Biosimilars Flashcards
(34 cards)
What are the examples of biological therapeutics
Antibodies
Nucleotides
Therapeutic proteins
Vaccines
What is the definition of biological medicine
A medicine whose active substance is made by a living organism
How do small molecule pharmaceuticals differ from biologicals
Size:
- sm 200-600 daltons in size
- b 10^3 (kilo) to 10^6 (mega) g/mol
structure:
- sm = simple
- b = complex
Synthesis:
- sm = usually organic compounds synthesised from petrochemical feedstock
- b = synthesised by unicellular or multicellular organisms
Action
- sm = dose-dependent on-target/off-target actions
- b = highly specific action
What molecules are possible to produce
- sm = generic molecules
- b = biosimilar molecules
What is the WHO definition of biosimilars
A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product)
What is the EMA (European medicines agency) definition of biosimilars
A biosimilar is a biological medicine highly similar to another already approved biological medicine (the “reference medicine”)
What is the FDA definition of biosimilars
A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product
Why are biosimilars not identical to the reference medicine
Protein folding is dependent on environmental conditions during manufacture
○ Tertiary structure is different
Post translational modifications
Give an overview of the historical development of biosimilars
2004
○ EU develops first legal; regulatory and scientific framework for approval of biosimilars
2006
○ Omnitrope, a somatotropin is the 1st biosimilar approved
2015
○ FDA approves filgrastim, a G-CSF analogue
what is the definition of pharmacokinetics (PK)
Describes what the body does to a drug, including absorption, distribution, metabolism, and excretion.
It determines the concentration of the drug at the site of action over time.
what is the definition of pharmacodynamics (PD)
Describes what the drug does to the body, including its mechanism of action, therapeutic effects, and side effects.
It explains the drug’s biological response at a given concentration.
What is the definition of therapeutics
Integrates PK and PD to design optimal drug dosing regimens that maximize therapeutic benefits while minimizing adverse effects.
How are PK, PD and therapeutics used together
Together, PK provides insight into drug exposure, PD links exposure to effect, and therapeutics applies this knowledge to treat diseases effectively
How does the development of biological therapeutics differ from small molecules
Size and Complexity:
- Biologicals (e.g., proteins, antibodies) are large, complex molecules, while small molecules are simple and chemically synthesized.
Production:
- Biologicals are produced using living systems (e.g., cells, microorganisms), while small molecules are synthesized chemically.
Target Specificity:
- Biologicals are highly specific, often targeting precise pathways, whereas small molecules can have broader activity.
Delivery:
- Biologicals often require injection due to instability in the digestive system, while small molecules can usually be taken orally.
Regulation and Cost:
- Biologicals have more complex development and regulatory pathways, often making them costlier and requiring advanced manufacturing techniques.
What are the potential immunological responses to a biological molecule
No immunological response
Limited immunological response
○ Transient development of antibodies; of no clinical consequence
Local immunological response at the site of administration
Systemic immunological response
○ Type 1 to 4 hypersensitivity reactions possible
Anti drug antibodies (ADAs)
○ ADAs have the potential to alter the pharmacokinetics and/or pharmacodynamics
The potential for immunogenicity MUST be evaluated for all biological molecules over the spectrum of the development proces
What are the patient factors that can influence immunogenicity
Immune system genetics (MHC genotype)
Gene defects (biological is de-novo antigen)
Age (immune response varies with age)
Disease (autoimmune or immunosuppression)
Concurrent treatments
Pre-existing antibodies
What are the product factors that can influence immunogenicity
Protein structure (common motifs less immunogenic)
Formulation and packaging
Dosing schedule (long term or re-exposure more immunogenic)
Aggregation and adducts formation more immunogenic
Impurities
PEGylation may shield antigenic regions
How does biosimilar development differ from reference medicines
Focuses on proving similarity to reference biologics in quality, safety, and efficacy.
It uses streamlined clinical trials and relies on existing data from the reference product, unlike reference medicines, which require full discovery and extensive trials
What are the modifications to the drug development process for biosimilars compared to standard drugs
Preclinical R&D
○ Analytical testing
○ Pre-clinical pharmacokinetics
○ Immunogenicity
○ Toxicity testing
Phase 1
○ First in man
○ Tolerability
○ Safety
○ Pharmacokinetics
○ Immunogenicity
Phase 2/3
○ Confirmatory studies to reduce residual uncertainty
○ Safety and immunogenicity
Phase 4
○ Risk management plan and pharmacovigilance
What are the objectives of biosimilar phase 1 clinical studies
- Tolerability
- Side effects and safety
§ Vital signs, ECG, LFTs, FBC, U&Es, others guided by pre-clinical testing
- Side effects and safety
- Pharmacokinetics (PK)
- Describe the basic PK parameters of drug and metabolites
§ Cmax, Tmax, AUC, t1/2, Vd, CI - Describe ADME in humans
- Determine the dose-concentration relationship over ascending single and multiple doses
§ Is it linear? i.e. dose double dose = double plasma concentration
- Describe the basic PK parameters of drug and metabolites
- Immunogenicity
- Pharmacodynamic activity
- Efficacy (biomarkers)
- Safety (TQT studies)
What are the objectives of biosimilar phase 2/3 clinical studies
Efficacy of the reference medicine has been proven in the pivotal clinical trial required for marketing authorisation
If equivalence of a biosimilar can be demonstrated then only confirmatory studies to reduce residual uncertainty surrounding
- Safety
- Immunogenicity
- Efficacy
What should be considered when designing a phase 3 biosimilar clinical trial
Outcome (determined in advance with the Regulators)
- The outcome is the demonstration (or not) of the primary end point (usually efficacy)
- (2-sided) equivalence against reference medicine
§ EMA suggests a 95% confidence interval
§ FDA suggests a 90% confidence interval
What is the difference between equivalence and non-inferiority in assessing the equivalence margin (ΔΔ)
Equivalence:
○ Objective: Demonstrates that a new treatment is neither significantly better nor worse than the standard within a predefined range (−Δ−Δ to +Δ+Δ).
○ ΔΔ: Represents the maximum acceptable difference in both directions.
○ Example: The new treatment’s efficacy falls entirely within the range of −Δ−Δ to +Δ+Δ.
Non-Inferiority:
○ Objective: Demonstrates that a new treatment is not worse than the standard by more than a predefined amount (−Δ−Δ).
○ ΔΔ: Defines the maximum acceptable loss of efficacy compared to the standard (only the lower limit is assessed).
○ Example: The new treatment’s efficacy is better than −Δ−Δ but may exceed the standard’s efficacy.
In summary, equivalence tests for comparability in both directions, while non-inferiority focuses only on ensuring the new treatment is not worse by a clinically significant margin
What is the definition of economics
The study of how resources are allocated
What are the assumptions that can be made about economics
All resources can be quantified in monetary value
All resources including wealth, are finite
Therefore choices are required
