reference biologics molecule must go through a standalone application
- when the patent on an original biological medicine expires, other competing companies can apply for marketing approvals for a corresponding biosimilar product
- ultimate goal of a biosimilar development program is to prove biosimilarity with the reference drug, rather than establish standalone safety or efficacy profile
- biosimilar undergoes comparative clinical trial to prove lack of clinical difference from reference molecule
describe the regulatory aspects in biosimilar development programs
- doesn’t need to repeat the entire clinical development program as the reference biologic molecule
- this advantage reduces costs and saves a lot of volunteers and patients from engaging in unnecessary trials - the approved pathway for biosimilars is more streamlined, simpler and cheaper than branded original biologics
what are the steps in biosimilar development
- select your reference biologic
- rigorously define the key quality attributes of that reference biologic
- develop a manufacturing, purification and formulation process to match the QTPPs of the reference biologic
- then do the similarity evaluation
compare the biologic and biosimilar development pathways
- in the biologic pathway, more clinical data is required
- but more biosimilar pathway, the preclinical stage is more extensive
- if adequate similarity can be established in the preclinical phase, much less clinical testing is required
- accelerating biosimilar development and cutting costs
what does the similarity evaluation test
- physicochemical properties
- in vitro/in vivo biological activity and function
- Pharmacokinetic and pharmacodynamic properties in vivo safety and toxicity profile
- pre clinical testing
what immune parameters is the preclinical testing of therapeutic MAB biosimilars based on
- target antigen binding- specificity and affinity
- recognition of and binding to all Fc gamma receptors
- Fab effector functions
- Fc fragment associated functions
- all parameters must be comparable to those obtained with reference biologic under same experimental conditions
what is meant by drift
characteristics of reference biologic can change over time
what do the key quality attributes provide
- provide quality target product profile (QTPP)
- to address QTPP drift, goal posts can be defined, providing established variations over time
- if physicochemical/functional parameters of the product fit within the reference biologic goal posts, it can be considered to be highly similar
give examples of QTPP drift
changes in amino acid of polypeptide or glycan profile
what can glycosylation modify
- protein folding
- cellular localisation
- protein activity
give examples of glycoproteins
- all full length mabs are glycoproteins
- contain chains of carbohydrates called glycans
how can glycans be altered
can be altered both quantitatively and qualitatively depending on expression system used
- this can drift during manufacture
- 3 structures: complex, hybrid and high mannose
describe the second step of preclinical testing of therapeutic mab biosimilars
- if similarity within QTPP goal posts have been established, in vivo testing may not be required
what are the limitations of using animal models
if a mouse is used, it will always raise anti drug antibodies against a fully human mab
describe the third step of preclinical testing of therapeutic mab biosimilars
- key use of animals in this step to establish pharmacokinetic/dynamic parameters
- new formulations/excipients may cause unwanted immune responses
what are the key physicochemical parameters of biosimilars
- must be produced in the same cell line as reference biologic
- final dosage form must be assessed to determine the functional impact of formulation and excipients
- post translational modifications seen in reference biologic are vital when developing biosimilar
- structural characterisations must be robust
why are clinical studies used
to eliminate any doubts that may exist over degree of similarity
outline the benefits of biosimilars
- cost reduced by competition- biologics can be expensive
- enhanced patient accessibility- with more biosimilars in circulation, more patients can have access to these treatment options
- incentive for innovation- having innovative, patentable new biologic products may be necessary to maintain a large marketshare hold in the wake of expiring patents
what is the guidance following the biosimilars approved for Humira (adalimumab)
- arrival of 4 biosimilars enabled big savings for NHS
- 9 of 10 new patients should be started on best value medicine within 3 months of biosimilar launch
- at least 80% of existing patients should be switched to best value biologic within 12 months
outline the disadvantages of biosimilars
- patient and prescriber education- need to know benefits of switching to biosimilars
- extrapolation issue- process of granting a clinical indication to a medicine without its own clinical safety and efficacy studies to support that indication
- interchangeability- indicates whether switching back and forth between 2 products doesn’t influence the efficacy or safety when compared to each product alone
- rare diseases- often utilise orphan drugs that are associated with high costs
- difficult to obtain a large enough, non heterogenous population for phase I and III trials
