Biosimilars Flashcards
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
What is the definition of opportunity cost
Sacrifice of next most favoured option
What is the difference between a supply curve and a demand curve
Supply curve:
○ Determined by marginal cost (supply cost < market price)
Demand curve:
○ Determined by marginal utility (opportunity cost to purchaser)
What is the relationship between supply and demand curves in healthcare
In healthcare, the supply curve reflects the services providers can offer at different prices, while the demand curve shows how much patients need or want at those prices.
Demand is typically inelastic (less responsive to price changes) due to the necessity of care
Supply is often constrained by resources and regulations.
The interaction between the two determines price and quantity, but factors like insurance, government policies, and ethical considerations heavily influence this relationship, often disrupting a simple market equilibrium.
How do biosimilars impact supply and demand curves
Tend to move the model towards a state of perfect competition
What are the benefits of biosimilars from a supplier’s perspective and why
Reduces marginal costs
○ leveraging established manufacturing processes and infrastructure developed during the production of the original biologic.
○ They benefit from reduced R&D expenses due to streamlined regulatory pathways, requiring demonstration of similarity rather than extensive clinical trials.
○ Economies of scale in production and competition-driven efficiencies further lower per-unit costs.
What are the benefits of biosimilars from a healthcare purchaser’s perspective
Reduces utility costs
○ by offering lower-priced alternatives to expensive biologics, enabling cost savings without compromising treatment efficacy.
○ This allows purchasers to allocate resources more efficiently, expand patient access to therapies, and manage budgets more effectively, ultimately increasing the overall value derived from healthcare spending.
What is the definition of clinical guidelines
Systematically developed statements to assist a practitioner and patient decisions about appropriate health care for specific clinical circumstances
What are the benefits of clinical guidance
Clinical
○ Improved clinical outcomes
○ Improved process of care
Economic
○ Optimise value for money
Societal
○ Equality in access to treatment
○ Justice
What are the potential challenges associated with clinical guidance
- Effectiveness issues
- Benefits achieved in clinical trials or other healthcare settings may not be fully achieved if limited applicability to:
§ Local population
□ Significant pharmacokinetic/pharmacodynamic differences may exist
§ Local comparator treatment
- Benefits achieved in clinical trials or other healthcare settings may not be fully achieved if limited applicability to:
- Clinical resistance to guidelines
- Risk that guidance might be applied to situations it was not intended
- Mitigation through guidance development process and stakeholder engagement
- Legal status of guidelines
- Does the existence of a guideline give rise to:
§ A right to a specific treatment
□ The NHS England and Wales is obliged to fund treatments which have a positive recommendation by NICE technology appraisal process
§ A right to a standard of treatment
□ Adherence to NICE clinical guidance is not required by law (unlike NICE TA) BUT is frequently used as evidence of the required standard of care by civil and criminal courts in England and Wales
- Does the existence of a guideline give rise to:
What is the clinical guideline development process
- What is the guideline trying to achieve and why?
- What effects do I want to achieve
- How will I measure them
- Is a guideline necessary
- What guidance already exists
- To what extent is it applicable to my situation
- Who should the guidance apply to?
- Which clinicians; patients and healthcare setting
- Who should evaluate the evidence (clinical; economical)?
- Who should review the guidance (stakeholders)?
- Stakeholder groups (clinicians; patients; budget holders)
- Evaluation plan (external expert review)
- Who should implement the guidance
- Who should be responsible for the maintenance and updates to the guidance
