Biosimilars

Question 1

what is the role of the medicines regulatory authority

Answer 1

1. ensure that biosimilars are as effective as the reference biologic before they are licensed
2. 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

Question 2

what are biosimilars

Answer 2

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

Question 3

what do changes in manufacturing process lead to

Answer 3

alters the characteristics of a biosimilar which means they must be compared to the originator biologic

Question 4

what is involved in the similarity evaluation

Answer 4

1. as biologics are produced in living cells there will always be batch to batch variation
2. even if manufactured under identical conditions, characteristics of biologics can still change (drift)
3. legal requirement to carry out preclinical and clinical re-evaluations of the product

Question 5

give examples of differences between biologics and small molecule drugs

Answer 5

1. biologics are often large, complex molecules with primary, secondary, tertiary and quaternary structure
   - small molecule drugs are generally small molecules with simple structures
2. 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

Question 6

describe the biologic and biosimilars clinical trials

Answer 6

1. a reference biologics molecule must go through a standalone application
2. when the patent on an original biological medicine expires, other competing companies can apply for marketing approvals for a corresponding biosimilar product
3. ultimate goal of a biosimilar development program is to prove biosimilarity with the reference drug, rather than establish standalone safety or efficacy profile
4. biosimilar undergoes comparative clinical trial to prove lack of clinical difference from reference molecule

Question 7

describe the regulatory aspects in biosimilar development programs

Answer 7

1. 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
2. the approved pathway for biosimilars is more streamlined, simpler and cheaper than branded original biologics

Question 8

what are the steps in biosimilar development

Answer 8

1. select your reference biologic
2. rigorously define the key quality attributes of that reference biologic
3. develop a manufacturing, purification and formulation process to match the QTPPs of the reference biologic
4. then do the similarity evaluation

Question 9

compare the biologic and biosimilar development pathways

Answer 9

1. in the biologic pathway, more clinical data is required
2. but more biosimilar pathway, the preclinical stage is more extensive
3. if adequate similarity can be established in the preclinical phase, much less clinical testing is required
   - accelerating biosimilar development and cutting costs

Question 10

what does the similarity evaluation test

Answer 10

1. physicochemical properties
2. in vitro/in vivo biological activity and function
3. Pharmacokinetic and pharmacodynamic properties in vivo safety and toxicity profile
4. pre clinical testing

Question 11

what immune parameters is the preclinical testing of therapeutic MAB biosimilars based on

Answer 11

1. target antigen binding- specificity and affinity
2. recognition of and binding to all Fc gamma receptors
3. Fab effector functions
4. Fc fragment associated functions
5. all parameters must be comparable to those obtained with reference biologic under same experimental conditions

Question 12

what is meant by drift

Answer 12

characteristics of reference biologic can change over time

Question 13

what do the key quality attributes provide

Answer 13

1. provide quality target product profile (QTPP)
2. to address QTPP drift, goal posts can be defined, providing established variations over time
3. if physicochemical/functional parameters of the product fit within the reference biologic goal posts, it can be considered to be highly similar

Question 14

give examples of QTPP drift

Answer 14

changes in amino acid of polypeptide or glycan profile

Question 15

what can glycosylation modify

Answer 15

1. protein folding
2. cellular localisation
3. protein activity

Question 16

give examples of glycoproteins

Answer 16

1. all full length mabs are glycoproteins
   - contain chains of carbohydrates called glycans

Question 17

how can glycans be altered

Answer 17

can be altered both quantitatively and qualitatively depending on expression system used
- this can drift during manufacture
- 3 structures: complex, hybrid and high mannose

Question 18

describe the second step of preclinical testing of therapeutic mab biosimilars

Answer 18

1. if similarity within QTPP goal posts have been established, in vivo testing may not be required

Question 19

what are the limitations of using animal models

Answer 19

if a mouse is used, it will always raise anti drug antibodies against a fully human mab

Question 20

describe the third step of preclinical testing of therapeutic mab biosimilars

Answer 20

1. key use of animals in this step to establish pharmacokinetic/dynamic parameters
2. new formulations/excipients may cause unwanted immune responses

Question 21

what are the key physicochemical parameters of biosimilars

Answer 21

1. must be produced in the same cell line as reference biologic
2. final dosage form must be assessed to determine the functional impact of formulation and excipients
3. post translational modifications seen in reference biologic are vital when developing biosimilar
4. structural characterisations must be robust

Question 22

why are clinical studies used

Answer 22

to eliminate any doubts that may exist over degree of similarity

Question 23

outline the benefits of biosimilars

Answer 23

1. cost reduced by competition- biologics can be expensive
2. enhanced patient accessibility- with more biosimilars in circulation, more patients can have access to these treatment options
3. incentive for innovation- having innovative, patentable new biologic products may be necessary to maintain a large marketshare hold in the wake of expiring patents

Question 24

what is the guidance following the biosimilars approved for Humira (adalimumab)

Answer 24

1. arrival of 4 biosimilars enabled big savings for NHS
2. 9 of 10 new patients should be started on best value medicine within 3 months of biosimilar launch
3. at least 80% of existing patients should be switched to best value biologic within 12 months

Question 25

outline the disadvantages of biosimilars

Answer 25

1. patient and prescriber education- need to know benefits of switching to biosimilars
2. extrapolation issue- process of granting a clinical indication to a medicine without its own clinical safety and efficacy studies to support that indication
3. interchangeability- indicates whether switching back and forth between 2 products doesn’t influence the efficacy or safety when compared to each product alone
4. 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